Specialist Forum October 2020

SPECIALIST Bringing you medical news that matters

www.medicalacademic.co.za

FORUM

Vol. 20 • No. 9 • October 2020

When breast is not best Your private practice this side of the peak

ß CARVEDILOL 6,25 mg 12,5 mg

25 mg

RESTORE

cardiac function

CARVETREND 6,25, 12,5, 25 mg. Each tablet contains 6,25, 12,5, 25 mg carvedilol respectively. S3 A37/7.1.3/0276, 0277, 0278. NAM NS2 08/7.1.3/0105, 0104, 0103. BOT S2 BOT1101790, 1791, 1792. For full prescribing information, refer to the professional information approved by SAHPRA, December 2014. CDF529/10/2019.

CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za

When your patient needs azithromycin, "Happy Kids...Happy Parents" "Happy Kids...Happy Parents" think ZITHROMAX! The Original Azithromycin

4

The Original Azithromycin

4

INDICATIONS Children : 1 year and over (under 45 kg)1 ZITHROMAX is indicated for pharyngitis/tonsillitis and otitis media caused by susceptible organisms.

Adults and children over 45 kg1: ZITHROMAX is indicated for mild to moderate infections caused by susceptible "Happy Kids...Happy Parents" "Happy Kids...Happy Parents" zithromycin organisms; in respiratory tract infections including bronchitis due to Haemophilus The lower Original Azithromycin influenzae, Moraxella catarrhalis, Streptococcus pneumoniae or Staphylococcus aureus and pneumonia due to Streptococcus pneumoniae or Haemophilus influenzae; uncomplicated skin and soft tissue infections; sinusitis due to Haemophilus influenzae, Zithromax since 1 993 Streptococcus pneumoniae or Staphylococcus and as an alternative to first line Zithromax sinceaureus; 1 993 26 Years 26 Years therapy of pharyngitis/tonsillitis.

S4 ZITHROMAX 200 mg /5 ml powder for oral suspension Reg No.: 27/20.1.1/0279. ZITHROMAX (azithromycin) is an azalide antibiotic. ZITHROMAX 4 200 mg/5 ml powder for oral suspension is a dry blend of azithromycin dihydrate and other excipients which yields on reconstitution with water a suspension containing the equivalent of 200 mg azithromycin per 5 ml. ZITHROMAX 200 mg/5 ml powder for oral suspension contains sucrose, sodium phosphate, hydroxypropyl ing agents. ZITHROMAX powder for oral suspension is free of other sugars, gluten and azo dyes.PHARMACOLOGICAL CLASSIFICATION A.20.1.1 - Broad and medium spectrum antibiotics. INDICATIONS Children : 1 year and over (under 45 kg): ZITHROMAX is indicated for pharyngitis/tonsillitis and otitis media caused by susceptible organisms. Adults and children over 45 kg: ZITHROMAX is indicated for mild to moderate infections caused by susceptible organisms; in lower respiratory tract infections including bronchitis due to Haemophi-

4

Reconstituting instructions for ZITHROMAX 200 /5 mg/5 powderfor for oral oral suspension Reg No.: S4 ZITHROMAX 200 mg ml mlpowder suspension for 1527/20.1.1/0279. ml and 30 ml bottles: The table below indicates volume of ZITHROMAX (azithromycin) is anthe azalide antibiotic.

ZITHROMAX water to be used for200 constitution: mg/5 ml powder for oral suspension is a dry blend of azithromycin dihydrate Amount of water to and be otherTotal deliverable volume Azithromycin concentration excipients which yields on reconstitution with water a suspension con-

taining the equivalent content) of 200 mg azithromycin per 5 ml. ZITHROMAX 200 mg/5 (azithromycin after reconstitution ml powder for oral suspension contains sucrose, sodium phosphate, hydroxypropyl 15ml (600 mg) 200 mg/5ml 9ml ing agents.

15ml 30 ZITHROMAX ml (1200 mg) powder for oral 200suspension mg/5ml is free of other sugars, gluten and azo dyes.PHARMACOLOGICAL CLASSIFICATION A.20.1.1 - Broad Shake well before each use. Oversized bottle provides shake space. Keep tightly and medium spectrum antibiotics. INDICATIONS Children : 1 year and closed. After mix-ing store below 30 oC (no refrigeration required) and discard any over (under 45 kg): ZITHROMAX is indicated for pharyngitis/tonsillitis and otitis unused suspension after 5 days. Use in children: 1 year and older: The total media caused by susceptible organisms. Adults and children over 45 kg: dose in children is 30 mg/kg which should be given as a single daily dose of 10 mg/kg ZITHROMAX is indicated for mild to moderate infections caused by susceptible orfor 3 days according to the following guidance: ganisms; in lower respiratory tract infections including bronchitis due to Haemophi< 15 kg: 10 mg/kg once daily on days 1-3.

- 15-25 kg: 200 mg (5 ml) once daily on days 1-3. ml) once daily on days 1-3. enzae; uncomplicated skin and soft tissue infections; sinusitis due to Haemophilus 26-35 kg: 300 mg (7,5 enzae; uncomplicated skin and soft tissue infections; sinusitis due to Haemophilus - 36-45 kg: 400 mg (10 ml) once daily on days 1-3.

CONTRA-INDICATIONS >45 kg: Dose as per adults with ZITHROMAX Capsules 250 mg.

CONTRA-INDICATIONS The majorityisofcontra-indicated side-effects areingastrointestinal origin hypersensitivity with anZITHROMAX is contra-indicated in patients with a known hypersensitivity to azith- SIDE-EFFECTSZITHROMAX patients with ainknown to azith(pain/cramps), flatulence, vomiting and diarrhoea romycin, erythromycin or any of the macrolide antibiotics. Because of the theoreti- orexia, nausea, abdominal romycin,discomfort erythromycin or any of the macrolide antibiotics.

Because of the theoretiin dehydration, dyspepsia, constipation and loose stools. There cal possibility of ergotism, ZITHROMAX and ergot derivatives should not be co-ad- less frequently resulting cal possibility of ergotism, ZITHROMAX ergot derivatives should not be co-adZITHROMAX® 200 mg/5 ml suspension (Reg. no.: 27/20.1.1/279). Each 5 ml suspension contains azithromycin dihydrate equivalent to 200 mg azithromycin.

Licensed from: Pliva, Zagreb,and Croatia.

The Original Azithromycin of hearing Use impairment, including hearing loss,Asdeafness ministered. Use in hepatic impairment: As the liver is the principal route of have been reports ministered.

1. in hepatic impairment: the liver isand theorprincipal route of 1. in patients with hepatic disease. tinnitus in some patients receiving ZITHROMAX. Interstitial nephritis acute with renalhepatic disease. excretion of ZITHROMAX, it should not be used excretion of ZITHROMAX, it should not be used inand patients Casespregnancy of abnormal liver including - failure have been reported.

Use during pregnancy and lactation: The Use during andfunction lactation: The hepatitis and have been reported.

Reductions in neutrophil counts have occaROMAX in pregnancy and lactation have not been established. WARNINGS cholestatic jaundiceROMAX in pregnancy and lactation have not been established. WARNINGS PP-ZIT-ZAF-0118 AND SPECIAL PRECAUTIONS Rare serious allergic reactions, including sionally been observed. have been rare reports of taste disturbances.

Asthenia ANDThere SPECIAL PRECAUTIONS Rare serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been reported. Some of these re- and parathesia haveangioedema been reported a causal have been andalthough anaphylaxis (rarelyrelationship fatal), havemay beennotreported.

Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer established. The following side-effects havehave occurred: Chest pain, melena, nephritis, actions with azithromycin resulted in recurrent symptoms and required a longer period of observation and treatment. Pseudomembranous colitis has been reported vaginitis, headache,period dizziness, convulsions, vertigo, somnolence and fatigue.

Palpiof observation and treatment.

Pseudomembranous colitis has been reported S4 ZITHROMAX 200 mg /5 ml powder for oral suspension Reg No.: Reconstituting for ZITHROMAX 200 mg/5 ml powder for oral and mayS4instructions range in severity from lifeml threatening.

Therefore it is important arrythmias ventricular tachycardia have although ZITHROMAX 200mild mgto /5 powder for oral suspension Reg tations No.: and Reconstituting instructions ZITHROMAX mlreported powderTherefore for oral it is important and including may range in for severity from mild200 to mg/5 lifebeen threatening. for 15this ml and 30 ml in bottles: Thewith table below indicates the volume of 27/20.1.1/0279. ZITHROMAX (azithromycin) is an azalide antibiotic. ZITHROMAX suspension to consider diagnosis patients diarrhoea administration a causalsuspension relationship with not been established.

Allergic reactions for 15 ZITHROMAX ml and 30 mlhas bottles: The table below indicates the volume of 27/20.1.1/0279.

ZITHROMAX (azithromycin) issubsequent an azalidetoantibiotic.

ZITHROMAX to consider this diagnosis in patients with diarrhoea subsequent to administration used for constitution: 200 mg/5 ml powder for oral suspension is a dry blend of azithromycin dihydrate water toofbeZITHROMAX. fororal signs of superinfection includingwater arthralgia, oedema, urticaria,Observation rash, photosensitivity, andwith anaphyto be of used for constitution: 200 mg/5 Observation ml powder for suspension is a dry with blendnon-susceptible of azithromycinordihydrate ZITHROMAX. for signs ofangioedema superinfection non-susceptible orof water including to be and other excipients which yields on reconstitution with water a suspension con- Amountganisms, Totalisdeliverable volume Azithromycin fungi, recommended.

Use in renal impairment: There laxis frequently fatal) have occurred - issee “Warnings”. frequently, serious Amount of water to be and other excipients which yields on reconstitution withconcentration water a suspension con- (less Total deliverable volume Less Azithromycin ganisms, including fungi, recommended.

Use in renal concentration impairment: There taining the equivalent of 200 mg azithromycin per 5 ml. ZITHROMAX 200 mg/5 are no data regarding ZITHROMAX usage in patients with renal impairment, thus skin reactions including erythema multiforme, Stevens Johnson syndrome and toxic taining the equivalent of 200 mg azithromycin per 5 ml. ZITHROMAX 200 mg/5 (azithromycin content) after reconstitution are no data regarding ZITHROMAX usage in after patients with renal impairment, thus (azithromycin content) reconstitution ml powder for oral suspension contains sucrose, sodium phosphate, hydroxypropyl caution ml should be exercised when prescribing in these patients.hydroxypropyl Use epidermal necrolysiscaution have occurred. derivatives: powder for oral suspension containsZITHROMAX sucrose, sodium phosphate, should beInteractions: exercised when Ergot prescribing ZITHROMAXBecause in these patients. Use (600of mg)age: 200 mg/5ml in children 1 year 9ml under15ml of the of ergotism, and ergot derivatives should not - theoretical possibility 15mlZITHROMAX (600 mg)of age: 200 mg/5ml in children under 1 year 9ml ing agents. ZITHROMAX powder for oral suspension is free of other sugars, gluten childrening less than 1ZITHROMAX year have not been established.

Special precautionary be co-administered.

Special administration advised with the following: 15ml agents. powder for oral suspension is free of other sugars, gluten 30 ml (1200 mg) 200 mg/5ml children less than301ml year have not been established.

Special precautionary 15ml (1200 mg) 200 mg/5ml and azo dyes.PHARMACOLOGICAL CLASSIFICATION A.20.1.1 - Broad monitoring is advised with the following: Cyclosporin: Some of Antacids: In patients receiving ZITHROMAX and antacids, ZITHROMAX should andeach azo dyes.PHARMACOLOGICAL CLASSIFICATION - Broad monitoring is advised with the following: Cyclosporin: Some of before use. Oversized bottle provides shake space. Keep tightly A.20.1.1 and medium spectrum antibiotics. INDICATIONS Children : 1 year and Shake well the related antibioticsantibiotics. interfere with the metabolism of cyclosporin.

In and be takenShake at least hour before or 2Oversized hours afterbottle theinterfere antacid. with Cimetidine: A single well1the before eachmacrolide use. provides shake Keep tightly and macrolide medium spectrum INDICATIONS year related antibiotics thespace. metabolism of cyclosporin. In After mix-ing below 30 oC studies (no refrigeration required) andChildren discard any: 1interover (under 45 kg): ZITHROMAX is indicated for pharyngitis/tonsillitis and otitis closed.the absence ofstore pharmacokinetic or clinical data investigating potential dose of closed. cimetidine administered 2below hours30before had data no effect on theany Afterthe mix-ing store oC (noZITHROMAX refrigeration required) and discard over (under 45 kg): ZITHROMAX is indicated for pharyngitis/tonsillitis and otitis absence of pharmacokinetic studies or clinical investigating potential interThe total suspension afterZITHROMAX 5 days. Useand in cyclosporin, children: caution 1 year should and older: media caused by susceptible organisms. Adults and children over 45 kg: unusedaction between bechildren exercised before45 pharmacokinetics ofaction azithromycin.

No interactions reported with the folThe total unused suspension after 5 days.

Use in children: 1 year and older: media caused by susceptible organisms.

Adults and over kg: between ZITHROMAX and cyclosporin, caution should be exercised before children is 30 mg/kg whichtwo should be Ifgiven as a single daily dose of 10 cyclosporin mg/kg ZITHROMAX is indicated for mild to moderate infections caused by susceptible or- dose inco-administration of these drugs. co-administration is necessary, Carbamazepine: In awhich pharmacokinetic interaction studydaily in healthy in children is 30 mg/kg should given as a single dose ofvol10 mg/kg ZITHROMAX is indicated for mild to moderate infections caused by susceptiblelowing: or- dose co-administration of these two be drugs.

If co-administration is necessary, cyclosporin according to the following guidance: ganisms; in lower respiratory tract infections including bronchitis due to Haemophi- for 3 days levels should be monitored and the dose Digoxin:due Some of unteers,for no3 significant observed onand thetheplasma levels ofaccordingly. carbamazepine days according towas the guidance: ganisms; in lower respiratory tractadjusted infectionsaccordingly. including bronchitis to Haemophilevelseffect should befollowing monitored dose adjusted Digoxin: Some of < 15 kg:the10macrolide mg/kg once daily onhave daysbeen 1-3. reported antibiotics to impair the metabolism of digoxin (in or its active metabolite.

Methylprednisolone: a pharmacokinetic interaction < 15 kg: 10the mg/kg once daily on days 1-3.beenInreported macrolide antibiotics have to impair the metabolism of digoxin (in (5 ml)patients. once daily on daysin1-3.

- 15-25 kg: the200 gut)mg in some Therefore, patients receiving concomitant ZITHROMAX, study in15-25 healthy ZITHROMAX no significant effectreceiving on the pharmacokg:volunteers, 200 mg (5inml) once daily had onTherefore, days 1-3.in patients the gut) some patients. concomitant ZITHROMAX, 300 mgazalide (7,5 ml) once daily days 1-3. enzae; uncomplicated skin and soft tissue infections; sinusitis due to Haemophilus 26-35 kg: a related antibiotic, andon digoxin the of raisedsinusitis digoxin levels kinetics 26-35 of methylprednisolone.

There evidenceofofraised any pharkg: 300 mg (7,5 ml)Theophylline: once daily onand days 1-3. isthenopossibility enzae; uncomplicated skin and1-3. softpossibility tissue infections; due toshould Haemophilus a related azalide antibiotic, digoxin digoxin levels should mg ml) once daily on - 36-45 kg: be 400 borne in(10 mind.

Warfarin: Indays a pharmacokinetic interaction study, ZITHROMAX macokinetic when ZITHROMAX anddays theophylline are co-administered to ZITHROMAX kg: 400 (10inml) onceWarfarin: daily on - 36-45interaction be mg borne mind.

In a1-3. pharmacokinetic interaction study, as per with ZITHROMAX 250dose mg. of warfarin administered healthy volunteers. Zidovudine: In a preliminary pharmacokinetic study of ZITHCONTRA-INDICATIONS >45 kg:didDose not alter theadults anticoagulant effect of aCapsules single 15mg adults with ZITHROMAX mg.dose of warfarin administered CONTRA-INDICATIONS >45 kg: Dose did as notper alter the anticoagulant effectCapsules of a single250 15mg The majority of side-effects are gastrointestinal in origin withbutanZITHROMAX is contra-indicated in patients with a known hypersensitivity to azith- SIDE-EFFECTS to healthy volunteers. and warfarin maywith be co-administered, mon-to azithROMAXSIDE-EFFECTS in HIV-positive patients treated ZITHROMAX with zidovudine, significant effect on thewith an-but monThe majority of side-effects areno gastrointestinal in origin ZITHROMAX isZITHROMAX contra-indicated in patients a known hypersensitivity to healthy volunteers. and warfarin may be co-administered, nausea, abdominal discomfort (pain/cramps), flatulence, vomiting and diarrhoea romycin, erythromycin or any of the macrolide antibiotics. Because of the theoreti- orexia, itoring ofromycin, the prothrombin time should as routinely performed. pharmacokinetic parameters of prothrombin zidovudine its glucuronide metabolite was found. orexia, nausea, abdominal discomfortand (pain/cramps), flatulence, and diarrhoeaTerfenerythromycin or anybe of continued the macrolide antibiotics.

BecauseTerfenof the theoretiitoring of the time should be continued asvomiting routinely performed. resulting in dehydration, dyspepsia, constipation and loose stools. There cal possibility of ergotism, ZITHROMAX and ergot derivatives should not be co-ad- less frequently adine:cal There have been less frequent reports ofand an interaction in patients receiving The onlyless significant difference in azithromycin kinetics was a shortening of thestools. time frequently resulting in dehydration, dyspepsia, constipation loose Therereceiving possibility of ergotism, ZITHROMAX ergot derivatives should not be co-adThe Original Azithromycin adine: There have been less frequent reports of anand interaction in patients Original reports ofandhearing impairment, including hearing loss, deafnesscould and not or be to reach maximal concentration when the first The ministered. Use in hepatic impairment: As the liver is the principal route of have been ZITHROMAX where the possibility of suchAs anthe interaction andincluding last levelsAzithromycin reports of hearing impairment, hearing loss, deafness andcould or not be ministered.terfenadine Use in hepatic impairment: liver is the principal route of have been ZITHROMAX and terfenadine where theday possibility ofwere suchcompared. an interaction 1. in someexcluded. patients receiving ZITHROMAX. Interstitial nephritis and acute renal excretion of ZITHROMAX, it should not be used in patients with hepatic disease. tinnitusentirely AND DIRECTIONS USE. ZITHROMAX LICENCE HOLDER: Pfizer Laboratories (Pty)AND Ltd. 85DIRECTIONS Bute Lanenephritis Sandton 21 USE. 6. tinnitus in some patients receiving ZITHROMAX. Interstitial and acute ZITHROMAX renal excretion ofDOSAGE ZITHROMAX, it should not be usedFOR in patients with hepatic disease. entirely excluded.

DOSAGE FOR beenmlreported. of abnormal liverbefunction including hepatitis and - failure have Use during pregnancy and lactation: The 200 mg/5 forCases oral suspension should administered 1954/000781/07.

Tel. No.: Cases 0860 PFIZER (734937).

Licensed from: Pliva, failure have200 been reported. of suspension abnormal liver function including hepatitis Usepowder during pregnancy and lactation: The as a single daily dose Reg.- No.: mg/5 ml powder for oral should be administered as a singleand daily dose jaundice have been reported.

Reductions in neutrophil counts have occaROMAX in pregnancy and lactation have not been established. WARNINGS cholestatic ZITHROMAX suspension should be administered to children using the 5 ml oral Zagreb, Croatia.

PI Ref No.: 20/09/1993 1. jaundice havesuspension been reported.

Reductions in neutrophil counts using have occaROMAX in pregnancy and lactation have not been established. WARNINGS cholestatic ZITHROMAX should be administered to children the 5 ml oral AND SPECIAL PRECAUTIONS Rare serious allergic reactions, including sionallydosing been observed. been rare reports of taste disturbances.

Asthenia syringeSPECIAL orThere the have spoon provided.

ZITHROMAX suspension be tak-including Please refer to the detailed package full prescribing Zit suspension AND PRECAUTIONS Rare serious allergic can reactions, sionally been observed.

There have been rare reportsinformation. of taste disturbances.

Asthenia dosing syringe orinsert the for spoon provided.

ZITHROMAX can be takangioedema and anaphylaxis (rarely fatal), have been reported. Some of these re- and parathesia have although a causal relationship may not have been en withangioedema food.been reported and anaphylaxis (rarely fatal), have been reported. Some of these re- and parathesia have food. been reported although a causal relationship may not have been en with actions with azithromycin have resulted in recurrent symptoms and required a longer established. The following side-effects have occurred: Chest pain, melena, nephritis, actions with azithromycin have resulted in recurrent symptoms and required a longer established. The following side-effects have occurred: Chest pain, melena, nephritis, period of observation and treatment. Pseudomembranous colitis has been reported vaginitis, headache, dizziness, convulsions, vertigo, somnolence and fatigue. Palpiperiod of observation and treatment. Pseudomembranous colitis has been reported vaginitis, headache, dizziness, convulsions, vertigo, somnolence and fatigue. Palpiand may range in severity from mild to life threatening. Therefore it is important tations and arrythmias including ventricular tachycardia have been reported although and may range in severity from mild to life threatening. Therefore it is important tations and arrythmias including ventricular tachycardia have been reported although to consider this diagnosis in patients with diarrhoea subsequent to administration a causal relationship with ZITHROMAX has not been established. Allergic reactions to consider this diagnosis in patients with diarrhoea subsequent to administration a causal relationship with ZITHROMAX has not been established. Allergic reactions

since 1 993 ars

y Parents"

The Original Azithromycin

y Parents"

9ml 15ml

(azithromycin content)

after reconstitution

15ml (600 mg)

200 mg/5ml

30 ml (1200 mg)

200 mg/5ml

Shake well before each use. Oversized bottle provides shake space. Keep tightly closed. After mix-ing store below 30 oC (no refrigeration required) and discard any unused suspension after 5 days. Use in children: 1 year and older: The total dose in children is 30 mg/kg which should be given as a single daily dose of 10 mg/kg for 3 days according to the following guidance: < 15 kg: 10 mg/kg once daily on days 1-3.

15-25 kg: 200 mg (5 ml) once daily on days 1-3.

26-35 kg: 300 mg (7,5 ml) once daily on days 1-3.

36-45 kg: 400 mg (10 ml) once daily on days 1-3. >45 kg: Dose as per adults with ZITHROMAX Capsules 250 mg.

SIDE-EFFECTS The majority of side-effects are gastrointestinal in origin with anorexia, nausea, abdominal discomfort (pain/cramps), flatulence, vomiting and diarrhoea less frequently resulting in dehydration, dyspepsia, constipation and loose stools. There The Original Azithromycin have been reports of hearing impairment, including hearing loss, deafness and or tinnitus in some patients receiving ZITHROMAX. Interstitial nephritis and acute renal failure have been reported. Cases of abnormal liver function including hepatitis and cholestatic jaundice have been reported. Reductions in neutrophil counts have occasionally been observed. There have been rare reports of taste disturbances. Asthenia and parathesia have been reported although a causal relationship may not have been established. The following side-effects have occurred: Chest pain, melena, nephritis, vaginitis, headache, dizziness, convulsions, vertigo, somnolence and fatigue. Palpitations and arrythmias including ventricular tachycardia have been reported although a causal relationship with ZITHROMAX has not been established. Allergic reactions including arthralgia, oedema, urticaria, rash, photosensitivity, angioedema and anaphylaxis (less frequently fatal) have occurred - see “Warnings”. Less frequently, serious skin reactions including erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrolysis have occurred. Interactions: Ergot derivatives: Because of the theoretical possibility of ergotism, ZITHROMAX and ergot derivatives should not be co-administered. Special administration advised with the following: Antacids: In patients receiving ZITHROMAX and antacids, ZITHROMAX should be taken at least 1 hour before or 2 hours after the antacid. Cimetidine: A single dose of cimetidine administered 2 hours before ZITHROMAX had no effect on the pharmacokinetics of azithromycin. No interactions reported with the following: Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite. Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, ZITHROMAX had no significant effect on the pharmacokinetics of methylprednisolone. Theophylline: There is no evidence of any pharmacokinetic interaction when ZITHROMAX and theophylline are co-administered to healthy volunteers. Zidovudine: In a preliminary pharmacokinetic study of ZITHROMAX in HIV-positive patients treated with zidovudine, no significant effect on the pharmacokinetic parameters of zidovudine and its glucuronide metabolite was found.

The only significant difference in azithromycin kinetics was a shortening of the time to reach maximal concentration when the first and last day levels were compared.

LICENCE HOLDER: Pfizer Laboratories (Pty) Ltd. 85 Bute Lane Sandton 21 6.

Reg. No.: 1954/000781/07. Tel. No.: 0860 PFIZER (734937). Licensed from: Pliva, Zagreb, Croatia. PI Ref No.: 20/09/1993 1.

Please refer to the detailed package insert for full prescribing information. Zit

"Happy Kids...Happy Breakthroughs that

change patients’ lives

"Happy Kids...Happy Parents" "Happy Kids...Happy Parents" The Original Azithromycin

Zithromax since 1 993 26 Years

y Parents"

Reconstituting instructions for ZITHROMAX 200 mg/5 ml powder for oral suspension for 15 ml and 30 ml bottles: The table below indicates the volume of water to be used for constitution: Amount of water to be Total deliverable volume Azithromycin concentration

Zithromax since 1 993

"Happy Kids...Happy 26 Years

Zithromax since 1 993

"Happy Kids...Happy 26 Years

"Hap

SF | CONTENTS

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

INSIDE this issue

4 EDITORIAL

30

5 NEWS

32

Your private practice this side of the peak

Celebrating the next generation of healthcare professionals

Are antibiotics necessary in acute otitis media?

PSYCHIATRY

CPD: Anosognosia a major challenge in schizophrenia

36 39

Summertime sadness The ‘big build’ model in male depression

8 ONCOLOGY NUTRITION 11

When breast is not best

14 17

ppy Kids...Happy

New data on Covid-19 recovery and targeted nutritional therapy An oncologist’s view on nutrition in the cancer patient

BONE HEALTH

CPD: Osteoporosis an overlooked disease in diabetes

21 CARDIOLOGY 24 ENT

Converting non-dippers to dippers

Pollen counts

16%

of cancer deaths amongst women worldwide are caused by breast cancer

Disclaimer: Please take note that the products featured in this journal are available in South Africa. Products may be marketed under a different name or might not be registered in your country. For more information, contact your local representative.

All content in The Specialist Forum is sourced independently and under no circumstances should articles be considered promotional unless specified with a postscript.

3

4

SF | GUESS EDITORIAL

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

This article was independently sourced by Specialist Forum.

Your private practice this side of the peak Vanessa Rogers on behalf of Natmed Medical Defence

M

Concerned about the state of your private practice because of declining patient numbers? Here are some tips to help you thrive once again – from ethical advertising, to forums working to enhance industry relations, and the role of professional indemnity throughout.

edical practitioners in private practice have experienced a significant decline in patient numbers due to the Covid-19 pandemic, with many patients opting to forego their usual treatments to minimise their risks of contracting the virus. This is likely to encourage you to shift your focus onto marketing.

According to their advertising guidelines (found in the Ethical Rules https://www.givengain.com/ unique/sasom/upload/advertising.pdf), the Health Professions Council of South Africa (HPCSA) allows medical professionals to advertise their services, but this must be done within the limits of ethical advertising.

Advertisements must not be unprofessional, untruthful, deceptive, or misleading, or cause consumers unwarranted anxiety that they may be suffering from any health condition. A medical practitioner cannot canvas or tout, or allow canvassing to be done for patients on his or her behalf. Be careful not to provide any guarantees, and not to discuss benefits unrelated to your area of professional practice.

Several features of your practice can be revised or reconfigured according to the post-Covid-19 peak. These may involve re-training your reception staff on professional patient service, revising your fees, putting in place a digital appointmentbooking facility to ease the way for patients, printing brochures with factual information on common conditions related to your practice area for display in your waiting room, and looking into a free or reduced parking rate for those

much earlier, resulted in specialists cancelling all elective procedures and appointment lists. These factors combined to produce an unprecedented decline in demand, placing thousands of practices at risk of insolvency.”

In response to this situation, the PHF set about developing a framework to save ailing practices and, at the same time, to protect medical schemes from a swell of high-cost claims when specialist services resumed. The framework can be viewed in detail at https://storage.googleapis. com/stateless-bhekisisa-website/wordpressuploads/2020/07/af0217db-memorandumstrategic-response-to-covid-19.pdf.

In essence, it suggests restructuring individual contracts between medical schemes and private practices, so that a portion of private healthcare funding can be released ahead of time. This should guarantee stalling practices at least 70% of their 2019 earnings, and any caps agreed to will allow medical schemes to keep their costs below historical budgets.

Another popular form of relief for ailing medical practices over the earlier part of 2020 could be sought, in the form of a rebate, from insurers of professional indemnity policies that specialists pay for each month – during a time when their highrisk surgical case loads had been dramatically reduced.

CEO of the South Africa Private Practitioners Forum, Dr Chris Archer, commented in June 2020: “The financial pressure on private practices is real and, unlike their public sector counterparts who are salaried, private medical practices face

visiting. Consider placing your doctor’s plaque in a different place or have it redone so that it becomes significantly more visible to passers-by.

The Progressive Health Forum (PHF), a national advocacy network of health experts and activists, said in July 2020: “The lockdown and patient fears significantly reduced healthseeking behaviour. In addition, the pre-emptive preparations for the surge in Covid-19, expected

significantly reduced income and require funds to honour staff and overhead commitments.”

It is worth ensuring that your insurance provider is able to provide a revised online quotation on your insurance premium that you feel is specifically geared towards yourself as a medical practitioner and your practice – the conditions of which may have changed dramatically over the Covid-19 peak. SF

EDITORIAL EDITOR: René Bosman René.bosman@newmedia.co.za SUB EDITOR: Gill Abrahams LAYOUT & DESIGN: Allison McCallum ADVERTISING ADVERTISING EXECUTIVES Charissa Piek | 082 306 1205 charissa.piek@newmedia.co.za DISTRIBUTION & SUBSCRIPTIONS Felicity Garbers felicity.garbers@newmedia.co.za PUBLISHING TEAM GENERAL MANAGER: Dev Naidoo PUBLISHING MANAGER: Johann Gerber Johann.Gerber@newmedia.co.za PRODUCTION MANAGER: Angela Silver ART DIRECTOR: David Kyslinger CONTACT Johannesburg Office: Ground floor, Media Park, 69 Kingsway Avenue, Auckland Park, 2092 Postal Address: PO Box 784698, Sandton, Johannesburg, 2146 T +27(0)11 877 6111 F +27(0)11 713 9024 www.medicalacademic.co.za PRINTING

COVER PRICE Specialist Forum per issue R80,00 VAT Incl.

ISSN: 2218-8282 Published by New Media, a division of Media24 (Pty) Ltd MANAGEMENT TEAM CEO: NEW MEDIA: Aileen Lamb COMMERCIAL DIRECTOR: Maria Tiganis BRAND STRATEGY DIRECTOR: Andrew Nunneley CHIEF FINANCIAL OFFICER: Venette Malone CEO: MEDIA24: Ishmet Davidson

HEAD OFFICE New Media House, 19 Bree Street, Cape Town 8001 PO Box 440, Green Point, Cape Town 8051 Tel: +27 (0)21 417 1111, Fax: +27 (0)21 417 1112 www.newmedia.co.za

Unless previously agreed in writing, The Specialist Forum owns all rights to all contributions, whether image or text.

SOURCES: Shutterstock, supplied images, editorial staff.

While precautions have been taken to ensure the accuracy of its contents and information given to readers, neither the editor, publisher, or its agents can accept responsibility for damages or injury which may arise therefrom. All rights reserved. © Specialist Forum. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, photocopying, electronic, mechanical or otherwise without the prior written permission of the copyright owners.

SF | NEWS

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

CELEBRATING the next generation of healthcare professionals

The 2020 Sponsors of Brave Campaign – a partnership between Adcock Ingram OTC and News24 – aims to celebrate the unsung heroes and brave professionals in healthcare. Season 2 recognises that pursuing a career in healthcare during the height of a pandemic is the definition of a Generation of Brave and aims to shine a spotlight on the succession of healthcare heroes.

S

eason 1 was a runaway success, showcasing the depth and breadth of heroism all around us. Some 3800 heroes from the front lines of healthcare in South Africa were nominated and 12 finalists emerged to have their stories shared and amplified. By the end of the competition, over 3.2 million readers engaged with the campaign, and two worthy winners were chosen, earning R25 000 for each of their preferred charities and a trip to an overseas medical conference of their choosing.

Nominations cast a wide net, culminating with two winning entries: » Pharmacist and community cornerstone, Nontutuzelo Sibango from the Eastern Cape who captured the public’s heart through her work supporting young athletes in her community » Clinic founder, Dr Hugo Templeman, of Ndlovu Care Group in Limpopo.

“We were blown away by the scale of nominations and the calibre of the healthcare professionals who ultimately won in the first season. It is exciting to anticipate what new champions season 2 will introduce as we

recognise aspiring healthcare professionals who personified practicing the Hippocratic oath during Covid-19,” says Yudhveer Singh of Adcock Ingram OTC.

demonstrate to this next generation – who have already faced so much – that we believe in them, and we will invest in them and their futures.”

Time to step up

Are you part of the next Generation of Brave?

Now, as our energy to face what is left of 2020 wanes, we need fresh faces that bring new stories and successes to celebrate and reinvigorate the nation. Therefore, the focus for season 2 is on students, graduates and those in community service gearing up to enter the healthcare profession during this unprecedented time in history.

Despite everything 2020 has thrown at them – business and school closures, shrinking term dates, rising unemployment, and exceptional uncertainty – our budding healthcare professionals have proven to be resilient.

“This year has been incredibly trying, but our Sponsors of Brave Campaign is all about hope and heroism,” says Andrea Firth, commercial editor of BrandStudio24.

“Bravery is not about the absence of fear, but of continuing on despite it. We want to give credit where it is due, and we want to

Are you an aspiring, current or recently graduated healthcare student or currently completing your community service year?

Adcock Ingram OTC and News24 are encouraging you to nominate yourself or a deserving candidate and you could win one of 10 x R5000 weekly prizes.

In addition, featured nominees could also stand a chance to win an impactful mentorship and two lucky students will walk away with R25 000 towards their studies.

Mentors will also be in line to win a trip to an overseas medical conference of their choice to the value of R50 000 and the opportunity to pay-it-forward by donating R25 000 to any registered NPO charity they wish to support.

Visit https://partners.24.com/ SponsorsofBrave/ website for more entry criteria, and to nominate yourself as a candidate or a mentor. SF

5

Glenma

rk, to

u ch i

ng t

he l

ives

of p

atie

nts

fo r

ov er

th

GLOBAL PRESENCE

re

ed

ec

ad

es

An organisation which truly transcends geographical boundaries

QUALITY AT GLENMARK Committed to consistently meet the highest regulatory standards

MANUFACTURING FACILITIES State-of-the-art facilities delivering high-quality products - globally

ZAGlen/09/2020/03

NEW S3

•

for Allergic Rhinitis 1

•

Immediate and sustained relief 2

•

Works within 10 - 15 minutes 2

Multi-Tasking RAPID Relief References: 1. Ryaltris® Professional Information. May 2020. 2. Patel P, Salaptek AM, Tantry SK. Effect of olopatadine-mometasone combination nasal spray on seasonal rhinitis symptoms in an environmental exposure chamber study. American College of Allergy, Asthma & Immunology. 2019;122:630-638.

S3 RYALTRIS® (Nasal spray). Reg. no. 53/21.5.1/0457. Each spray delivers 600 µg olopatadine (as olopatadine hydrochloride) and 25 µg mometasone furoate (as mometasone furoate monohydrate). Contains the preservative benzalkonium chloride 0.02 % w/w. Sugar free. For full prescribing information refer to the professional information approved by the South African Health Products Regulatory Authority. Date of publication: 5 May 2020.

HCR: Glenmark Pharmaceuticals South Africa (Pty) Ltd. First Floor, Block A, 34 Monte Carlo Crescent, Kyalami Park, Midrand, 1684. P.O. Box 5537, Halfway House, 1685. Tel: +27 (0) 11 564 3900. F: +27 (0) 11 564 3939. www.glenmarkpharma.co.za.

ZAR/09/2020/03

Glenmark, touching the lives of patients for over three decades.

SF | ONCOLOGY

8

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Photo credit: Shutterstock.com

This article was independently sourced by Specialist Forum.

When breast is not best Breast cancer (BCa) is the most common cancer in women, and the second most common cancer overall. Worldwide, one in eight women are affected. In South Africa, this figure is higher, with an estimated 31.4 in 100 000 women affected (2011 figure).

B

Ca accounts for around 16% of cancer deaths amongst women worldwide.

In 2013, deaths from BCa and cancers of the female genital tract, accounted for 0.7% and 1% respectively, of all deaths in South Africa.

Currently in South Africa, access to highquality cancer care is variable. The private sector offers high quality care, but at a cost.

In the public sector, where more than 80% of South Africans seek healthcare, highquality breast-cancer services are available, but limited.

The 2020 American National Comprehensive Cancer Network (NCCN) guideline on therapy for patients with recurrent/stage IV BCa was published recently. This article focuses on systemic therapy recommendations.

Only therapies available in South Africa will be highlighted.

obtained, as well as if other disease sites are not immediately life-threatening. Radiation therapy may be considered as an alternative to surgery.

The South African guideline recommends palliative therapy including hormonal, chemotherapy (ChT) and radiotherapy for women with metastatic disease, and neoadjuvant therapy as well as surgery for women with non-metastatic disease.

Systemic therapy for stage IV/recurrent disease Hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) Table 1: The top 10 countries with the highest rates of breast cancer in 2018 Rank Country

Age-standardised rate per 100 000

1

Belgium

113.2

2

Luxembourg

109.3

Primary treatment approach

3

Netherlands

105.9

For women with metastatic BCa and an intact

4

France (metropolitan)

99.1

5

New Caledonia (France)

98.0

6

Lebanon

97.6

7

Australia

94.5

8

UK

93.6

9

Italy

92.8

10

New Zealand

92.6

primary tumour, the NCCN recommends systemic therapy as the primary treatment approach. Surgery should be considered after initial systemic treatment for women who require palliation of symptoms or those at risk of complications, such as skin ulceration, bleeding, fungation and pain.

Surgery should only be undertaken if complete local clearance of the tumour may be

overexpression, tumour burden, and patient preference are important factors in selecting an appropriate therapeutic strategy for patients with stage IV/recurrent disease.

The aim of systemic treatment is to prolong survival and enhance quality of life (QoL). It is not curative, stress the authors of the guideline.

To enhance QoL, the use of minimally toxic endocrine therapies (ET) is recommended versus cytotoxic therapy.

At diagnosis, patients are initially stratified according to whether bone metastases are present. These two patient subsets (those with and without bony metastases) are then stratified further by tumour HR and HER2 status.

Therapy for bone metastases Complications from bone metastases include pain, decreased performance status, and decreased QOL, as well as skeletal-related events (SREs). SREs are defined as the need for radiation or surgery to bone, pathologic fractures, spinal cord compression and hypercalcemia of malignancy.

The NCCN recommends treatment with a bone modifying agent (bisphosphonates) in addition to ChT or ET if bone metastasis is present. Expected survival is ≥3 months.

The use of bisphosphonates in metastatic disease is a palliative care measure. Numerous randomised trials support the use of bisphosphonates for patients with metastatic

SF | ONCOLOGY

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

disease to bone. In metastatic bone disease, bisphosphonate treatment is associated with fewer SREs, fewer pathologic fractures, and less need for radiation therapy and surgery to treat bone pain. However, no impact on overall survival (OS) has been reported.

Three studies have compared zoledronic acid dosed every four weeks versus every 12 weeks. Findings show that among women with BCa and bone metastases, zoledronic acid administered once every 12 weeks versus once every four weeks does not compromise efficacy and has similar rates of SREs. The use of bisphosphonates should be accompanied by calcium and vitamin D supplementation with daily doses of calcium of 1200mg to 1500mg and vitamin D3 of 400IU to 800IU. The risk of renal toxicity necessitates monitoring of serum creatinine before administration of each dose. Dose reduction or discontinuation is advised if renal function

bisphosphonates is initiated. Bisphosphonates are associated with a risk of development of osteonecrosis of the jaw.

is reduced. Current clinical trial results support the use of bisphosphonates for up to two years.

A dental examination is recommended before patients therapy with intravenous (IV)

of completing adjuvant ET, or patients who progress on first-line ET for metastatic disease, are eligible for second-line ET either as monotherapy or in combination with a targeted

Metastatic HR-positive, HER2-Negative The NCCN recommends that women with HR-positive, HER2-negative tumours and no visceral crisis should be treated with ET alone or in combination with targeted agents. Women whose disease progresses after a year from the end of adjuvant endocrine-based therapy, and those who present with de novo stage IV/ metastatic BCa are eligible for first-line ET. Many premenopausal and postmenopausal women with HR-positive BCa benefit from sequential use of ET as the disease progresses.

Women with BCa who respond to an endocrine-based therapy with either shrinkage of the tumour or long-term disease stabilisation (clinical benefit) should receive additional ET as the disease progresses.

Those who progress on or within 12 months

Table 2: South African BCa guideline staging Stage Description 1

Cancer is relatively small and contained within the organ it started in

2

Tumour is larger than in stage 1, but the cancer has not started to spread into the surrounding tissues. Sometimes stage 2 means that cancer cells have spread into lymph nodes close to the tumour.

This depends on the particular type of cancer

3

Cancer is larger. It may have started to spread into surrounding tissues and there are cancer cells in the lymph nodes in the area

4

Cancer has spread from where it started to another body organ.

This is also called secondary or metastatic cancer

agent. The optimal sequence for ET is not well defined. The choice would depend on previous therapy, tolerance of treatment, and patient preference.

Have you experience abnormal vaginal bleeding?

Yes or No Have you noticed any changes to your breast?

Yes or No

Have you ever had a pap smear?

Yes or No

Do you do selfbreast exam regularly?

Yes or No

Family history of cancer?

Photo credit: Shutterstock.com

Yes or No.

Figure 1: The high-5 method for patient risk assessment

If YES is answered to any of the above questions, follow-up is required.

Source: National Department of Health South Africa

9

10

SF | ONCOLOGY

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Although studies in HR-positive BCa patients have not included premenopausal women, the NCCN recommends that premenopausal women with HR-positive disease should have adequate ovarian suppression/ablation, and then be treated in the same way as postmenopausal women.

Endocrine-based therapies Endocrine-based therapies should be used in the first-line versus second- and subsequentline settings. Preferred first-Line therapy for HR-positive, HER2-negative patients include: » In post- or premenopausal women who receive ovarian ablation or ovarian function suppression with a luteinizing hormonereleasing hormone agonist, treatment with an aromatase inhibitor (AI) in combination with cyclin-dependent kinase (CDK) 4/6 inhibitor is recommended. The South African guideline recommends anastrazole, exemestane or letrozole. This combination has demonstrated improved progression-free survival (PFS) compared to an AI alone » The combination of ribociclib and letrozole has also been studied as first-line therapy in postmenopausal women with HR-positive, HER2-negative recurrent/stage IV BCa. Improvement in PFS (25.3 vs 16 months, hazard ratio [HR] for progression or death was 0.56). Improved overall response rate [ORR] of 43% vs 29%) was noted with ribociclib plus letrozole, compared with letrozole alone » Most trials studying CDK 4/6 inhibitor with an AI have mainly included postmenopausal women and only a small subset of premenopausal women on ovarian suppression. In the Study of Efficacy and Safety in Premenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer (MONALEESA)-7 trial, 672 pre- or perimenopausal women with HR-positive, HER2-negative advanced BCa, were randomly assigned to first-line treatment with ribociclib or placebo with goserelin, plus either a nonsteroidal AI or tamoxifen. An improvement in PFS was seen with the addition of ribociclib (median PFS 24 vs 13 months, HR 0.55). At 3.5 years, an improvement in OS was reported with ribociclib (70% vs 46%) » Fulvestrant, an oestrogen receptor antagonist, was originally approved as a monthly intramuscular injection (250mg per month). However, a higher dose has been proven to be more effective in subsequent randomised trials. Howell et al found that fulvestrant was as effective as anastrozole in terms of ORR (36.0% vs 35.5%). An improved time to progression was seen with fulvestrant alone, compared with anastrazole (median time to progression was

23.4 months for fulvestrant vs 13.1 months for anastrozole). This study used a higher loading dose of 500mg every two weeks for three doses and then maintenance dose of 500mg monthly. The median OS was observed to be longer in the fulvestrant group than in the anastrozole group (54.1 vs 48.4 months). Di Leo et al compared fulvestrant 500mg every two weeks for three doses followed by 500mg monthly versus fulvestrant 250mg monthly. The PFS was superior with the fulvestrant 500mg regimen, indicating an increased duration of response with the higher dose of fulvestrant. The final analyses demonstrated an increase in median OS (4.1 months) and reduced risk of death (19%) with a dose of 500mg compared with 250mg. Median OS was 26.4 versus 22.3 months » In the phase III trial MONALEESA-3, patients with advanced HR-positive breast cancer, who had no prior ET or had progressed

500mg Versus Exemestane in Postmenopausal Women With Metastatic Breast Cancer Resistant to Adjuvant Nonsteroidal Aromatase Inhibitors in Clinical Practice: A Multicenter Retrospective Study, the effect of fulvestrant alone or in combination with anastrozole or exemestane was studied in patients with advanced BCa with acquired resistance to a nonsteroidal AI. An AI had been given as adjuvant treatment to 18% of patients for a median of 27.9 months, and to 82% of patients for locally advanced/metastatic disease for a median of 19.3 months. Median PFS was 4.8 months, 4.4 months and 3.4 months for patients treated with fulvestrant alone, anastrazole plus fulvestrant, and fulvestrant plus exemestane, respectively. No differences were observed for ORR, clinical benefit rate, and OS » In postmenopausal women, there is evidence supporting the use of an AI as first-line therapy for recurrent disease. Prospective

on prior therapy, the combination of ribociclib with fulvestrant showed improved PFS versus fulvestrant alone (21 vs 13 months). The PFS benefits were consistent across patients with and without prior ET. In a subsequent analysis, a significant improvement in OS was observed. At 42 months, the estimated OS was 57.8% in the ribociclib group and 45.9% in the placebo group. Comparison across multiple trials, including those in the second-line settings, studying the combination of fulvestrant with palbociclib or abemaciclib have shown statistically significant improvement in PFS » The combination of two endocrine agents as first-line treatment in postmenopausal women with HR-positive metastatic BCa has been reported from studies comparing single-agent anastrozole versus anastrozole plus fulvestrant. In one study, the combination of fulvestrant with anastrozole was not superior to single-agent anastrozole (time to progression HR 0.99). The Fulvestrant

randomised trials comparing AIs head-tohead have shown that all AIs are the same » Tamoxifen is the commonly used selective oestrogen-receptor modulator for premenopausal women. In postmenopausal women, AI monotherapy has been shown to have superior outcome compared with tamoxifen, although the differences are modest. A phase III trial comparing tamoxifen with exemestane as first-line endocrine therapy for postmenopausal women with metastatic breast cancer showed no significant differences in PFS or OS between the two arms.

Take-home messages The NCCN category 1 preferred regimen include: » A CDK 4/6 inhibitor with an AI » Fulvestrant with or without a CDK 4/6 inhibitor » Fulvestrant with a nonsteroidal AI. The NCCN category 2A preferred regimen includes: » Nonsteroidal AIs (anastrozole, letrozole), steroidal AI (exemestane), and SERM » (tamoxifen or toremifene) » For premenopausal women, first-line ET includes ovarian suppression/ablation and endocrine therapy listed previously for postmenopausal women or alternately with a SERM alone.

References Di Leo A, Jerusalem G, Petruzelka L et al. Final Overall Survival: Fulvestrant 500mg vs 250mg in the Randomized CONFIRM Trial. J Natl Cancer Inst, 2014.

Dordley L. The reality of breast cancer in South Africa. https://www.capetownetc.com/news/the-reality-ofbreast-cancer-in-sa/#:~:text=Breast%20cancer%20 affects%20approximately%2027,cases%20is%20 on%20the%20rise.

Gradishar WJ, Anderson BO, Abraham J et al. Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. JNCCN, 2020.

Howell A, Robertson JFR, Albano JQ et al. Fulvestrant, Formerly ICI 182,780, Is as Effective as Anastrozole in Postmenopausal Women With Advanced Breast Cancer Progressing After Prior Endocrine Treatment. Journal of Clinical Oncology, 2002.

Lince-Derochei N, Benn C, van Rensburg C et al. Breast cancer in South Africa: developing an affordable and achievable plan to improve detection and survival.

SAHR, 2017.

National Department of Health. Clinical guidelines for breast cancer control and management, 2018.

World Cancer Research Fund. Breast cancer statistics. https://www.wcrf.org/dietandcancer/cancer-trends/ breast-cancer-statistics SF

SF | NUTRITION

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

New data on Covid-19 recovery and targeted nutritional therapy

This article was independently sourced by Specialist Forum.

This is an executive summary of key highlights from the dedicated session on Covid-19 Recovery and Targeted Nutritional Therapy hosted by Nutricia at the 2020 first virtual European Society for Clinical Nutrition and Metabolism (ESPEN) Congress (19-21 September).

LEEP-Covid Paul Wischmeyer, associate vice-chair for clinical research in the department of anaesthesiology at Duke University (United States) Between 60%-80% of patients treated in intensive care units (ICU) are functionally impaired. Patients treated in the ICU setting and those who undergo major surgery can lose up to 1kg of lean body mass per day, which negatively impact treatment outcomes.

It has been hypothesised that the severe acute respiratory syndrome coronavirus-2, causative agent of Covid-19, which leads to hyperinflammation and excessive immune response, causes hypercatabolism.

Hypercatabolism causes mitochondrial dysfunction, affecting muscle quality, which can lead to prolonged fatigue. In more severe infections, it increases the risk of morbidity and mortality. About 53% of Covid-19 patients experience fatigue up to 60 days after discharge, severely impacting their quality of life (QoL).

Effective nutritional support is therefore essential to improve patients’ survival odds. A study examining the outcome of a large cohort of ICU patients in relation to the per cent of administered calories divided by resting energy expenditure (% AdCal/REE) obtained by indirect calorimetry (IC) and to protein intake, found that both underfeeding and overfeeding appear to be harmful to critically ill patients. Patients achieving an Adcal/REE of 70% had a survival advantage.

The Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN) Covid-19 guideline recommends early enteral nutrition (EN) nutrition within 24-36 hours of ICU admission or within 12 hours of intubation or placement on mechanical ventilation. The use of a nasogastric tube (NG) is recommended. The SCCM/ASPEN guideline recommends starting with low dose EN (hypocaloric or trophic), advancing to full dose EN slowly over the first week of critical illness to meet

energy goal of 15kcal/kg -20kcal/kg actual body weight, which should meet 70%-80% of caloric requirement and protein goal of 1.2g/kg-2g/kg.

During the chronic ICU phase, and post-ICU

complication in ICU and post-ICU patients that have been with intubation/mechanical ventilation or with tracheotomies or NG tubes, in patients with acute respiratory infection/

discharge, higher protein/caloric targets should be provided preferably combined with exercise.

Post-ICU discharge, achieving protein targets is more difficult than reaching caloric goals, in particular after removal of the feeding tube.

After hospital discharge, probably very highdose protein and calorie feeding for prolonged duration is necessary to optimise the outcome.

High-protein oral nutrition supplements are likely essential in this period. Several pharmacological options are available to combine with nutrition therapy to enhance the anabolic response and stimulate muscle protein synthesis.

In the recovery phase (post-ICU discharge), increase kilocalories and encourage patient to become active. Recommending high protein oral nutritional supplements to build and maintain muscle function will be beneficial.

Prof Wischmeyer and his team were involved in the Longitudinal Evaluation of Energy Expenditure and Metabolic Pathophysiology of Covid-19 study.

The aim of the study was to evaluate longitudinal metabolic and cardiac pathophysiology in patients with Covid-19 to understand, guide and optimise metabolic clinical care during acute hospitalisation. Covid-19 has led to significant, EE/metabolic changes, systemic mitochondrial dysfunction, significant muscle wasting and loss of function throughout the course of illness and during recovery. These findings will soon be published in the Journal of Critical Care.

pneumonia/respiratory insufficiency with a severe disease needing high concentration of oxygen or non-invasive mechanical ventilation and also in patients discharged from acute hospitals to rehabilitation centres, nursing homes or other facilities. OD is associated to prolonged hospitalisation, dehydration, and severe nutritional and respiratory complications (aspiration pneumonia), hospital readmissions and mortality.

One of the primary causes of OD in persons with compromised respiratory systems, including those with Covid-19, stems from the incoordination between swallowing and respiration. Respiration and swallowing display an intricate relationship, with both systems sharing neurologic, physiologic, structural and functional interdependence.

The aim of Prof Clavé and his team’s study titled Oropharyngeal Dysphagia in Patients With COVID-19 was to assess the prevalence of OD and nutritional risk in these patients and to know their needs of compensatory treatment following the application of an early intervention, and to assess whether OD and malnutrition are indicators of poor prognosis for Covid-19 patients.

The team used the volume-viscosity swallowing test (V-VST) to assess the prevalence of OD, and NRS2002 to assess the nutritional risk in admitted patients with confirmed Covid-19. Nutritional status was measured at three to six month’s post-discharge.

The study found that the prevalence of OD on admission was 50%. These patients had a 75% risk of malnutrition of which 27% were at risk of moderate to severe malnutrition. In hospitalised patients, the prevalence of OD was 55%, the incidence 36% and the prevalence of malnutrition was 66%. Covid-19 patients lost on average 9.3kg.

The pathophysiology of OD is multifactorial,

Management of oropharyngeal dysphagia in Covid-19 patients Prof Pere Clavé, director of Academic Studies and Research and Development, Hospital de Mataró (Spain) Oropharyngeal dysphagia (OD) is a common

11

SF | NUTRITION

12

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

including post ICU neurological factors, respiratory insufficiency, invasive respiratory support, muscle weakness, sarcopenia and cachexia. Diagnosis should be based on clinical measures. Instrumental assessments are aerosol generated and should only be performed when essential, and by those wearing personal protective equipment.

There is currently no active treatment for OD, said Prof Clavé. He recommended that compensatory strategies should be used in all patients with AD. A minimal massive intervention procedure should the followed, which include: Place the patient in the correct posture during meals (chin down when necessary) Remove oxygen masks and suing nasal cannulas (2L/min-3L/min) Encourage the patient to be autonomous when eating and drinking Using the optimal viscosity according to

is everybody’s problem, nobody seems to take responsibility – especially once a patient is discharged. In Norway only 8% of patient’s nutritional status is measured at discharge. In Sweden, 15% and in Denmark 18% are measured.

Dr Collins stressed that healthcare systems need to do better. A study showed that 45% of malnourished patients received inappropriate advice to limit caloric intake and 47% received general advice that did not address malnutrition.

Despite 88% receiving oral nutritional supplementation during their hospital admission, only 6.6% were scripted post-discharge.

First-line interventions for malnourished patients in the out-patient setting is often delayed, despite the fact that guidelines recommend food fortification as first-line management for one month (up to three months).

If weight continues to decline, the patients should be prescribed a powered oral supplement.

Funding and reimbursement for nutritional support are also lacking. To optimise outcomes

the V-VST (select 250mPa.s or 800mPa.s for each patient) Screen early for malnutrition and initiating early intervention with oral nutritional supplementation on admission Assess nutritional status, supporting and monitoring ASAP during admission If EN is required, do not combine with oral intake, NG tube is recommended and PEG insertion should be postponed Triple adaptation of solid foods (texture, caloric and protein content) at discharge

Promote oral health.

in malnutrition, targeted multimodal interventions should be initiated that take a disease-course approach ensuring the right patients, receive the right nutrition support, at the right time, in order to maximise the response to treatment.

All Covid-19 patients need to be screened across the healthcare continuum for malnutrition, sarcopenia and frailty. Malnutrition should be diagnosed using the Global Leadership Initiative on Malnutrition criteria. The five criteria for malnutrition include non-volitional weight loss, low body mass index, and reduced muscle mass as phenotypic criteria, and reduced food intake/ assimilation and inflammation/disease burden as etiologic criteria. It is proposed that the diagnosis of malnutrition be based upon the presence of at least one phenotypic criterion and one etiologic criterion. Treatment needs to be assertive, targeted and coordinated.

1

2

3 4

5 6 7 8 9

Tackling the malnutrition carousel Dr Peter Collins, senior lecturer, Nutrition and Dietetics at Griffith University (Australia) Up to 40% of patients admitted to hospital are malnourished and up to 70% of patients weigh less on discharge. Malnutrition increases length of hospital stay, the risk of complications, is associated with high healthcare costs and patients require post-discharge support.

Due to the complex aetiology of respiratory disease, tackling malnutrition can be challenging, said Dr Collins. Respiratory diseases are associated with complex disease processes and are dynamic and progressive.

Against this backdrop, nutrition is not always at the top of the list of clinical priorities. Another challenge is time constraints. The average length of hospitalisation for respiratory diseases in the ICU setting in the United Kingdom is six days, in the United States 5.5 days and in Australia 4.7 days.

A third challenge is that although malnutrition

Muscle-targeted nutrition Dr Emanuele Cereda, nutrition scientist, International Center for the Assessment of Nutritional Status, University of Milan (Italy) Providing adequate nutritional support may not always be possible, particularly in acute disease as highlighted by the Covid-19 pandemic. However, every effort should be made to guarantee highquality nutritional support in hospitalised patients to prevent malnutrition and to enable optimal recovery after discharge, said Dr Cereda.

Underfeeding often occurs in patients in the ICU setting. This might be due to the lack of availability of oral nutritional supplements, EN formulas, PN bags or pumps and limited human resources to assist with feeding.

Immobility, poor nutrition, and inflammation

trigger and accelerate muscle loss or sarcopenia, which commonly occurs in ageing patients or those that are immobile. Sarcopenia is associated with negative patient outcomes and high healthcare utilisation. These patients are at high risk of morbidity and mortality.

Dr Cereda discussed the findings of their recent study on the role of muscle-targeted nutritional support. The title of the study is Improving rehabilitation in sarcopenia (IRIS): A double-blind randomised, controlled study. The aim of the study was to assess the efficacy of muscle-targeted nutritional supplementation on physical performance, functional and muscle recovery in older patients with sarcopenia.

Participants did not have severe cognitive impairment and were admitted to an in-patient rehabilitation facility. A secondary aim was to assess the economic benefits of the abovementioned therapy.

Participants in group 1 were randomised to an intervention formula oral containing 20g of whey protein 3g leucine, vitamin D (10µg) per 200ml serving, twice daily. Group 2 followed a hospital diet and received an Iso-caloric control intervention twice per day. Both groups received individualised physical rehabilitation. Primary study endpoint at discharge was change in gait speed. Secondary outcomes included QoL, cognitive status, body composition, physical performance and functional status.

Other outcomes were health economics and nutritional outcomes.

Results In terms of the primary endpoint, supplementation with the intervention formula resulted in greater increase in mean gait speed.

A significant effect was also found for muscle mass and all key secondary outcomes, functional and cognitive endpoints. In terms of health economics, the study found that a greater proportion of patients (84.3% vs 60.3%) in group 1 went home instead of being transferred to an institution. In addition, a greater proportion of patients in group 1 experienced a reduction in intensity of care (85.9% vs 63.5%). It is recommended that in older adults with reduced mobility, energy and protein intake should be increased to 27kcal/kg/day-30kcal/kg/day and 1.0g/kg/day-1.2kg/day. Although energy increased in both study groups (from 20.5kcal/kg/day23.5kcal/kg/day), it did not reach the minimum suggested target. However, mean protein intake in patients receiving the interventional formula was 1.1g/kg/day, while it was only 0.08g/kg/day in group 2. The use of a muscle-target nutritional therapy is recommended because it is the only one with evidence-based efficacy in increasing muscle mass and improving muscle function in the absence of concomitant physical therapy in older patients with sarcopenia, concluded Dr Cereda. SF

PE R

Nutriciaâ&#x20AC;&#x2122;s complete offering for your patients

12

l 5m

300 18 3Gluten 00 Free 0

For further informa on please contact: Nutricia Southern Africa (Pty) Ltd Customer Care: 087 350 2310 / Fax: 086 612 4711 / Email: home.za@nutricia.com Hours: Monday to Friday from 8:30 a.m. to 4:30 p.m. (excluding public holidays)

14

SF | NUTRITION

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

This article was independently sourced by Specialist Forum.

An oncologist’s view on nutrition in the cancer patient

A 2016 survey conducted among cancer patients found that about 73% of respondents experienced feeding problems during their illness and treatment, while 60% indicated that food was a concern to both them and their families.

Furthermore, about 42% said they felt ‘forced’ by their families to eat, 66% indicated that their appetite is influenced by their mood (depression), while 59% stated the latter led to reduced social interaction.

Dr Stefan Rauh

C

learly nutrition is a very important topic for cancer patients, but many oncologist do not view it as part of their treatment scope, said Dr Stefan Rauh, researcher and practicing medical oncologist at the Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg. He served as chairperson of the European Society of Medical Oncology (ESMO) Practising Oncologists’ Committee/Working Group, was a member of the ESMO Educational Steering Committee and member of the board.

He is President of the Société Luxembourgeoise d’Oncology, a European Union medical specialists’ working group, a member of the American Society of Clinical Oncology, the American Society of Haematology as well as Health Volunteers Overseas.

Dr Rauh recently presented a CPD accredited webinar for Specialist Forum readers, sponsored

by Nutricia. The title of his presentation was An oncologist’s view on nutrition in the cancer patient. Please note that the video is available on replay. To access the replay video, please go to www.medicalacademic.co.za and click on the webinar tab.

Do oncologist view nutrition as important?

A 2006 British survey conducted among trainee oncologists found that 91% and 56%, respectively, agreed that nutrition played an important role in the risk of mortality and morbidity in cancer patients. Some 76% agreed that malnutrition played a role in the length of hospital stay, 95% agreed that it impacted patients’ quality of life and 78% said it increases the risk of treatment toxicity.

In clinical practice, however, data from a national survey about nutrition conducted among Italian oncologists, showed that respondents had a poor understanding about the value of nutrition in the outcomes of cancer patients.

Some oncologists belief that food issues should not be emphasised too much and adopt an ‘eat what-you-like’ approach, perhaps trying to ‘protect’ patients from directive and humiliating discussions with their family members.

Others may be confused by conflicting data and evidence. Today, they can, however, rely on available international guidelines for nutritional support in patients with cancer. Good modern clinical guidelines are based on the highest quality of evidence according to current data leading to a general consensus in state-ofthe-art diagnosis and therapy of diseases and a standardised approach to patient care. This is highly appreciated in situations of multiple treatment options, in situation of sparse evidence or of uncertainty.

What impact does nutrition have on cancer patients?

Nearly 33% of cancer deaths can be attributed to cachexia or ‘wasting’ syndromes. Cachexia is characterised by a dramatic loss of skeletal muscle mass and often accompanied by substantial weight loss. It is a form of metabolic mutiny in which the body overzealously breaks down skeletal muscle and adipose tissue, which stores fat. Patients suffering from cachexia are often frail and weak.

Cachexia occurs in many cancers, usually at the advanced stages of disease. It is most commonly seen in a subset of cancers, led by pancreatic and gastric cancer, but also lung, oesophageal, colorectal, and head and neck cancer.

Cancer-related cachexia can be defined and classified as follows: » Weight loss >5% over the past six months » Body mass index (BMI) <20 and any degree of weight loss greater than 2% » Appendicular skeletal muscle index consistent with sarcopenia (another wasting syndrome) and weight loss of more than 2%.

The stages of cancer cachexia are: » Precachexia: Weight loss of <5%, along with other symptoms such as impaired glucose tolerance or anorexia » Cachexia: Weight loss >5% or other symptoms and conditions consistent with the diagnostic criteria for cachexia » Refractory cachexia: Patients experiencing cachexia who are no longer responsive to cancer treatment, have a low performance score, and have a life expectancy of less than three months.

Weight loss in cancer patients can be caused by systemic inflammation, pain, complications of the disease (eg oesophagus cancer), treatment-related side-effects (eg nausea), psychological causes (eg depression) as well as comorbidities (eg dental complications).

The management of these multiple causes is challenging. The oncologist needs to prioritise which to address first, said Dr Rauh.

Weight loss at the start of chemotherapy is associated with reduced response rates and increased toxicity and is included as an important adverse event. In a 2019 survey, only 35% of patients indicated that their oncologist discussed their weight during each consultation, and 28% said it was discussed sometimes.

“I find this very surprising, because weight loss has an impact on our treatment decisions and patient outcomes,” said Dr Rauh. See table 1.

According to Dr Rauh, the correlation between weight loss and patient outcomes illustrated in table 1 can be used as both predictive and prognostic, which can aid oncologists in initiating timely interventions.

What should oncologists do better?

Studies have shown the positive impact of early initiation of supportive care such as nutrition, on the quality of life of patients as well as treatment outcomes. Nevertheless, data show that symptoms of malnutrition are

For Care is a specialized nutri onal supplement for cancer pa ents available in a 125ml.

Op mal Chemo dose for op mal treatment outcome

Diabe c pa ents TASTE

Stress induced hyperglycemia

3 Flavours

Increased risk of weight loss with Chemo

High Protein, High Energy & EPA Enriched is clinically proven

Hyperglycemia due to Cor sol VOLUME

Low Glycemic Index

Nega ve effect on performance / Dose limi ng toxicity

204 11g EP A 2.6g Other options available to cancer patients Dysphagia in Cancer kcal Protein

358 0.2 g Gluten Lactose

Free

•

A food and fluid thickener with amylase resistant features for the dietary management of dysphagia.

•

Does not change the taste of food or fluid

Fibre

6.4 g

Higher Protein Protein

300 18 gg Gluten Fibre

Free

kcal

0g

•

Pa ents with high energy and protein requirements

Protein

9.5 2.2 g Calcium

mg

34

l

PE R2 0

kcal

0m

kcal

Protein

300 8 g g

Lactose, fat, Gluten

Free

kcal

For pa ents that dislike milk tas ng supplements

•

High energy carbohydrate oral supplement

0

Protein

g 20 0 Lactose & Gluten

•

Fibre g

Milk Prot

Free Free

For further informa on please contact: Nutricia Southern Africa (Pty) Ltd Customer Care: 087 350 2310 / Fax: 086 612 4711 / Email: home.za@nutricia.com Hours: Monday to Friday from 8:30 a.m. to 4:30 p.m. (excluding public holidays)

16

SF | NUTRITION

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

often underestimated and undertreated in most cancer patients.

We have successfully integrated pain control and other symptom-orientated supportive care into our practice: Let us all make nutrition an equal factor of consideration in our professional care and adopt current guidelines, stressed Dr Rauh.

All aspects of nutrition among patients with cancer have to be considered, including the psychological aspects. The psychological aspects of nutrition and cancer consist of behavioural, emotional, perceptual, and attitudinal responses.

Among the behavioural consequences are learnt food aversions, changes in food preferences and anticipatory nausea and vomiting. Documented emotional responses are depression and anxiety associated with eating. Attitudinal responses include social, religious, cultural and other values that may change as a consequence of the disease.

Medical oncologists are asked to assess all of these issues and refer the patients to the appropriate specialist according to the identified problem. Therefore, medical oncologists primarily need to be aware of the complexity of nutrition and require better training on nutrition as a supportive care issue, stressed Dr Rauh.

How should medical oncologists care about their patients’ nutrition?

Ideally, nutritional problems should be dealt with by nutrition specialists. This is still unfortunately far from reality in many institutions. While an interdisciplinary environment including nutrition specialists is clearly a standard to strive for, oncologists are asked to manage basic features. Therefore: » Every oncologist should be aware of existing updated guidelines concerning the nutrition of patients with cancer » The scientifically proven benefit of nutritional screening and interventions make it mandatory to address these issues in all the patients » Screening for malnutrition is simple and should be mandatory during every visit or

new admission of any patient with cancer, so as to identify as early as possible malnutrition (the earlier it is detected, the more treatment strategies will be likely to be beneficial). Several nutrition-screening tools are considered reliable for patients with cancer (eg Malnutrition Screening Tool, Mini Nutritional Assessment Short Form Revised, Malnutrition Universal Screening Tool and Nutritional Risk Screening 2002) and allow a quick and easy nutrition screening, thus freeing up resources that may be reallocated in higher priority nutrition activities » Medical oncologists should be knowledgeable concerning possible interventions. Most of all, they should consider addressing nutritional (as well as other supportive care) issues in a multidisciplinary manner, both to diagnose possible remediable causes for malnutrition as well as decide interventions » The European Cancer Patient Coalition developed a Cancer Patient’s Bill of Rights.

According to the bill, every patient with cancer has the right to nutritional screening and prompt referral for comprehensive nutritional assessment when a nutritional risk has been identified » Time constraints may not let medical oncologists to offer all the information about the mechanisms and consequences of cachexia that patients and their families would desire. Similarly, medical oncologists rarely have enough time to thoroughly investigate all the side effects a patient with cancer complains of. Therefore, a multidisciplinary approach with nurses and other allied healthcare professionals that strictly collaborate with medical oncologists in offering correct information and performing a systematic nutritional screening, using validated tools, both at diagnosis and at regular intervals depending on the clinical status, may be a successful strategy to overcome the lack of time and guarantee patients with cancer their rights » Nutrition risk screening of patients with cancer is the first step to allow early recognition of

Table 1: The impact of weight loss on patient outcomes Weight Description loss grade

Outcomes

0

Weight-stable patients (weight loss ±2.4% with BMI ≥28kg/m2)

Longest survival

1

BMI 20kg/m2 to 25kg/m2 and weight loss ≤2.4%, or BMI ≥28kg/m2 and weight loss 2.5% to 6.0%

Median survival 14.6 months

2

BMI 20kg/m2 to 28kg/m2 and weight loss 2.5% to 6%, or BMI ≥28kg/m2 and weight loss 6% to 11%

Median survival 10.8 months

3

BMI ≤20kg/m2 and weight loss <6%, or BMI 20 to 28kg/m2 and Median survival weight loss 6% to 11%, BMI 22 to >28 kg/m2 and weight loss 7.6 months 2 11% to 15%, or BMI ≥28kg/m and weight loss >15%

4

BMI ≤20kg/m2 and weight loss 6% to 11%, BMI ≤22kg/m2 and weight loss 11% to 15%, or BMI ≤28kg/m2 and weight loss >15%

Median survival of 4.3 months

nutritional problems and refer patients identified as at nutritional risk to health professionals with documented skills in clinical nutrition for appropriate nutritional management » Patients and their families are confronted daily with overwhelming amounts of nonprofessional nutritional proposals, some purely commercial. Medical oncologists should not avoid discussion of this topic, trying to offer evidenced-based strategies.

Barriers to overcome The relatively low priority of nutritional support in today’s clinical oncology has to be overcome: More room for education in the medical oncologist’s curriculum is needed to make future oncologists aware and train them.

The ESMO/American Society of Clinical Oncology global core curriculum refers very briefly to the fact that a trainee should learn and understand ‘supportive measures in relation to all kinds of systemic anticancer therapies’.

Nutritional assessment and management should become an integrative part of clinical trials. This would further enhance its importance and facilitate integrating management strategies into daily practice.

Guidelines should provide clear and easy to follow algorithms, adapted to different phases of the journey of a patient with cancer and according to needs at diagnosis, during treatment and follow-up.

The development of checklists at the oncologist’s and the patients’ disposal could facilitate guideline implementations.

Guidelines need to be locally implemented to be efficient. Nutritional multidisciplinary working groups should be created in every cancer centre, who should ‘translate’ current guidelines into practice. Clear tasks and responsibilities would have to be defined for all participants. In the future, this could be part of a national or other accreditation framework for an oncologic centre of excellence.

Assessment/screening of nutritional status at baseline should be part of mandatory global patient evaluation. Patients should be implicated in these steps to better understand specific needs.

Conclusion Medical oncologists have an important role to play in the assessment of the nutritional status of cancer patients to initiate timely intervention.

Nutritional status has been shown to directly impact cancer patient outcomes. A number of nutrition guidelines for cancer patients has been published. The good news is that ESMO will be publishing comprehensive guidelines on the nutritional needs of cancer patients in the near future. He called on societies to publish cancer nutrition guidelines in oncology journals and not only in those aimed at nutritionists. SF

SF | CPD: BONE HEALTH

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Osteoporosis an overlooked disease in diabetes

This article was independently sourced by Specialist Forum.

Over the past few years, evidence shows that people with diabetes are at extremely high risk of osteoporosis and fracture. Both type 1 (T1DM) and type 2 (T2DM) diabetes are associated with a decrease in bone quality, which leads to an increase in low stress fractures, a condition called diabetic osteopathy. Combined with the fact that the ageing population is increasing worldwide, and T2DM is expected to affect an estimated 578 million by 2030, it is imperative that the management of these two metabolic diseases are stepped up.3,10,12

O

steoporosis is a disease in which the density and quality of bone are reduced. As bones become more porous and fragile, the risk of fracture is greatly increased, increasing the risk of morbidity and mortality. The loss of bone occurs silently and progressively. Often there are no symptoms until the first fracture

occurs – hence the description of osteoporosis as the ‘silent disease’.11

Gaps in the management of osteoporosis and diabetes Low diagnosis and treatment rates, postulates the International Osteoporosis Foundation (IOF), are due to a lack of patient knowledge about the

disease, a lack of dialogue about osteoporosis between patient and physician, and restricted access to diagnosis and treatment before the first fracture, resulting in underdiagnosis and undertreatment of the disease.1 An estimated 80% of people, who have already had at least one osteoporotic fracture, are neither identified nor treated, according to the IOF.1

in numbers1 ONE FRAGILITY fracture occurs every

1 in 3

women worldwide are affected by osteoporosis

PP-TE-ZA-0265 September 2021

80%

forearm fractures

70%

hip fractures

of hip fractures occur in men over the age of 50

1 in 5

men worldwide are affected by osteoporosis

61%

of osteoporotic fractures occur in women.

Of those:

20%-25%

(about

9 million

per annum)

75%

75%

humerus fractures

58%

spine fractures

of hip, spine and distal forearm fractures occur among patients 65 years old or over

30%-70% of fractures can be prevented if treated (depending on the drug and the patient population)

20%

of patients die in the first year following hip fractures, mostly due to pre-existing medical conditions

17

18

SF | CPD: BONE HEALTH

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

For example, only a small percentage of patients with vertebral fractures come to clinical attention. The proportion of vertebral fractures that go unrecognised, during local assessment of a thoracolumbar lateral radiograph, is as high as 46% in Latin America, 45% in North America, and 29% in Europe/South Africa/Australia.1 A recent report on the burden of fragility fractures in six European countries revealed that 73% of women and 63% of men eligible for treatment, do not receive any. In addition, the proportion of patients starting a pharmacological treatment in the year after a fracture is low. In France, Sweden, and Spain, 85%, 84% and 72% of fracture patients remained untreated one year after fracture, respectively. This despite the fact

Box 1: Capture the fracture (please) According to Prof Cyrus Cooper, former President of the IOF, there is a large care gap worldwide that is leaving millions of fracture patients at serious risk of future fractures. To address this gap, the IOF launched the ‘Capture the Fracture’ campaign to make secondary fracture prevention a reality. 9 As part of the campaign, the IOF developed standards, guides, and models, as well as resources, tools and educational programmes to assist clinicians and healthcare facilities.

One of the models supported by the IOF is the establishment of FLSs.9 A FLS is a multi-disciplinary healthcare delivery model for secondary fracture prevention. FLS aims to systemically identify, treat, and refer all eligible patients within a local population who have suffered a fragility fracture with the aim of reducing their risk of subsequent fractures. 9 A growing body of evidence suggests that FLSs are a cost-effective care delivery model that has the potential to reduce the risk of refracture, increase the number of high-risk patients being treated and improve adherence to treatment. 9 A recent review and meta-analysis indicated that FLS improved the rate of fractured patients getting BMD tests, starting treatment, and adhering to treatment by about 20%. The results also showed a significant reduction in the refracture rates. 9 In another recent study investigating different FLS model types (A to D), found that the most complete FLS model (type A) was associated with reduction in refracture risk (hazard ratio [HR] 0.18–0.67 over two to four years), increased assessment of BMD (relative risk [RR] 2–3), increased treatment initiation (RR 1.5–4.25) and adherence to treatment (65% –88% at one year). See box 2 for an explanation of the different FLS models.9

that a prior fracture is associated with an 86% increased risk of a subsequent fracture.1,9,11 The situation is further exacerbated by poor adherence to medication. Studies show that only 40% of patients take treatment for more than one year. At two years, only 20% of patients are still taking their medication.1 In terms of management, a similar scenario is prevalent in diabetes care – especially in T2DM, which accounts for 90%-95% of cases.

Globally one in two individuals living with T2DM are undiagnosed. The African region has the highest percentage of undiagnosed people compared with other regions. About 62.3% of the people with the diabetes do not know they are affected.6,14 Glycaemic control is the cornerstone of diabetes treatment. However, only 50% of diabetic patients meet recommended glycaemic targets (HbA1C <7.0%). This is mainly as a result of non-adherence to diabetes treatment, which ranges from 23% to 77%.13,15

The fracture risk of T1DM increases because of a decrease in bone mineral density (BMD).

In patients with T1DM the impaired bone formation is caused by an absolute deficiency of insulin and insulin-like growth factor-1. This causes lower values of peak bone mass. While bone mass decreases in T1DM, in T2DM bone mass increases. Studies have shown that T2DM patients have between 5% and 10% higher areal BMD than healthy subjects. 3,5,18 Research shows that frank hyperinsulinaemia in T2DM may cause this increase in bone formation. Hyperinsulinaemia is defined as elevated circulating insulin in relationship to its usual level relative to blood glucose.

Hyperinsulinaemia is often an indicator of metabolic dysfunction. In short, T2DM reduces bone quality rather than BMD. Studies have shown that T2DM patients have between 5% and 10% higher areal BMD than healthy subjects.3,4,5,16, According to the World Health Organization, osteoporosis is defined as a BMD that lies 2.5

In addition, some anti-diabetic agents have been shown to increase fracture risk. Treatment with for example thiazolidinediones increases the risk of fractures in women with T2DM independent of age and duration of exposure.6

standard deviations (SD) or more below the average value for young healthy women (a T-score of <-2.5 SD).19 The most widely validated technique to measure BMD is dual energy X-ray absorptiometry (DXA). A challenge in diabetes patients is the fact that DXA measurements may underestimate fracture risk in patients with diabetes. Thus, a BMD intervention threshold at T-score −2 at spine or hip could be considered appropriate.18,19 According to Ferrari et al, risk assessment tools like FRAX do not fully capture the increased risks of fracture in diabetes patients.

One option is to substitute rheumatoid arthritis (RA) with T2DM in FRAX. The authors write that in their opinion, such a FRAX adjustment for T2DM can be clinically useful.18

Risk factors Falls are the main cause of fracture, contributing to about 90% of hip fractures.

About 30% of people over age 65 fall annually, with about 10%-15% of falls in the elderly resulting in fracture, and almost 60% of those who fell the previous year will fall again.1 Other risk factors include for example:1 » A parental history of fracture » A physical inactive and sedentary lifestyle » Impaired neuromuscular function (eg reduced muscle strength, impaired gait, and balance) » Smoking can lead to lower bone density » A high intake of alcohol confers a significant risk of future fracture (eg over four units of alcohol/day can double the risk of hip fracture) » Prolonged use of corticosteroids is the most common cause of secondary osteoporosis (30%-50% of patients on long term corticosteroid therapy will experience fractures) » Proton pump inhibiting drugs can reduce the absorption of calcium from the stomach » Low body weight » Use of anxiolytics, sedatives, neuroleptics, and antidepressants has been shown to increase risk of hip fracture

The osteoporosis, diabetes convergence A growing body of evidence suggests that hyperglycaemia, one of the hallmarks of diabetes, may impair bone matrix formation and biochemical competence. In both types of diabetes, bone displays inferior quality and strength. 3,5,6

Fracture risk in diabetes patients The Nurses’ Health Study (n=109 983) tracked the health outcomes of women (34–59 years old) for over two decades. One of the foci of this study was the occurrence of hip fractures.

The team found that the risk of hip fracture in women with T1DM was six-fold higher compared to those without diabetes.6 The British Health Improvement Network study used longitudinal electronic medical record data to evaluate incident fractures in men and women (0-89 years old) with T1DM. Median follow-up was 4.7 years.6 They found that the risk of incident fracture of any type increased in both sexes with T1DM, and in all age groups, compared to those without diabetes. When stratified by age, women (40-49 years) with T1DM, had an 82% higher risk of fracture at any site than women without diabetes. Younger women with T1DM (30–39 years old) had a 316% increase in the risk of hip fracture compared to those without.6

SF | CPD: BONE HEALTH

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Men (60–69 years) with T1DM also had double the risk of fracture at any site compared to men without diabetes in the same age group. The same study performed secondary analyses evaluating hip fracture specifically and found that men (60-69 years) with T1DM had a 421% increased risk of hip fracture, compared to those without diabetes.6 The Women’s Health Initiative study followed the health outcomes of postmenopausal women (n=93 676) for seven years. Women with T2DM at baseline had a 20% increased risk of fracture at any site after adjusting for multiple covariates, including frequency of falls.6 The Study of Osteoporotic Fractures (n=9654) in women 65 years or older had a mean follow-up of 9.4 years. Radiology reports were used to confirm reported incident fractures.

The team found that women, diagnosed with diabetes after the age of 40, had a 30% increased risk of having any non-vertebral fracture and an 82% increased hip fracture risk

not alter the effect of alendronate on BMD gain versus placebo.18 Two small observational studies showed than alendronate improved lumbar spine BMD but not hip BMD similarly in postmenopausal osteoporotic patients with and without diabetes.18 Data extracted from the Danish national prescription registry reported that diabetes, with or without complications, did not influence fracture risk in patients who adhered to alendronate.18 Another Danish cohort study found no difference in the anti-fracture efficacy of alendronate or etidronate at the hip, lumbar spine, and forearm. The study also concluded that risk of hip fracture with these treatments was similar in T1DM, T2DM, and non-diabetic patients.18 In three phase III Japanese trails, which included women with diabetes, risedronate treatment showed similar responses on lumbar spine BMD and bone markers between diabetic and non-diabetic patients.18

A study investigating the informationseeking behaviours of young adults found that although they had extensive networks that would enable information seeking, they rarely actively sought information on nutrition for osteoporosis prevention. 8 This underlines the importance of packaging information in such a way that it increases their willingness to engagement in prevention behaviours. Ways in which this can be done effectively is for example social media platforms.8 Osteoporosis prevention programmes should focus on encouraging small-scale, convenient lifestyle modifications, targeted at young adults, and coupled with short explanations. 8 As mentioned earlier, older patients also have a lack of knowledge about osteoporosis and its consequences. To address this knowledge gap, the American Society for Bone and Mineral Research assembled a multi-stakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture

compared to those without diabetes.6 A cross-sectional study from Japan used spinal and thoracic radiographs in participants over 50 years old to determine the risk of vertebral fractures. The team found that men and women with T2DM had a 373% and 82% increased risk of having prevalent vertebral fractures, respectively, after adjustment for lumbar spine bone density.6

In the Multiple Outcomes of Raloxifene Evaluation, raloxifene showed higher efficacy in reducing vertebral fracture risk in diabetic women compared to those without diabetes.

Anti-fracture efficacy of raloxifene was similar between patients with and without diabetes in the Raloxifene Use for The Heart trial and in a Danish cohort.18 The Direct Analysis of Non-vertebral Fractures in the Community Experience study assessed the effects of teriparatide (20μg per day, subcutaneous up to 24 months) on skeletal outcomes in patients with and without T2DM. Teriparatide treatment had a similar effect in diabetic versus non-diabetic persons on vertebral and total hip BMD. Interestingly, the effect on femoral neck was greater in the diabetic treated patients compared to those without diabetes.

Incidence of non-vertebral fracture at six months was similar in both groups.18 Data are not available for intravenous bisphosphonates (ibandronate, zoledronic acid) in diabetic patients. The risk of renal impairment may limit the utility of these therapies in diabetes patients.18

among people aged 65 years and older with a hip or vertebral fracture.1,7 An important overarching principle for the recommendations is that people aged 65 years or older with a hip or vertebral fracture should be optimally managed in the context of a multidisciplinary clinical system that includes case management (one example is a fracture liaison service [FLS]) to assure that they are appropriately evaluated and treated for osteoporosis and risk of future fractures. See box 1 for an explanation of what a FLS is.7,10

By 2050, the worldwide incidence of hip fracture in men is projected to increase by 310% and 240% in women, compared to rates in 19901 Managing osteoporosis in the diabetes patient To date, no trials have directly evaluated the anti-fracture efficacy of osteoporosis treatment in diabetic patients. Management is therefore largely empirical and derives from the good clinical practice and experience of the physician.18 The clinical evidence regarding the efficacy of anti-osteoporosis treatments in diabetic patients is based on post-hoc subgroup analyses. In the Fracture Intervention Trial, postmenopausal women, including diabetic participants with a femoral neck T-score <−1.6 were randomly treated with alendronate or placebo for three years. The researchers found that diabetes did

Preventing future fractures Any fracture unrelated to motor vehicle accidents that is sustained between the ages of 20 and 50 years is associated with a 74% increase in the future risk of fractures after the age of 50 years.

Thus, it is important not only to treat a patient’s present fracture, but also to implement a plan for future fracture risk reduction.2 Young adults still have the potential to mitigate their bone loss. One of the essential components of reducing the risk of future fractures, include effective osteoporosis prevention education programmes. It is important that information is presented in a format that they can identify with, have access to, and can apply to their own lives.8

Recommendations

1

Communicate three simple messages to people aged 65 years or older with a hip or vertebral fracture (as well as to their family/ caregivers) consistently throughout the fracture care and healing process: » Their broken bone likely means they have osteoporosis and are at high risk for breaking more bones, especially over the next one to two years » Breaking bones means they may

Box 2: FLS models explained17

» Type A is defined as a service that identifies, investigates, and initiates treatment » Type B services identify and investigate patients but then refer back to the primary care physician for treatment initiation » Type C services identify patients at risk and inform them and their primary care physician. However, they do not undertake any assessment or treatment of the patients » Type D services identify at-risk patients and inform and educate them but take no further part in communicating their findings to other stakeholders in the patient’s care.

19

SF | CPD: BONE HEALTH

20

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

2

3

suffer declines in mobility or independence, and they will be at higher risk of dying prematurely » Most importantly, there are actions they can take to reduce their risk, including regular follow‐ups with their usual healthcare provider as for any other chronic medical condition.

Ensure that the usual healthcare provider for a person aged 65 years or older with a hip or vertebral fracture is made aware of the occurrence of the fracture. If unable to determine whether the patient’s usual healthcare provider has been notified, act to be sure the communication is made Regularly assess the risk of falling of people aged 65 years or older who have ever had a hip or vertebral fracture. » At a minimum, take a history of their falls within the last year » Minimise the use of medications associated with increased fall risk

» Evaluate patients for conditions

4

5

6

associated with an increased fall risk.

Strongly consider referring patients to physical and/or occupational therapists or a physiatrist for evaluation and interventions to improve impairments in mobility, gait, and balance and to reduce fall risk Offer pharmacologic therapy for osteoporosis to people aged 65 years or older with a hip or vertebral fracture to reduce their risk of additional fractures.

Do not delay initiation of therapy for bone mineral density (BMD) testing.

First‐line pharmacologic therapy options for people aged 65 years or older with a hip or vertebral fracture, include: » Oral bisphosphonates alendronate and risedronate, which are generally well tolerated, familiar to health care professionals, and available at low cost » Intravenous zoledronic acid » For patients at high risk of fracture, particularly those with vertebral fractures, anabolic agents may be useful, although consultation with or referral to a specialist would also be appropriate.

Because osteoporosis is a life‐long chronic condition, routinely follow and re-evaluate people aged 65 years or older with a hip or vertebral fracture who are being treated for osteoporosis.

Purposes include: » Reinforcing key messages about osteoporosis and associated fractures » Identifying any barriers to treatment plan adherence that arise » Assessing the risk of falling » Monitoring for adverse treatment effects

» Evaluating the effectiveness of the

treatment plan » Determining whether any changes in treatment should be made, including whether any anti‐osteoporosis pharmacotherapy should be changed or discontinued.

6. Valderrabano RJ and Linares MI. Diabetes mellitus and bone health: epidemiology, etiology and implications for fracture risk stratification. Clinical Diabetes and Endocrinology, 2018.

7. Conley RB, Adib G, Adler RAA et al. Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition. Journal of Bone and Mineral Research, 2019.

8. Holland A. Osteoporosis knowledge translation

About 1.6 million hip fractures occur worldwide each year, by 2050 this number could reach between 4.5 million and 6.3 million1

for young adults: new directions for prevention programs. Health Promotion and Chronic Disease Prevention in Canada, 2017.

9. Akesson K, Marsh D, Mitchell PJ et al. IOF Fracture Working Group Capture the Fracture: a Best Practice Framework and global campaign to break the fragility fracture cycle. Osteoporos Int, 2013.

10. Borgström F, Karlsson L, Ortsäter N et al. Fragility fractures in Europe: burden, management and opportunities. Archives of Osteoporosis, 2020.

11. International Osteoporosis Foundation. What causes osteoporosis?

12. Saeedi P, Petersohn I, Paraskevi S et al. Global and

Conclusion Osteoporosis is often referred to as the silent disease because the first indication of the disease is often a fracture. Evidence is increasing that patients with T1DM and T2DM are at high risk of osteoporosis and fracture. Because of this high risk, it would be reasonable to screen diabetic patients for osteoporosis. The current osteoporosis guidelines for screening can be used for patients with T1DM and also T2DM, but it is important to bear in mind that that fracturing can occur at higher BMD levels in patients with diabetes. A prior fracture is associated with an 86% increased risk of any fracture. Hip fractures cause the most morbidity. Up to 20% of patients die in the first year following hip fractures, mostly due to pre-existing medical conditions. Less than 50% who survive a hip fracture regain their previous level of function. About 40% are unable to walk independently, 60% require assistance a year later and 33% are totally dependent or in a nursing home in the year following a hip fracture.

Prevention of subsequent fractures is therefore crucial. The implementation of FLSs at healthcare facilities has been shown to effectively reduce refracture risk, increase assessment of BMD, treatment initiation and adherence to treatment.1,3,9

References 1. International Osteoporosis Foundation (2017).

Osteoporosis: Incidence and burden.

2. Chau DL, Goldstein-Fuchs J, Edelman SV et al.

Osteoporosis Among Patients With Diabetes: An Overlooked Disease. Diabetes Spectrum 2003.

3. Jackuliak P and Payer J. Osteoporosis, Fractures, and Diabetes. International Journal of Endocrinology, 2014.

4. Falchetti A. Diabetic Osteopathy. Journal of Diabetes Research, 2020.

5. Starup-Linde J and Vestergaard P. Diabetes and osteoporosis: cause for concern? EjE-online, 2015.

regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas.

Diabetes Research and Clinical Practice, 2019.

13. MB Davidson. How Our Current Medical Care System Fails People With Diabetes. Diabetes Care, 2009.

14. Bantie GM, Wondaye AA, Arike EB et al. Prevalence of undiagnosed diabetes mellitus and associated factors among adult residents of Bahir Dar city, northwest Ethiopia: a community-based crosssectional study. BMJ Open, 2019.

15. Kassahun A, Gashe F, Mulisa E, and Rike WA. Nonadherence and factors affecting adherence of diabetic patients to anti-diabetic medication in Assela General Hospital, Oromia Region, Ethiopia. J Pharm Bioallied Sci, 2016 16. Thomas DD, Corkly BE, Istfan NW and Apovian CM. Hyperinsulinemia: An Early Indicator of Metabolic Dysfunction. Journal of the Endocrine Society, 2019.

17. Walters S, Khan K, Ong T and Sahota O. Fracture liaison services: improving outcomes for patients with osteoporosis. Clinical Interventions in Aging, 2017.

18. Ferrari SL, Abrahamsen B, Napoli N et al. Diagnosis and management of bone fragility in diabetes: an emerging challenge. Osteoporosis International, 2018.

19. WHO scientific group report. Assessment of osteoporosis at primary healthcare level, 2004. SF

To com plete this mo nth’s C PD questio nnaire, please go t o www.m edicalac ademic.c o.za and na v igate t o t he C PD sec tion of the we bsite.

SF | CARDIOLOGY

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Cardiovascular (CV) outcomes are affected by circadian blood pressure (BP) patterns in treated hypertensives.

Circadian patterns are controlled by the central clock in the suprachiasmatic nucleus of the hypothalamus and peripheral clocks located throughout the body. Light and food cues entrain these clocks to the time of day.

This synchronicity contributes to the regulation of a variety of physiological processes with effects on overall health.

I 1

2

3

Four patterns have been described: » Dippers (normal physiological change) » Extreme dippers (>20% nocturnal dip) » Risers/reverse dippers (>10% higher nighttime BP vs daytime) » Non-dippers (nocturnal fall <10%). Nondipping hypertension is associated with activation of the renin-angiotensinaldosterone system.

Importance of ABPM monitoring Recent guidelines recommend the assessment of not only clinic BP but also out-of-clinic BP.

Home BP measurement or ambulatory BP monitoring (ABPM) is recommended for the management of hypertension throughout the 24-hour day.

ABPM studies have demonstrated that BP while asleep is a better predictor of CV disease (CVD) than office or daytime BP – especially among patients treated with antihypertensives and individuals who show normotensive office BP or daytime BP. Studies have also shown that a dipping BP pattern (a >20% change in night-time values compared to daytime values) is associated with cardiac changes and unfavourable CV outcomes. Non-dipping has been associated with CV risk factors, target organ damage, and risk of future cerebrovascular events and secondary hypertension. Left ventricular hypertrophy (LVH), carotid intimamedia thickening, microalbuminuria, and cerebrovascular diseases are much more prevalent in non-dippers.

The mechanism of these variations in BP is not clear. It is postulated that at night, the balance in the autonomous nervous system

Photo credit: Shutterstock.com

Converting non-dippers to dippers

n healthy humans, both systolic BP (SBP) and dystolic BP (DBP) have a circadian rhythm that repeats every 24 hours.

Healthy individuals experience a 10%– 20% decrease in BP at night.

Dips in BP take place in three windows of sleep: BP starts declining in the vesperal window Reaches the plateau level in the basal window

Rises in the pre-awakening window.

21

This article was independently sourced by Specialist Forum.

A dippin g BP patte (>20% c rn in night- hange t compare ime values d values) is to daytime a with unf ssociated avou CV outc rable omes probably shifts towards the sympathetic nervous system.

CVD risks in non-dippers Insulin resistance, which is an important CV risk factor, has been associated with BP nondipping. In a cross-sectional study involving 103 hypertensive subjects with comparable daytime BP readings, the homeostasis model assessment index for insulin resistance was higher in non-dippers compared to dippers (2.0 ± 0.3 versus 1.4 ± 0.3). LVH, atrial natriuretic peptide, and brain natriuretic peptide were also statistically significantly elevated in non-dippers.

In a cross-sectional observational study of 84 untreated hypertensive patients, pulse wave velocity was higher among non-dippers compared to dippers, (8.91 ± 2.53 m/second versus 7.66 ± 1.08 m/second) suggesting increased arterial stiffness in non-dippers.

Red cell distribution width, which is closely related to adverse cardiovascular outcomes, was higher in non-dippers compared to dippers (14.1% ± 1.33% versus 13.5% ± 0.89%).

22

SF | CARDIOLOGY

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Oxidative stress is higher in non-dippers compared to dippers as evidenced by increased levels of asymmetric dimethyl arginine among non-dippers. Mean platelet volume, which is a determinant of platelet activation, was higher among non-dippers compared to dippers (9.72 ± 0.52fL versus 9.38 ± 0.33fL). Inflammatory markers, such as c-reactive protein, were also higher among non-dippers.

Chronotherapy Chronotherapy, defined as the treatment of an illness or disorder by administering a drug at a time of day believed to be in harmony with the body’s natural rhythms, probably represents the best therapeutic approach in nocturnal hypertension.

The prospective Monitorización Ambulatoria de la Presión arterial y Eventos Cardiovasculares or MAPEC study by Hermida et al, was specifically designed to test the hypothesis that bedtime chronotherapy with ≥1 hypertension medications exerts better BP control and CVD risk reduction than conventional therapy eg all medications ingested in the morning.

A total of 2156 hypertensive patients were randomised to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00 and at 30-min intervals at night for 48 hours.

Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required.

Despite lack of differences in ambulatory BP between groups at baseline, subjects ingesting medication at bedtime showed at their last available evaluation significantly lower mean sleep-time BP, higher sleep-time relative BP decline, reduced prevalence of non-dipping (34% versus 62%), and higher prevalence of controlled ambulatory BP (62% versus 53%).

After a median follow-up of 5.6 years, participants ingesting ≥1 BP-lowering medications at bedtime exhibited a significantly lower relative risk of total CVD events than those ingesting all medications upon awakening.

The difference between the treatment-time groups in the relative risk of major events (including CVD death, myocardial infarction, ischemic stroke, and haemorrhagic stroke) was highly statistically significant.

The progressive decrease in asleep BP and increase in sleep-time relative BP decline towards a more normal dipping pattern, two novel therapeutic targets requiring proper

patient evaluation by ambulatory BP, were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival.

Bedtime chronotherapy with ≥1 BP-lowering medications, compared to conventional upon-waking treatment with all medications, more effectively improved BP control, better decreased the prevalence of non-dipping, and, most importantly, significantly reduced CVD morbidity and mortality.

Chronotherapy probably represents the best therapeutic approach in nocturnal hypertension Converting non-dippers to dippers Lacourcière et al (2006) conducted a multi-centre, 14-week study of telmisartan and ramipril in patients (n=812) with mildto-moderate hypertension using ABPM. Patients were randomised to titrated doses of telmisartan 40mg/80mg/80mg or ramipril 2.5mg/5mg/10mg once daily in the morning.

The primary endpoint was the efficacy of both drugs on mean ambulatory DBP and SBP during the last six hours of a 24‐hour dosing interval was evaluated. Secondary efficacy variables were changes from baseline in BP control during each of the 24‐hour periods and in‐clinic trough cuff BP. Telmisartan 80mg was superior to ramipril 5mg and 10mg in change from baseline in the last six-hour ABPM mean DBP and SBP at both eight and 14 weeks, respectively. At 14 weeks, the adjusted mean change from baseline in DBP for telmisartan 80mg was -8.8mmHg compared with that for ramipril 10mg of ‐5.4mmHg. For SBP, the adjusted mean change from baseline for telmisartan 80mg was ‐12.7mmHg compared with that for ramipril 10mg of ‐7.9mmHg. At 14 weeks, telmisartan 80mg also yielded superior reductions from baseline in trough cuff BP compared with ramipril 10mg (diastolic BP: ‐11.0mmHg v ‐7.8mmHg, respectively, systolic BP: ‐14.3mmHg v ‐9.1mmHg, respectively.

Measures of 24‐hour BP control favoured telmisartan 80mg versus ramipril 10mg, as did other secondary ABPM endpoints during the daytime, night‐time and morning periods.

Hermida et al (2007) investigated the possibility of converting non-dippers to dippers using telmisartan administered at night.

Telmisartan has the largest terminal half-life

(about 24 hours) compared to other angiotensin receptor blockers.

Patients with hypertension (n=125) were randomly assigned to receive telmisartan (80mg/d) as a monotherapy either on awakening or at bedtime. BP was measured for 48 hours before and after 12 weeks of treatment. Significant BP reduction after treatment was similar for both groups.

Bedtime administration of telmisartan, however, was more efficient than morning dosing in reducing the nocturnal BP mean.

The sleep time-relative BP decline was slightly reduced after telmisartan on awakening but significantly increased with bedtime dosing, thus reducing the prevalence of non-dipping from baseline by 76%.

The authors concluded that telmisartan administered at bedtime, as opposed to morning dosing, improved the sleep timerelative BP decline toward a more dipper pattern without loss in 24-hour efficacy.

Nocturnal BP regulation is significantly better achieved with bedtime dosing of telmisartan. These results should be considered when prescribing this class of antihypertensive medication for treatment of essential hypertension.

Goss et al (2014) A retrospective pooled analysis of the Prospective, Randomized Investigation of the Safety and Efficacy of MICARDIS vs Ramipril Using ABPM studies conducted in Europe and South Africa (PRISMA I) and in the United States and Canada (PRISMA II) was carried out to investigate the effects of telmisartan and ramipril on dipper status (extreme dippers, dippers, non-dippers, risers/reverse dippers), and BP variability in 1279 patients (with normal sleeping patterns and valid 24-hour ambulatory BP monitoring recordings at baseline and end point). After 14 weeks’ treatment, telmisartan had a greater SBP reduction and higher smoothness index in all four dipper groups compared with ramipril.

In addition, the tendency toward dipping was significantly higher in patients treated with telmisartan than ramipril. In patients with an early morning SBP surge >35mmHg, telmisartan treatment was associated with significantly greater reductions from baseline in the night-time low mean, early morning mean and early morning SBP surge compared with ramipril (P=0.026, P<0.0001 and P=0.0006, respectively).

The authors concluded that in this retrospective analysis, telmisartan was shown to normalise the circadian BP pattern to a dipper profile in a larger proportion of patients than ramipril and reduce early-morning SBP surge in high-risk patients, indicative of a cardioprotective effect.

References available on request. SF

BISOPROLOL: • HIGHLY SELECTIVE ß-BLOCKER • 24 HOUR BP REDUCTION • DOSING FLEXIBILITY

For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Fax +27 21 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za BILOCOR 5, 10. Each tablet contains 5, 10 mg bisoprolol fumarate respectively. S3 A38/5.2/0053, 0051. NAM NS2 06/5.2/0061, 0062. For full prescribing information, refer to the professional information approved by SAHPRA, 23 July 2010. BILOCOR CO 2,5/6,25, 5/6,25, 10/6,25. Each tablet contains 2,5, 5, 10 mg bisoprolol fumarate respectively and 6,25 mg hydrochlorothiazide. S3 A44/7.1.3/1010, 1011, 1012. NAM NS2 13/7.1.3/0260, 0261, 0262. For full prescribing information, refer to the professional information approved by SAHPRA, 6 May 2019. BRH560/05/2020.

24

SF | ENT

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Photo credit: Shutterstock.com

This article was independently sourced by Specialist Forum.

Pollen counts

33% of

the wor ld populati ’s o suf fers f n rom allergies The University of Cape Town’s lung institute has warned that South Africans can expect higher levels of allergic rhinitis (AR) or hay fever this summer. According to the institute’s latest report, high levels are predicted for Johannesburg, Pretoria, and Bloemfontein. Tree pollen seems to be the main culprit.1

A

bout 33% of the world’s population suffers from allergies. AR is one of the most common diseases in adults. 2,5 Allergy experts warn that the prevalence of pollen allergies may rise exponentially in future as a result of climate change. 2,4 Three main factors related to climate change fuel increases in allergens. Carbon dioxide, the heat-trapping gas that is the primary cause of our warming planet, increases the growth rate

of many plants and increases the amount and potency of pollen.4 Rising temperatures extend the growing season and the duration of allergy season. And an extended spring season alters the amounts of blooms and fungal spores that are known to exacerbate allergy symptoms.4 Carbon dioxide is among the four fundamentals needed for plant growth. The others include water, nutrients and light. Carbon dioxide is so good at producing extra nutrients

for some plants, including ones like ragweed that are most problematic for hay fever, that even a small increase will have a big effect.4 Left unchecked, rising carbon dioxide levels and further warming pose serious risks for allergy sufferers. While some further warming over the next few decades is locked in, swift and deep reductions in heat-trapping emissions will benefit not only allergy sufferers, but all who are impacted by a changing climate. 4

Once-daily relief of Allergic Rhinitis and CIU* Triple the stopping power ANTIHISTAMINIC (EARLY)3 Strong peripheral H1-receptor blocking1

ANTI-ALLERGIC3 Inhibits the mast-cell release of acute inflammatory mediators1,2

ANTI-INFLAMMATORY (LATE)3 Inhibits the release of chronic inflammatory mediators1,2

Indicated in adults, adolescents and children over the age of 2 years for the relief of: Itchy, watery, red eyes

Itchy ears

Congestion, stuffiness, sneezing and runny, itchy nose

Allergic cough, itchy throat

Skin itch, hives

* Chronic Idiopathic Urticaria

ONLY DESLORATADINE HAS UP TO 27-HOUR HALF-LIFE2 References: 1. Villa E, Rogkakou A, Garelli V, et al. Review of desloratadine data using the ARIA Guidelines. World Allergy Organ J. 2012;5(S1): 6-13.

2. Bousquet J, Bindslev-Jensen C, Canonica GW, et al. The ARIA/EAACI criteria for antihistamines: an assessment of the efficacy, safety and pharmacology of desloratadine.

Allergy. 2004;59(S77): 4-16. 3. Deselex® Syrup and tablets [professional information]. Isando: Bayer; 2013.

S2 NeoClarityne Tablets: 5.0 mg desloratadine – 35/5.7.1/0208 S2 NeoClarityne Syrup: 2.5 mg desloratadine – 37/5.7.1/0226 The safety and efficacy of NeoClarityne® in children under the age of 2 years has not been established. For full prescribing information refer to the approved professional information.

Bayer (Pty) Ltd. 27 Wrench Road, Isando, 1600, Gauteng, South Africa. Tel: +27 11 921 5000 Co. Reg. No. 1968/011192/07 L.ZA.MKT.02.2020.3471

26

SF | ENT

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

South Africa’s allergy season typically starts with trees pollinating from August until October, however, grass pollen then takes over with its greatest peak from November to March.

What is allergic rhinitis and what are the symptoms?

AR is an inflammatory, immunoglobulin E- (IgE) mediated disease. IgE are antibodies produced by the immune system. These antibodies travel to cells that release chemicals, causing an allergic reaction. This reaction usually causes symptoms in the skin, gut and respiratory tract – all major sites of parasitic invasion. 3 AR can also be defined as inflammation of the inside lining of the nose that occurs when a person inhales something, he or she is allergic to, such as animal dander or pollen. 5 According to the World Allergy Organization it is hypothesised that IgE evolved as a defence mechanism against parasitic infestation.

Helminths stimulate a vigorous IgE production, including a parasite-specific IgE antibody. 3 However, another hypothesis for the beneficial function of IgE antibodies is that they have an important gate keeper function (early

recognition of foreign material) or a general potentiation of the immune system response by improved antigen presentation. 3 Furthermore, allergies triggered by IgE potentially provide a beneficial function to the host. Allergic reactions are all mechanisms that expel allergenic proteins from the body. Allergic reaction seen in AR include nasal congestion, rhinorrhoea (nasal drainage), sneezing, and/or nasal itching. Sneezing for example help expel allergenic proteins. 3,5

Allergic rhinitis classification AR can be classified by:5 » The temporal pattern of exposure to a triggering allergen eg seasonal (pollens), perennial/year-round (eg dust mites), or episodic (environmental from exposures not normally encountered in the patient’s environment, eg visiting a home with pets) » Frequency of symptoms » Severity of symptoms.

Otolaryngology AR guideline. The guideline was recently endorsed (2020) by the American Academy of Family Physicians. 5 Key recommendations: Clinicians should make the clinical diagnosis of AR when patients present with a history and physical examination consistent with an allergic cause and one or more of the following symptoms: » Nasal congestion » Runny nose » Itchy nose » Sneezing.

Findings of AR consistent with an allergic cause include, but are not limited to, clear rhinorrhoea, nasal congestion, pale discoloration of the nasal mucosa, and red and watery eyes Clinicians should perform and interpret, or refer to a clinician who can perform and interpret, specific IgE (skin or blood) allergy testing for patients with a clinical

1

2

Classifying AR in this manner may assist in choosing the most appropriate treatment strategies for an individual patient, according the authors of the 2015 American Academy of

Table 1: Recommendations for IgE-specific tests 5 Test

Recommendation Advantages

Skin tests (skin prick or intradermal)

Recommended

Disadvantages

Allows for direct observation Possible systemic of the body’s reaction to a allergic reaction specific antigen (anaphylaxis) Considered more sensitive than blood testing

Maybe affected by patient’s medication

Intradermal can be used when additional sensitivity is required or skin prick negative

3 4

Less expensive than blood testing Blood

Recommended

No risk of anaphylaxis Not affected by patient’s medication Can be used for patients with skin conditions such as dermatographism and severe eczema

Requires reliable laboratory Potential for laboratory errors

5 6

Can be used for patients on beta blockers or with comorbid medical conditions that preclude skin testing IgG or total IgE

Recommended against

Other nonspecific No tests eg acoustic recommendations rhinometry, for or against olfactory testing, microarray testing, nasal nitric oxide measurements, nasal allergen challenges

Does not yield information helpful for the management of AR

7

8 9

diagnosis of AR who do not respond to empiric treatment, or when the diagnosis is uncertain, or when knowledge of the specific causative allergen is needed to target therapy. See table 1 for the advantages and disadvantages of different tests Clinicians should not routinely perform sinonasal imaging in patients presenting with symptoms consistent with a diagnosis of AR Clinicians may advise avoidance of known allergens or may advise environmental controls (eg removal of pets, the use of air filtration systems, bed covers and acaricides [chemical agents that kill dust mites]) in AR patients who have identified allergens that correlate with clinical symptoms Clinicians should recommend intranasal steroids for patients with a diagnosis of AR whose symptoms affect their quality of life Clinicians should assess patients with a clinical diagnosis of AR for, and document in the medical record, the presence of associated conditions such as asthma, atopic dermatitis, sleepdisordered breathing, conjunctivitis, rhinosinusitis and otitis media Clinicians should recommend oral second-generation/less sedating antihistamines for patients with AR and primary complaints of sneezing and itching Clinicians may offer intranasal antihistamines for patients with seasonal, perennial, or episodic AR Clinicians should not offer oral leukotriene receptor antagonists as primary therapy for patients with AR

Sinus pain and congestion?

The range can be used by the whole family, from over 2 years of age.

SINUCLEAR syrup For the relief of symptoms such as nasal congestion, sniffing and headache associated with the common cold and influenza.

SINUCLEAR capsules For the temporary symptomatic relief of nasal, sinus and Eustachian tube mucal congestion and associated pain and fever due to colds and influenza

S2 SINUCLEAR (capsules) Reg. No.:27/5.8/0101. Each capsule contains phenylpropanolamine hydrochloride 18 mg and paracetamol 325 mg. S2 SINUCLEAR Paediatric Syrup. Reg. No.:30/5.8/0053. Each 5 ml contains Pseudoephedrine hydrochloride 15,000 mg, Triprolidine hydrochloride 0,625 mg and Paracetamol 125,000 mg. For full prescribing information refer to the professional information approved by the medicines regulatory authority (SINUCLEAR Capsules 01/1993. SINUCLEAR Syrup 09/2010). Trademarks are owned by or licensed to the Aspen Group of companies. Š 2019 Aspen Group of companies or its licensor. All rights reserved. Marketed by Aspen Pharmacare for Pharmacare Limited. Co. Reg. No.: 1898/000252/06. Healthcare Park, Woodlands Drive, Woodmead, 2191. ZAR-SGC-00003 10/19

Marketed by Aspen Pharmacare www.aspenpharma.com Medical Hotline 0800 118 088

SF | ENT

28

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Clinicians may offer combination pharmacologic 10 therapy in patients with AR who have inadequate

11

12 13 14

response to pharmacologic monotherapy Clinicians should offer, or refer to a clinician who can offer, immunotherapy (sublingual or subcutaneous) for patients with AR who have inadequate response to symptoms with pharmacologic therapy with or without environmental controls Clinicians may offer, or refer to a surgeon who can offer, inferior turbinate reduction in patients with AR with nasal airway obstruction and enlarged inferior turbinates who have failed medical management Clinicians may offer acupuncture, or refer to a clinician who can offer acupuncture, for patients with AR who are interested in nonpharmacologic therapy No recommendation regarding the use of herbal therapy for patients with AR.

References 1. University of Cape Town. Pollen counts. Report Date: 4 September 2020. https://pollencount.co.za/ 2. Shade K-T, Conroy ME, Washburn N et al. Sialylation of immunoglobulin E is a determinant of allergic pathogenicity. Nature, 2020.

3. Portnoy J. IgE in Clinical Allergy and Allergy Diagnosis (2015). World Allergy Organization. https://www. worldallergy.org/educationand-programs/education/ allergic-disease-resourcecenter/professionals/ ige-in-clinical-allergyand-allergy-diagnosis.

4. Union of Concerned Scientists. A Changing Climate Worsens Allergy Symptoms. https://www. ucsusa.org/resources/ climate-change-worsensallergy-symptoms 5. Seidman MD, Gurgel R, Lin SY et al. Clinical Practice Guideline: Allergic Rhinitis. Otolaryngology– Head and Neck Surgery,

Photo credit: Shutterstock.com

2015. SF

Allergy e xperts warn th at the prev alence o f pollen a llergies ma rise exp onential y ly in future a s a resu lt of climate change

GUARD AGAINST ALLERGIES1

NOT YOUR REGULAR SALINE SPRAY. A nasal allergy spray which forms a Hydro Barrier1,2,3 • PROTECTS AGAINST ALLERGENS1 • CLEANSES THE NOSE1

SNEEZING

ITCHY

RUNNY NOSE

BLOCKED NOSE

SPEAK TO YOUR PHARMACIST ABOUT RUPANASE® References: 1. Rupanase Allergy Nasal Spray Package Insert. July 2016. 2. Ectoin® scientific information. [cited 2020 July 28]; Available from: http://www.ectoin.net/EN/wirkweise. 3. Eichel A et al. MetaAnalysis of the Efficacy of Ectoine Nasal Spray in Patients with Allergic Rhinoconjunctivitis. Journal of Allergy. 2014.

Proprietary name (and dosage form): Rupanase Allergy Nasal Spray. Classification: Medical Device. Name and business address of applicant: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07. 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For more information speak to your healthcare professional. Further information is available on request from iNova Pharmaceuticals. IN3736/20.

SF | ENT

30

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Photo credit: Shutterstock.com

This article was independently sourced by Specialist Forum.

Are antibiotics necessary in acute otitis media?

Acute otitis media (AOM) is one of the most common diseases in children.

About 60% of children under the age of three years have experienced at least one AOM episode and about 24% display three or more episodes. OM is a global problem and is found to be slightly more common in males than in females.

O

M is defined as an infection of the middle ear space. Infection of the middle ear can be viral, bacterial, or coinfection. The most common bacterial organisms causing OM are Streptococcus pneumoniae, followed by non-typeable Haemophilus influenzae, and Moraxella catarrhalis.

Following the introduction of the conjugate pneumococcal vaccines, the pneumococcal organisms have evolved to non-vaccine serotypes. The most common viral pathogens of OM include the respiratory syncytial virus, coronaviruses, influenza viruses, adenoviruses, human metapneumovirus and picornaviruses.

Signs and symptoms Although one of the best indicators for OM is otalgia, many children with OM can present with non-specific signs and symptoms, which can make diagnosis challenging. These symptoms include pulling or tugging at the ears, irritability, headache, disturbed or restless sleep, poor feeding, anorexia, vomiting or diarrhoea. About 66% of the patients present with fever, which is typically low grade.

According to the American Academy of Pediatrics (AAP) guidelines, evidence of moderate to severe bulging of the tympanic membrane, or new onset of otorrhea not caused by otitis externa or mild tympanic membrane (TM) bulging with recent onset of ear pain or erythema is required for the diagnosis of AOM. These criteria are intended only to aid primary care clinicians in the diagnosis and proper clinical decision making but not to replace clinical judgment.

Risk factors

Diagnosis

Several risk factors can predispose children to develop AOM. The most common risk factor is a preceding upper respiratory tract infection.

Other risk factors include male gender, adenoid hypertrophy (obstructing), allergy, day-care attendance, environmental smoke exposure, pacifier use, immunodeficiency, gastroesophageal reflux, parental history of recurrent childhood OM, and other genetic predispositions.

OM is diagnosed clinically via objective findings on physical exam (otoscopy) combined with the patient’s history and presenting signs and symptoms. Several diagnostic tools are available such as a pneumatic otoscope, tympanometry and acoustic reflectometry to aid in the diagnosis of OM. Pneumatic otoscopy is the most reliable and has a higher sensitivity and specificity as compared to plain otoscopy, though tympanometry and other modalities can facilitate diagnosis if pneumatic otoscopy is unavailable.

Histopathology Histopathology varies according to disease severity. Acute purulent OM (APOM) is characterised by oedema and hyperaemia of the subepithelial space, which is followed by the infiltration of polymorphonuclear (PMN) leukocytes. As the inflammatory process progresses, there is mucosal metaplasia and formation of granulation tissue. After five days, the epithelium changes from flat cuboidal to pseudostratified columnar with the presence of goblet cells.

In serious acute OM (SAOM), inflammation of the middle ear and the eustachian tube has been identified as the major precipitating factor. Venous or lymphatic stasis in the nasopharynx or the eustachian tube plays a vital role in the pathogenesis of AOM. Inflammatory cytokines attract plasma cells, leukocytes and macrophages to the site of inflammation. The epithelium changes to pseudostratified, columnar or cuboidal. Hyperplasia of basal cells results in an increased number of goblet cells in the new epithelium.

Aetiology OM is a multifactorial disease. Infectious, allergic, and environmental factors contribute to OM. Causes and risk factors include: » Decreased immunity due to human immunodeficiency virus (HIV), diabetes, and other immuno-deficiencies » Genetic predisposition » Mucins which include abnormalities of this gene expression, especially upregulation of mucin 5B, oligomeric mucus/gel-forming (MUC5B) » Anatomic abnormalities of the palate and tensor veli palatini » Ciliary dysfunction » Cochlear implants » Vitamin A deficiency » Bacterial pathogens, streptococcus pneumoniae, haemophilus influenza, and Moraxella (Branhamella) catarrhalis, are responsible for more than 95%

SF | ENT

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

» Viral pathogens such as respiratory syncytial virus, influenza virus, parainfluenza virus, rhinovirus and adenovirus » Allergies » Lack of breastfeeding » Passive smoke exposure » Day-care attendance » Lower socioeconomic status » Family history of recurrent AOM in parents or siblings.

Pathophysiology OM begins as an inflammatory process following a viral upper respiratory tract infection involving the mucosa of the nose, nasopharynx, middle ear mucosa and Eustachian tubes.

Due to the constricted anatomical space of the middle ear, the oedema caused by the inflammatory process obstructs the narrowest part of the Eustachian tube leading to a decrease in ventilation.

This leads to a cascade of events resulting in an increase in negative pressure in the middle ear increasing exudate from the inflamed mucosa and build-up of mucosal secretions, which allows for the colonisation of bacterial and viral organisms in the middle ear.

The growth of these microbes in the middle ear then leads to suppuration and eventually frank purulence in the middle ear space. This is demonstrated clinically by a bulging or erythematous tympanic membrane and purulent middle ear fluid. This must be differentiated from chronic serous OM (CSOM) which presents with thick, amber-coloured fluid in the middle ear space and a retracted tympanic membrane on otoscopic examination.

Both will yield decreased TM mobility on tympanometry or pneumatic otoscopy.

Management Once the diagnosis of AOM is established, the goal of treatment is to control pain and to treat the infectious process with antibiotics.

Non-steroidal anti-inflammatory drugs such as acetaminophen, can be used to achieve pain control.

AOM is one of the most frequent reasons for antibiotic prescription in children, accounting for up to 25% of the total number. Treatment of OM with antibiotics is controversial, and directly related to the subtype of OM in question. Without proper treatment, suppurative fluid from the middle ear can extend to the adjacent anatomical locations and result in complications such as tympanic membrane perforation, mastoiditis, labyrinthitis, petrositis, meningitis, brain abscess, hearing loss, lateral and cavernous sinus thrombosis and others.

In the United States, the mainstay of treatment of an established diagnosis of AOM

is high dose amoxicillin, and this has been found to be most effective in children under two years of age.

Treatment in countries like the Netherlands is initially watchful waiting, and if unresolved, antibiotics are warranted. However, the concept of watchful waiting has not gained full acceptance in the United States and other countries due to the risk of prolonged middle ear fluid and its effect on hearing and speech, as well as the risks of complications.

The AAP recommends that if there is clinical evidence of SAOM, oral antibiotics are indicated to treat bacterial infection, and high-dose amoxicillin or a second-generation cephalosporin are first-line agents. If there is a TM perforation, treatment should proceed with ototopical antibiotics safe for middle-ear use such as ofloxacin (not approved in South Africa), rather than systemic antibiotics, as this delivers much higher concentrations of antibiosis without any systemic side-effects.

When a bacterial aetiology is suspected, the antibiotic of choice is high-dose amoxicillin for ten days in both children and adult patients who are not allergic to penicillin. Amoxicillin has good efficacy in the treatment of OM due to its high concentration in the middle ear.

In cases of penicillin allergy, the AAP recommends azithromycin as a single dose of 10mg/kg or clarithromycin (15mg/kg per day in two divided doses). Other options for penicillinallergic patients are cefdinir (14mg/kg per day in one or two doses), cefpodoxime (10mg/kg per day, once daily), or cefuroxime (30mg/kg per day in two divided doses).

Those patients whose symptoms do not improve after treatment with high dose amoxicillin, high-dose amoxicillin-clavulanate (90mg/kg per day of amoxicillin component, with 6.4mg/kg per day of clavulanate in two divided doses) should be given.

In children who are vomiting or if there are situations in which oral antibiotics cannot be administered, ceftriaxone (50 mg/kg per day) for three consecutive days either intravenously or intramuscularly is an alternative option.

Systemic steroids and antihistamine have not been shown to have any significant benefit.

Patients who have experienced four or more episodes of AOM in the past twelve months should be considered candidates for myringotomy with tube (grommet) placement, according to the AAP guidelines.

Recurrent infections requiring antibiotics is clinical evidence of Eustachian tube dysfunction, and placement of the tympanostomy tube allows ventilation of the middle ear space and maintenance of normal hearing. Furthermore, should the patient acquire OM while a functioning tube is in place, they can be treated with ototopical antibiotic drops rather than systemic antibiotics.

The 2015 South African guideline recommends that antibiotics may be deferred for 48 hours while symptomatic therapy is administered, except for AOM cases associated with a bulging tympanum and a temperature of >38°C. Although controversial, write the authors, immediate treatment is warranted.

In addition, if symptoms persist or worsen, antibiotics should be started. A useful approach is to provide a prescription to be filled only if no improvement by 48 hours. This approach is reasonable where good follow-up is possible in children ≥2 years of age.

However, in patients with limited access to healthcare and because of the risks of a serious infection with S. pneumoniae and/ or H. influenzae, the authors recommend that treatment commence from the first visit, provided the AOM is correctly diagnosed.

Antibiotics should be considered especially in the following cases: » Recurrent AOM

» Immunocompromised patients » Neonates » Structural ear, nose, throat or immunological abnormalities

» Fever (temperature >38°C) » Pain >48 hours » Day-care attendees or siblings of children attending day-care centres.

Prognosis The prognosis for most of the patients with OM is excellent. Mortality from AOM is a rare occurrence in modern times. Due to better access to healthcare in developed countries, early diagnosis and treatment have resulted in a better prognosis of this disease. Effective antibiotic therapy is the mainstay of treatment.

Multiple prognostic factors affect the disease course. Children presenting with less than three episodes of AOM are three times more likely to have their symptoms resolved with a single course of antibiotics as compared to children who develop this condition in seasons apart from winter.

Children who develop complications can be difficult to treat and tend to have high rates of recurrence. Intratemporal and intracranial complications, while very rare, have significant mortality rates.

References Brink AJ, Cotton MF, Feldman H et al. Updated recommendations for the management of upper respiratory tract infections in South Africa. SAMJ, 2015.

Chiappini E and Marchisio P. Updated Guidelines for the Management of Acute Otitis Media in Children by the Italian Society of Paediatrics. The Paediatric Infectious Disease Journal, 2019.

Danishyar A and Ashurst JV. Acute Otitis Media.

StratPearls, 2020. https://www.ncbi.nlm.nih.gov/ books/NBK470332/ SF

31

SF | CPD: PSYCHIATRY

32

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Anosognosia a major challenge in schizophrenia

This article was independently sourced by Specialist Forum.

Anosognosia or poor insight is a cardinal symptom of schizophrenia. Between 57% to 98% of patients are affected. In essence anosognosia is a lack of awareness that you have a specific disease or illness. Other elements of anosognosia include inability to recognise signs and symptoms, consequences, deficits and understanding the need for treatment of a disease or illness.1

A

study by Warman et al found that patients suffering from delusions tend to be overly confident in their own judgment compared to those without delusions and healthy controls. However, their self-reflectiveness is the same as normal controls. Individuals without delusions reported low self-reflectiveness relative to healthy controls and individuals with delusions, though they were not overconfident in their judgment. 2 Several theories have been put forward to explain poor insight in psychotic patients: 1 » Clinical model: Postulates that insight is a primary symptom attributable to the psychotic process » The psychological denial model: Postulates that poor insight is a coping mechanism to preserve emotional well-being by protecting against distress » The neuropsychological model: Contends that poor insight is caused by inadequate neurocognition caused by brain deficits.

How anosognosia is measured According to Beck et al, there are four aspects of cognitive insight, defined as the ability to detect and correct misinterpretations, that can be disrupted in psychosis:3 Impairment of ability to be objective about delusional experiences and cognitive distortions Reduced capacity to put these experiences into perspective Unresponsiveness to corrective information from others Overconfidence in delusional judgments.

This led to the development of the Beck Cognitive Insight Scale (BCIS), a self-report questionnaire that measure self-reflectiveness and selfcertainty. Self-reflectiveness includes statements measuring objectivity, reflectiveness, and openness to feedback. The latter measures the certainty of one’s beliefs and judgments.3 The aim of these statements is to capture patients’ recognition that they could be wrong even when they felt strongly that they were right (#8), that other people could be

1

they were willing to consider other people pointing out that their beliefs were wrong (#12). Additional statements evaluate patients’ acceptance of the notion of alternative explanations (#14), receptiveness to feedback (items #12), being able to make more adaptive attributions (#5, #15), and being able to admit to inadequate cognitive strategies (#4). 3 Perspective is based on the recognition that patients had misconstrued peoples’ attitudes towards themselves (#1), that they had jumped to conclusions too fast (#4), that certain experiences that had seemed real were due to

their imagination (#5), that some of the ideas he or she believed to be true were false, and that some of their unusual experiences were due to their being upset or stressed (#15). 3 The second set of statements (self-certainty) in the BCIS addresses decision-making regarding jumping to conclusions, certainty about being right, and resistance to correction.

These statements address a patient’s certainty about his or her beliefs and conclusions, such as doing something if it feels right (#7), dogmatic rightness (#2, #13), and resistance to feedback from others (#9, #10, #11). 3

Table 1: The Beck Cognitive Insight Scale Below is a list of sentences about how people think and feel. Please read each sentence in the list carefully. Indicate how much you agree with each statement by placing an X in the corresponding space in the column next to each statement.3 Statement

0 1 2 3 (Do not (Agree (Agree (Agree agree at all) slightly) a lot) completely)

1. At times, I have misunderstood other people’s attitudes towards me 2. My interpretations of my experiences are definitely right 3. Other people can understand the cause of my unusual experiences better than I can 4. I have jumped to conclusions too fast 5. Some of my experiences that have seemed very real may have been due to my imagination 6. Some of the ideas I was certain were true turned out to be false.

7. If something feels right, it means that it is right 8. Even though I feel strongly that I am right, I could be wrong

2

9. I know better than anyone else what my problems are

3

11. I cannot trust other people’s opinion about my experiences

4

more objective (#3) than they were, and that

10. When people disagree with me, they are generally wrong 12. If somebody points out that my beliefs are wrong, I am willing to consider it 13. I can trust my own judgment at all times 14. There is often more than one possible explanation for why people act the way they do 15. My unusual experiences may be due to my being extremely upset or stressed Self-reflectiveness score Minus (-) Self-certainty score Equals (=) Composite cognitive insight index score * Notes: *Beck et al derived a composite cognitive insight index score by subtracting the self-certainty score from the self-reflectiveness score. A high score on the self-reflective subscale and low score on the self-certainty subscale are regarded as being normal.

SF | CPD: PSYCHIATRY

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Consequences of anosognosia Anosognosia has been linked to poor outcomes in multiple ways. The negative influence of poor insight has been demonstrated in relation to quality of life, rehospitalisation, poor outcome of psychosis and poor treatment adherence.

Numerous studies have shown that nonadherence to treatment range from 26.5% to 58.8%. 2,4

This article was independently sourced by Specialist Forum.

Psychoeducation of families, improvement in insight and amelioration of cognitive impairments are some of the interventions that have been proposed to improve anosognosia.4 Since insight is a factor which needs explanations based on cultural aspects, it is imperative to develop culturally validated and acceptable forms of treatment.4 A meta-analysis reviewing the impact

of various treatments on insight found that cognitive behavioural therapy (CBT), adherence therapy, and psychoeducation have small-tomoderate effects on insight.1 Social skills training and video selfobservation may be beneficial in treating insight, found the authors, but noted that more evidence is needed to evaluate the efficacy of these treatments.1

Table 2: British Association for Psychopharmacology treatment recommendations (2019)5 Phase

Recommendations

First-episode psychosis

Where the diagnosis of psychotic disorder is suspected in primary care, patients should be referred to secondary services as soon as practicable, with a delay of no more than a week if possible The initial assessment in secondary care should include appropriate history, mental state and physical examinations, and consideration of psychiatric and physical comorbidity The initial assessment should seek to exclude alternative diagnoses and this may include clinical appraisal of the initial course of psychosis without antipsychotic treatment for around two weeks in order to exclude acute/transient psychotic disorders or substance-induced psychotic disorders. This strategy should only be employed when risks such as aggression, self-harm, self-neglect, vulnerability, or deterioration can be appropriately monitored and mitigated. In that case, gamma-aminobutyric acid modulating drugs such as benzodiazepines may be prescribed for anxiety or insomnia for up to two weeks before being tapered off Pre-treatment investigations should include electrolytes, liver function tests and an electrocardiogram (ECG) to exclude congenital conduction abnormalities and the presence of a suspect Brugada syndrome. Ideally, these investigations should be performed before the first prescription. Where this is not possible, consideration should be given to the choice of antipsychotic medications identified in relevant meta-analyses as less arrhythmogenic, for example with a relatively low affinity for human ether-a-go-go-related gene potassium channels and a low propensity to lengthen the QTc interval. Blood pressure, prolactin, lipids, and blood glucose are important but less time-sensitive, though best assessed before first prescription to exclude any abnormality and allow assessment of any subsequent change due to potential adverse effects. Full neurological examination is required in the absence of neuroimaging (computed tomography or structural magnetic resonance imaging) and of N-Methyl-d-aspartic acid receptor autoantibody assays. Thyroid function tests are also mandatory Secondary care multidisciplinary teams should make a psychiatric diagnosis but be prepared to revise it In circumstances other than an initial assessment of the course of illness for up to two weeks, to exclude transient or substance-induced psychotic disorders (in the absence of continued substance use), definitive treatment should begin as soon as possible in view of the appreciable risks of harm or deterioration that have been identified in this group. Where possible, antipsychotic medication should be selected for individual patients on the basis of likely adverse effects. Doses should in most circumstances be sufficiently low to minimise adverse effects, with effective doses often below conventional lower dose thresholds

Treatment delay and refusal

For patients accepting only psychological treatment interventions, efforts should be made to persuade them to agree to a trial of antipsychotic medication.

The effectiveness of treatment using psychological interventions in the absence of antipsychotic medication is uncertain and the risks of no treatment at all appear substantial It may be appropriate to detain patients for compulsory assessment of the response to medication in those circumstances where there are evident risks of immediate physical, interpersonal or social harm, but otherwise the risk of a poor response of psychotic or negative symptoms related purely to delayed pharmacological treatment is not predictable on an individual basis, so it may be appropriate rather to engage the patient in psychological treatment and monitor their progress When patients decline assessment and treatment despite efforts at engagement, given the risks of untreated illness it may be necessary to detain them to enable assessment and treatment

Initial treatment Antipsychotic medication is the first line of treatment for psychosis. Initial doses should be below those typical in established illness but sufficient for with antipsychotic efficacy, as demonstrated in studies of first-episode patients medication Differences in efficacy (rather than effectiveness) of antipsychotic medications are not well evidenced in first episodes of schizophrenia, though some agents (eg olanzapine, amisulpride, risperidone) might perform slightly better than others. Differences in adverse effects may well drive much of the observed differences in discontinuation. The adverse effect profile, including liability for sedation and adverse metabolic effects, should thus largely determine the choice of antipsychotic medication, in collaboration with the patient as far as possible Where there is risk, or distress, due to excitement, severe anxiety, hostility or insomnia, benzodiazepine or antihistamine drugs may be appropriate adjunctive agents Targets and trials of antipsychotic treatment

Trials of antipsychotic efficacy should be monitored using comprehensive symptom assessment scales. Assessments should if possible be made at baseline and the end of a pre-determined trial period (usually two weeks initially). Trials of an initial dose may need to last only two weeks. Total trial length for an agent at up to the maximum dose may be around six weeks Sufficient response to initial treatment may be defined as a reduction of 25% in total score (eg within two weeks) on a symptom assessment scale. A 40%– 50% reduction or two clinical global impression scale points indicates a definitive response (eg after six weeks). Remission of symptoms is an appropriate target for overall treatment of the initial episode Where an antipsychotic medication has failed to achieve a satisfactory response after six weeks, or remission in conjunction with other interventions over a longer period, it is appropriate to switch to another antipsychotic agent and repeat the trial process. Since the evaluation of the impact of adjunctive psychological treatments may require six months or more, it may require months to determine that remission cannot be achieved

Maintenance treatment and discontinuation

After remission has been achieved, maintenance treatment with antipsychotic medication at a standard dose will substantially reduce the risk of relapse for at least two years and is likely to be appropriate Patients should be offered the option of depot/long-acting injectable (LAI) antipsychotic medication for maintenance treatment, given the evidence of lower risk of relapse Where remission has been maintained for more than two years after a single episode, whether medication should be continued or withdrawn should be reviewed, unless low-grade psychotic symptoms indicate that the psychotic process is not fully abated Decisions about the duration of maintenance treatment should be made jointly by the clinician and patient, considering the pros and cons of withdrawal versus continuing medication, including risk of relapse and medication side effects. The nature of the index episode (including speed of onset, insight, severity, and risk) can be helpful in assessing the risks associated with any future relapse

33

34

SF | CPD: PSYCHIATRY

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Clozapine for first-episode psychosis

Where a patient’s illness meets criteria for treatment-refractory psychotic or disorganisation symptoms despite adequate trials of two antipsychotic medications, provision of family intervention and CBTp (where available), and review of diagnosis and medication adherence, a trial of clozapine should be considered. This point should be achievable within one to three years of initiating treatment

Acute psychotic episode

Choice of antipsychotic drug should be based on the same criteria as suggested for first episode, but should additionally consider: ñ Any preference a patient may have for any particular antipsychotic medication ñ A patient’s past experience of individual antipsychotic medications in terms of relief of symptoms and side effects, including aversive subjective experiences Seek to conduct an adequate trial of the chosen antipsychotic medication in terms of dosage, duration (up to four weeks at optimum dosage) and medication adherence Antipsychotic dosage should be titrated against side effects and efficacy If starting an antipsychotic medication that the person has not previously been prescribed, the initial dosage should be at the lower end of the licensed range and slowly titrated upwards, if indicated, to the optimal range for that drug, and not exceeding the maximum licensed dose The initial antipsychotic dosage regimen, including the speed of titration, should be consistent with the recommendations The justification for prescribed antipsychotic dosages outside the range should be documented in the clinical records Regular combined antipsychotic medication should not be prescribed routinely, except for short periods when switching from one antipsychotic medication to another

Medication regimen

Antimuscarinic agents should not be generally prescribed prophylactically with antipsychotic medication, but rather their use for emergent extrapyramidal problems responsive to such medication (eg parkinsonism and acute dystonia) should be determined on an individual basis, taking account of factors such as a patient’s history of extrapyramidal side effects and the risk of antimuscarinic side effects The potential impact of comorbid substance use on the therapeutic efficacy and side-effect risk of antipsychotic medication should be considered. This should be discussed with patients and carers as appropriate Regular review of a patient’s antipsychotic medication regimen should address the following: ñ Therapeutic efficacy, in terms of change in clinical domains such as symptoms, behaviour and cognition ñ Side effects of treatment ñ Medication adherence ñ Physical health

Recommendations Established schizophrenia requires continued maintenance with doses of antipsychotic medication within the licensed range. Choice of antipsychotic medication for maintaining should follow the respective recommendation for first-episode schizophrenia, but for each individual patient the following should also be taken into consideration: response ñ Prior treatment response ñ Experience of side effects ñ Level of medication adherence ñ Comorbid physical illness As with acute treatment, each prescription of a maintenance antipsychotic medication should be an individual trial An oral antipsychotic medication regimen should be kept as simple as possible with respect to both the number of tablets to be taken and the number of times each day Before considering a switch in antipsychotic medication, the current antipsychotic medication should be optimised, and an adequate trial conducted in terms of dosage, duration and adherence The care plan should address remediable risk factors for relapse, such as comorbid substance use, poor adherence, and a critical environment Any reduction in dosage of antipsychotic medication should be cautious and closely monitored, given the increased risk of relapse An intermittent, targeted treatment approach with antipsychotic medication should generally be avoided LAI antipsychotic formulations should be considered where the need to monitor medication adherence is a priority within the care plan or if the patient prefers the convenience of this approach (see box 1) Wherever possible, the prescriber should agree jointly with the patient on the choice of, and desired outcomes from pharmacological treatment and how these can be achieved The effectiveness of medication should be monitored and any identified side effects should be actively managed as appropriate

LAI antipsychotic preparations11 According to the authors of the British guideline several studies have found that treatment with LAI antipsychotic preparation outperform oral antipsychotic medication in preventing rehospitalisation, improving adherence and management.

A meta-analysis of cohort studies found that treatment with LAI antipsychotic preparations was associated with a reduction in hospitalisations of 15% compared with oral antipsychotic medication, despite greater illness severity in those patients receiving the LAI preparations.

The key advantage of depot/LAI antipsychotic medications in clinical practice is improved adherence. A lack of adherence to such a regimen (through failure to accept the injection) will be immediately evident to the

clinical team, allowing them the opportunity to take appropriate, prompt action.

Furthermore, if administration has been documented there is the potential to clarify whether a poor therapeutic response represents treatment refractoriness rather than poor medication adherence.

The potential benefits of LAI antipsychotic medication over oral preparations also include more consistent bioavailability, removal of the need to remember tablets, and regular contact with the clinical team administering the injection, allowing for regular assessment and follow-up.

The choice of LAI antipsychotic medication for a particular patient should take into account differences between these preparations in terms of their individual pharmacokinetic profiles as well as their pharmacological and side-effect profiles.

To comple te this mo nth’s C PD questio nnaire, please go t o www.m edicalac ademic.c o.za and na vigate t o t he C PD s of the w ection ebsite.

References Lehrer DS and Lorenz JL. Anosognosia in Schizophrenia: Hidden in Plain Sight. Innov Clin Neurosci, 2014.

Warman DM, Lysaker PH, Martin JM et al. Cognitive insight and psychotic disorder: the impact of active delusions.

Schizophr Res, 2007.

Beck AT, Baruch E, Balter JM et al. A new instrument for measuring insight: the Beck Cognitive Insight Scale.

Schizophrenia Research, 2004.

Joseph B, Narayanaswamy JC and Venkatasubramanian G. Insight in Schizophrenia: Relationship to Positive, Negative and Neurocognitive Dimensions. Indian J Psychol Med, 2015.

Barnes TRE, Drake R, Paton Carol et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology. British Journal of Pharmacology, 2019. SF

Make XEPLION your FIRST CHOICE for long-acting treatment. ®

Once-per-month XEPLION® is well placed to help patients achieve long-term treatment continuation together with the associated life benefits. 1, 2 References: 1. Taipale H, Mittendorfer–Rutz E, Alexanderson K, et al. Antipsychotics and mortality in nationwide cohort of 29 823 patiens with schizophrenia. Schizophrenia Research 2017. Available from: http://doi.org/10.1016/ jschres.2017.12.010. 2. Decuypere F, Serman J, Geerts P, et al. Treatment continuation of four long-acting antipsychotics medications in the Netherlands and Belgium: A retrospective database study. PLoS ONE 2017;12(6):e0179049. https://doi.org/10.1371/journal.pone.0179049.

S5 XEPLION® 50, 75, 100 or 150mg Prolonged release suspension for intramuscular injection. Each pre-filled syringe contains sterile paliperidone palmitate equivalent to 50, 75, 100 or 150mg of paliperidone respectively. Reg. Nos.:44/2.6.5/0866; 44/2.6.5/0867; 44/2.6.5/0868; 44/2.6.5/0870. JANSSEN PHARMACEUTICA (PTY) LTD, (Reg. No. 1980/011122/07), No 2, Medical Street, Halfway House, Midrand, 1685. www.janssen.com. Medical Info Line: 0860 11 11 17.

For full prescribing information refer to the latest package insert (May 2019).

CP-96966

SF | PSYCHIATRY

36

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Photo credit: Shutterstock.com

This article was independently sourced by Specialist Forum.

Summertime sadness

More than 800 000 people commit suicide every year, accounting for 1.5% of the total deaths in the world.

According to the World Health Organization (WHO) this equates to a life lost to suicide every 40 seconds.

Even more concerning is that the WHO estimates that, for every suicide, there are 20 attempted suicides.

S

uicide is a complex behaviour consisting of an interplay between many risks and protective factors impacting at individual, family, community and societal levels. Suicide varies with sex and agegroups across different countries and regions.

South Africa has one of the highest suicide rates in the world, according to the WHO. Kootbodien et al (2020) analysed trends in suicide mortality in South Africa from 1997 to 2016. The team found that when analysing mortality rates by sex and age, suicide rates were highest in South African men, aged 15 to 44 years, and women older than 75 years.

According to the WHO the link between suicide and mental disorders (in particular, depression and alcohol use disorders) is well established, but many suicides happen impulsively in moments of crisis.

Kootbodien et al found that in South Africa unemployment is an independent risk factor of suicide as it is associated with an increased risk of mental illness, vulnerability to stressful life conditions and often, can contribute towards a lack of social cohesion. In low- and middleincome countries, completed suicide has been associated with poverty, unemployment, and debt as well as low education levels.

The study also found that suicide deaths were more prevalent in December (11.7%) and January (9.2%). The lowest rates were recorded in winter (May to July), with a mean prevalence of 7.2%). This is consistent with the findings of a previous South African study (1997) that found suicide rates peak in the spring or summer, with a decline in winter.

Seasonal affective disorder South African born psychiatrist, Dr Norman Rosenthal, and colleagues are credited as being the first to describe seasonal affective disorder (SAD). Based on the findings of their study, Dr Rosenthal penned the book Winter Blues.

According to the Diagnostic and Statistical Manual of Mental Disorders DSM-5, the criteria for depression with a seasonal pattern or SAD,

include having depression that begins and ends during a specific season every year (with full remittance during other seasons) for at least two years, and having more seasons of depression than seasons without depression over a lifetime.

In an interview, Dr Rosenthal explains that besides the lack of environmental light, which is a major cause of winter SAD, there are two other leading causes, namely biological predisposition, and stress.

“People who are predisposed to developing SAD include those with family members with the condition, as well as other forms of depression.

In addition, gender is a factor. Women are about four times as likely to develop SAD as are men.

During the winter months, people with SAD are less able to handle stress than they are at other times of year. For example, having to get to work early in the morning, to work long hours or to meet deadlines are all particularly stressful for those with a tendency to develop SAD, especially when these stresses occur during the winter.”

Several theories have been suggested to explain why some people develop SAD. These include: Sluggish transmission in brain serotonin systems Insensitivity of the eyes to environmental light Abnormal circadian (daily) rhythms. Some people with SAD may have abnormalities in the genes responsible for serotonin transmission or for sensitivity of the retina to light (perhaps because of abnormalities in the retinal pigment called melanopsin).

1

2

3

But what about summer SAD? Dr Rosenthal and colleagues went on to identify a summer version of SAD. In summer, he explains, people become depressed as the days get longer and hotter.

“We still don’t know why the summer triggers depressions regularly in some people – perhaps it’s the intense heat or maybe too much light.

People with this type of depression often have symptoms that are different from those with winter-SAD (see table 1).

“They often lose appetite, sleep and weight, and are agitated rather than lethargic – all opposite to the typical symptoms of winter-SAD. In some ways summer-SAD is more dangerous than the winter version because those who suffer this malady are more likely to feel suicidal (which may go along with their feelings of agitation).”

People with bipolar disorder, he says, are at high risk of summer SAD. These patients tend to have problems with being over activated, irritable and angry in summer. Although many people think of mania as a state of excessive elation and exuberance – which may occur – that is often not the case. The agitation, restlessness and sleep loss that occur with hypomania often come along with a short fuse and a bad temper or suppressed anger.

Tonetti et al postulate that heat and humidity may play a role in increasing the risk for summer SAD. A study comparing individuals with SAD in Italy versus India found that there was a higher predominance of winter SAD in Italy and summer SAD in India. A possible explanation is that this may be due to higher summer temperatures in India compared with Italy.

An Australian study by Morrissey et al found a 9-fold higher incidence of summer SAD versus winter SAD in a tropical climate with heat and humidity described as the two most influential factors affecting mood and behaviour.

Table 1: Symptoms of winter vs summer SAD Winter SAD

Summer SAD

Increased appetite

Decreased appetite

Carbohydrate cravings

Weight loss

Weight gain

Insomnia

Hypersomnia

Psychomotor agitation

Psychomotor retardation

Social withdrawal

Social withdrawal Restlessness Irritability

Occasional violent behaviour

Loss of interest in activities

Loss of interest in activities

DULOXETINE HCI

HARMONY IN MENTAL HEALTH

STRONGER TOGETHER DUAL:

ACTION & CONTROL 1 FOR DEPRESSION & DPNP*

Dr. Reddy’s

HELPLINE 0800 21 22 23 www.sadag.co.za

Dr. Reddy’s

* Depression, as defined by DSM-IV Criteria; DPNP = Diabetic peripheral neuropathic pain Reference: 1. Yelate 30/60 package insert. Dr. Reddy’s Laboratories (Pty) Ltd. December 2012 S5 Yelate 30/60. Each capsule contains duloxetine hydrochloride equivalent to duloxetine 30/60 mg. Reg No’s 44/1.2/0114;0115. Dr. Reddy’s Laboratories (Pty) Ltd. Reg no. 2002/014163/07. 204 Rivonia Road, Block B, Morningside, Sandton. 2057. www.drreddys.co.za. ZA/01/2020-22/Yel/001 For full prescribing information refer to the package insert approved by the medicines regulatory authority.

N E U R O P S Y C H I AT R Y G O O D

H E A L T H

C A N ’ T

W A I T

38

SF | PSYCHIATRY

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

Table 2: Treatment recommendations Patient population

Treatment Recommendation/s

Adolescents

Initial treatment ñ Cognitive-behavioural therapy (CBT) ñ Interpersonal psychotherapy (IPT) for adolescents Fluoxetine as a first-line medication compared to other medications for adolescent patients with major depressive disorder (MDD), specifically when considering medication options If fluoxetine is not a treatment option or is not acceptable, the panel recommends shared decision-making regarding medication options with a child psychiatrist in addition to the clinician, patient, and their parents/guardians or family members actively involved in their care Because of safety concerns in this patient population, the authors recommend against using the following medications for adolescent patients with MDD: ñ Clomipramine ñ Imipramine ñ Mirtazapine ñ Paroxetine ñ Venlafaxine However, when other options are not available, effective, and or acceptable to the patient, the panel recommends shared decision-making between the patient and clinician If these medications are being considered, the panel recommends: ñ Paroxetine over clomipramine when both are being considered ñ Paroxetine over imipramine when both are being considered There was no information available for other comparisons between the listed medications

Adults

Treatment Initial treatment for MDD

For initial treatment of adult patients with depression, the panel recommends either psychotherapy or second-generation antidepressants If considering combined treatment, the panel recommends CBT or IPT, plus a second-generation antidepressant For adults with depression for whom psychotherapy or pharmacotherapy is either ineffective or unacceptable the panel suggests the following options: ñ Exercise monotherapy ñ St. John’s Wort monotherapy

Sub-clinical For adult patients with subclinical depression, the panel suggests that clinicians depression offer psychotherapy (psychotherapy in general including both CBT and non-CBT psychotherapies eg interpersonal counselling, problem-solving therapy, life-review therapy) Non- and For adult patients with depression who have either not responded or only partially partial responded to initial antidepressant medication treatment the panel recommends responders the following options: ñ Switch from antidepressant medication alone to cognitive therapy alone or ñ Switch from antidepressant medication alone to another antidepressant medication For adult patients with depression who have either not responded or only partially responded to initial antidepressant medication treatment the panel suggests that clinicians offer one of the following psychotherapies/interventions and select between treatments as follows: ñ Add psychotherapy (IPT, CBT, or psychodynamic therapy) to the antidepressant medication treatment ñ Augment with another antidepressant medication For adult patients with MDD who have either not responded or only partially responded to initial adequate second-generation antidepressant treatment attempt there is insufficient evidence to determine differences in treatment effect for the following: ñ Switching to another second-generation antidepressant ñ Switching to a nonpharmacologic (eg CBT monotherapy) ñ Augmenting with guided CBT self-help

Other research points to allergies as the culprit. Several studies have found that pollen is associated with an increase in depression and summer SAD typically starts in spring when pollen counts are rising. Another study showed that rising pollen counts were associated with summer SAD, but not with winter SAD, giving credence to the theory that allergies may play a role in summer SAD.

How is SAD treated?

Although it may be helpful to avoid heat (eg by staying in air-conditioned rooms) and too much light (eg wearing wrap-around dark glasses), the mainstay of treatment is starting antidepressant medications early and staying ahead of the curve as the summer progresses, thereby preventing the depression from deepening, recommends Dr Rosenthal.

The 2019 American Psychological Association guideline recommends the following for the treatment of adolescents and adults with depression:seee table 2.

Can SAD be prevented?

According to Nussbaumer-Streit et al, about 60% of depression-related treatment is provided by general practitioners (GPs). A major barrier that patients encounter when searching for help, is that GPs do not recognise SAD symptoms.

As a result, SAD patients often remain mis- or underdiagnosed and continued to suffer from symptoms and functional disability.

To ensure that patients receive the immediate care they need, GPs have to be aware of the symptoms, mechanisms, treatment, and preventive options of SAD. In particular, patients who are lacking experience with SAD and have not learned to master their disease need support from physicians and therapists.

Raising general awareness of SAD is important so those who experience it can recognise their symptoms and receive the necessary support in their social and working environment.

The inability of patients to integrate preventive treatments into their everyday working and social lives highlights the need for a broad range of treatment options that can better meet patient needs.

Conclusion A 2020 South African study found that suicide rates increase during spring and summer months. The major contributor to suicide is depression. Various factors may cause summer SAD including heat, humidity and allergies.

The early initiation of antidepressants and psychotherapies are recommended. Campaigns to raise awareness among the general public and increase knowledge about SAD among GPs are urgently needed.

References available on request. SF

SF | PSYCHIATRY

October 2020 | Vol. 20 No. 9 Photo credit: Shutterstock.com

www.medicalacademic.co.za

39

This article was independently sourced by Specialist Forum.

The 'big build' model in male depression

Major depressi ve disorder (MDD) i growing s in overal ld burden.

It is pred isease MDD wi i ll be the cted that leading c of diseas ause e burden by 2 It is alrea Men in South Africa are four times more likely to dy the le 030. ading commit suicide than women. This is one of the cause in women findings of a comprehensive report published in 2019 worldwid by the World Health Organization (WHO). e.

T

he American Psychiatric Association’s Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM‑5) classifies depressive disorders into: » Disruptive mood dysregulation disorder » MDD » Persistent depressive disorder (dysthymia) » Premenstrual dysphoric disorder » Depressive disorder due to another medical condition.

The common features of all the depressive disorders are sadness, emptiness, or irritable mood, accompanied by somatic and cognitive changes that significantly affect the individual’s capacity to function. Because of false perceptions, nearly 60% of people with depression do not seek medical help – the majority being male.

therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). Research findings imply a role for neuronal receptor regulation, intracellular signalling, and gene expression over time, in addition to enhanced neurotransmitter availability.

Seasonal affective disorder, a form of MDD that typically arises during autumn and winter, is mediated by alterations in CNS levels of 5-HT. It appears to be triggered by alterations in circadian rhythm and sunlight exposure.

Vascular lesions may contribute to depression by disrupting the neural networks involved in emotion regulation. Frontostriatal pathways that link the dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, dorsal cingulate as well as other components of limbic circuitry, in particular, the hippocampus and amygdala, have been implicated in MDD.

What causes MDD?

Suicide rates in South Africa

The underlying causes of MDD has not been clearly defined, however current evidence points to a complex interaction between neurotransmitter availability and receptor regulation and sensitivity.

Clinical and preclinical studies suggest a disturbance in central nervous system (CNS) serotonin (5-HT) activity. Other neurotransmitters implicated include norepinephrine (NE), dopamine (DA), glutamate, and brain-derived neurotrophic factor (BDNF).

The role of CNS 5-HT activity in the pathophysiology of MDD is suggested by the

In 2016, the year on which the WHO data is based, 6476 South Africans committed suicides, which translates into a mean rate of 12.8 per 100 000 compared to the mean global rate of 10.5 per 100 000. The rate among South African men is 21.8 per 100 000.

The peak suicide rate for men is the 20–40 years age range – due in part to substance use and high rates of impulsive behaviour in younger men. However, men aged 65 years and older have the highest suicide rate of any age group, according to Prof Kay Wilhelm of the School of Psychiatry at the University of New South Wales (Australia).

Why don’t men seek help?

The prevalence of MDD is higher in women than in men. Its global annual prevalence is 5.5% and 3.2%, respectively, representing a 1.7fold greater incidence in women. Men’s lower overall rate of depression, reflects a number of issues, including psychosocial barriers to seeking help, writes Prof Wilhelm.

Barriers to men seeking help for MDD include: » Feelings of weakness and vulnerability » Fear » Denial » Personal beliefs (including a sense of immunity and immortality or difficulty relinquishing control).

Rates of depression are highest in men who: » Have anxiety disorders of early onset » Are single » Are socially isolated » Are medically ill » Display alcohol or substance abuse.

As men grow older, their overall rate of depression is influenced by their higher mortality.

How to men deal with depression?

According to Prof Wilhelm, men often display different symptoms and behaviours in response to depression. Women, she explains, have greater emotional literacy and are more likely to volunteer how they feel, while men are more likely to do something about their negative affect such as risk-taking, self-harm, substance abuse and rage.

Some of men’s experience (eg irritability, emotional withdrawal) lay outside the standard

40

SF | PSYCHIATRY

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

diagnostic criteria for MDD. Men are less likely to cry, overeat, self-soothe, and much less likely to talk about it or seek help. Instead they are more likely to withdraw socially.

The ‘big build’ model According to Brownhill et al, the ‘big build’ model provides an understanding of the emotional build up when men don’t give voice to their feelings of depression. The ‘big build’, explain the authors, depicts men’s ‘strong’ outer physical appearance but, at the same time, belies men’s inner distress.

The concept links men with MDD’s ‘acting in’ (internalised) and ‘acting out’ (externalised) behaviours and aligns with previous descriptions of male depressive syndrome (MDS). MDS is characterised by an increase in the intensity or frequency of angry outbursts, low stress tolerance, acting-out behaviour, low impulse control, substance abuse and suicide.

Behaviour manifestations (often not associated with men being depressed) present at different stages on men’s trajectory of emotional distress, explain Brownhill et al. For example, avoidant behaviour such as sickness absence may be subtle and difficult to detect as an early signal of depression. Working long hours is often used as a coping mechanism by men to distract or avoid problems.

Tailoring treatment to men’s needs Clinicians should take how men experience

depression and how they communicate their feelings into consideration. Men tend to present with vague or general types of health-related questions or complaints. They are less direct and hope the doctor will ‘guess’ the problem without them having to volunteer it.

Prof Wilhelm recommends that treatment of depression in men should follow the general principles of: » Psychoeducation » Behavioural strategies » Psychological therapies » Antidepressant medication as appropriate.

Medication alone and psychotherapy can relieve depressive symptoms. Combination therapy has also been associated with significantly higher rates of improvement in depressive symptoms, increased quality of life and better treatment compliance. There is also empirical support for the ability of cognitive behavioural therapy (CBT) to prevent relapse.

Electroconvulsive therapy is useful for patients

who are depressed exhibit the ‘cognitive triad’ of MDD, which includes a negative view of themselves, the world, and the future. Patients with MDD also exhibit cognitive distortions that help to maintain their negative beliefs.

CBT for depression typically includes behavioural strategies (eg activity scheduling), as well as cognitive restructuring to change negative automatic thoughts and addressing maladaptive schemas.

There is evidence supporting the use of CBT with individuals of all ages. It is also considered efficacious for the prevention of relapse. It is particularly valuable for elderly patients, who may be more prone to problems or side effects with medications.

Mindfulness-based cognitive therapy (MBCT) was designed to reduce relapse among individuals who have been successfully treated for an episode of recurrent major depressive disorder. The primary treatment component is mindfulness training. MBCT

who are not responding well to medications or are suicidal.

specifically focuses on ruminative thought processes as being a risk factor for relapse.

Research indicates that MBCT is effective in reducing the risk of relapse in patients with recurrent depression, especially in those with the most severe residual symptoms.

Cognitive behavioural therapy Men often do well with CBT and problemsolving techniques. CBT is a structured, and didactic form of therapy that focuses on helping individuals identify and modify maladaptive thinking and behaviour patterns (16 to 20 sessions).

It is based on the premise that patients

Figure 1: 2020 National Institute of Health and Care Excellence algorithm for the treatment of MDD 1 Person starting antidepressant treatment

3

Additional considerations for people with a chronic physical health problem

2 4

5

6 7 8

11

Choosing an antidepressant

NICE Pathway on medicines optimisation

Starting antidepressant treatment: information, monitoring and initial lack of response Is there an adequate response to treatment?

No Sequencing treatments after an inadequate response Is there an adequate response to treatment?

Yes

9

Yes Continuation and relapse prevention

No Continuation and relapse prevention

10

Stopping or reducing antidepressants

Pharmacology

» SSRIs: SSRIs have the advantage of ease

of dosing and low toxicity in overdose. They are also the first-line medications for lateonset depression. SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vilazodone and vortioxetine » Serotonin/norepinephrine reuptake inhibitors (SNRIs): SNRIs include venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran. These agents can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression.

SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs » Atypical antidepressants: Atypical antidepressants include bupropion, mirtazapine, nefazodone and trazodone.

They have all been found to be effective in monotherapy in major depressive disorder and may be used in combination therapy to treat depression » Serotonin-dopamine activity modulators (SDAMs): SDAMs include brexpiprazole and aripiprazole. SDAMs act as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and noradrenaline brexpiprazole is indicated as adjunctive therapy for MDD » Tricyclic antidepressants (TCAS): TCAs include the following: Amitriptyline,

S5

S5

42

SF | PSYCHIATRY

October 2020 | Vol. 20 No. 9 www.medicalacademic.co.za

clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline and trimipramine. TCAs have a long record of efficacy in the treatment of depression. They are used less commonly because of their side-effect profile and their considerable toxicity in overdose » Monoamine oxidase inhibitors (MAOIs): MAOIs include isocarboxazid, phenelzine, selegiline, and tranylcypromine. These agents are widely effective in a broad range of affective and anxiety disorders. Because of the risk of hypertensive crisis, patients on these medications must follow a lowtyramine diet. Other adverse effects can include insomnia, anxiety, orthostasis, weight gain and sexual dysfunction.

Selecting appropriate treatment According Cipriani et al (2018) all antidepressants were more efficacious than placebo in adults with MDD. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis. The team included placebocontrolled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with a confirmed diagnosis of MDD. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause).

In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine were more effective than other antidepressants, whereas fluoxetine, fluvoxamine, reboxetine and trazodone were the least efficacious drugs.

For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were more tolerable than other antidepressants, whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone and venlafaxine had the highest dropout rates.

Conclusion MDD has very high morbidity and mortality contributing to high rates of suicide. Even though effective drug treatment is available, nearly 50% may not initially respond. Complete remission is not common but at least 40% achieve partial remission in 12 months.

However, relapses are common and many patients require a variety of treatments to control the symptoms. The quality of life of most patients with depression is poor.

References Brownhill S, Wilhelm K, Barclay L et al.‘Big Build’:

What about ketamine?

In March 2019, the American Food and Drug Administration (FDA) approved esketamine for treatment-resistant depression (TRD). Although there is currently not a standard definition of TRD, it is commonly defined as a minimum of two prior treatment failures and confirmation of prior adequate dose and duration.

Esketamine was given breakthrough designation, an expedited review process for drugs intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).

Daly et al (2018) conducted the first clinical study on the efficacy of intranasal esketamine for TRD in about 33% of patients with MDD do not respond to treatment. The team assessed the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients (n=126) with TRD. Participants were randomised to placebo, esketamine 28mg, 56mg or 84mg twice weekly.

Participants continued their existing antidepressant treatment during the study.

During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every two weeks.

The primary efficacy endpoint was change from baseline to day eight (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.

Change in MADRS total score in all three esketamine groups was superior to placebo with a significant ascending dose-response relationship. Improvement in depressive symptoms appeared to be sustained despite reduced dosing frequency in the open-label phase. Response appeared to persist for more than two months with a lower dosing frequency.

In their study, Fedgchin et al (2019) enrolled patients (n=346) with moderateto-severe depression who did not respond to antidepressants in the current depression episode. Eligible patients were randomised to twice-weekly nasal spray treatment (esketamine [56mg or 84mg] or placebo) Cipriani A, Furukawa TA, Salanti G et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet, 2018.

Daly EJ, Singh JB, Fedgchin M et al. Efficacy and

Contraindications Ketamine is contraindicated in those patients who have underlying conditions in which increased blood pressure would pose a risk of complications such as aortic dissection, uncontrolled hypertension, myocardial infarction or aneurysms.

It is contraindicated in those who have shown prior hypersensitivity to the drug.

It is not recommended for use during obstetrics, pregnancy or for women who are breastfeeding as it is unknown if this medication passes into breast milk. Use in chronic alcoholics and the acutely alcoholintoxicated patient may cause death.

It is contraindicated in patients with schizophrenia due to the potential for exacerbating the underlying condition. In patients with cerebrospinal fluid (CSF) elevations, the use of ketamine is controversial due to questionable elevations of the CSF caused by ketamine. Some studies indicate that the concern for CSF elevation with ketamine has been overstated. Newer research suggests that ketamine may improve cerebral perfusion pressure and may, in fact, have neuroprotective properties.

Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol, 2019.

Gaynes BN, Lux L, Gartlehner G et al. Defining treatment-resistant depression, Depress Anxiety, 2020.

Ochs-Ross R, Daly EJ, Zhang Y et al. Efficacy and

Safety of Intranasal Esketamine Adjunctive to Oral

Safety of Esketamine Nasal Spray Plus an Oral

Antidepressant Therapy in Treatment-Resistant

Antidepressant in Elderly Patients With Treatment-

Depression: A Randomized Clinical Trial. JAMA

Resistant Depression—TRANSFORM-3. Journal of

Psychiatry, 2018.

Fedgchin M, Trivedi M, Daly EJ et al. Efficacy and

Hidden Depression in Men. Australian and New

Safety of Fixed-Dose Esketamine Nasal Spray

Zealand Journal of Psychiatry, 2005.

Combined With a New Oral Antidepressant in

Chand SP and Arif H. Depression. StatPearls, 2020.

plus a newly initiated, open-label, oral antidepressant taken daily for four weeks.

The primary efficacy endpoint was change from baseline to day 28 in the MADRS score, performed by blinded, remote raters.

The treatment effect (MARDS score) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo.

Safety was similar between esketamine/ antidepressant groups and no new doserelated safety concerns were identified. The team concluded that their study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapidacting antidepressant for patients with TRD. Ochs-Ross et al (2020) did however find that esketamine was less effective in MDD patients older than 65 compared to younger patients.

Treatment-Resistant Depression: Results of a

Geriatric Medicine, 2020.

Rosenbaum SB, Gupta V and Palacios JL. Ketamine.

StatPearls, 2020.

Wilhelm KA. Men and depression. Australian Family Physician, 2009. SF

desvenlafaxine

S5 EXSIRA 50 mg and 100 mg extended–release tablets (Reg. nos.: 42/1.2/0935, 41/1.2/0427). Each tablet contains desvenlafaxine succinate equivalent to 50 mg and 100 mg desvenlafaxine respectively.

PHARMACOLOGICAL CLASSIFICATION: A 1.2 Psychoanaleptics (antidepressants). INDICATIONS: Major depressive disorder: EXSIRA tablets are indicated for the treatment of major depressive disorder (MDD). CONTRAINDICATIONS: Hypersensitivity to EXSIRA, venlafaxine hydrochloride or to any excipients in the EXSIRA formulation. EXSIRA is an inhibitor of both norepinephrine and serotonin reuptake. EXSIRA must not be used in combination with a monoamine oxidase inhibitor (MAOI), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of EXSIRA, at least 7 days should be allowed after stopping EXSIRA before starting an MAOI. Severe adverse reactions have been reported when therapy is initiated with SSRI/SNRI medicines such as EXSIRA soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of SSRI/SNRI medicines. These

hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death (see (see WARNINGS AND SPECIAL PRECAUTIONS and SIDE EFFECTS). Pregnancy and lactation (see PREGNANCY AND LACTATION). WARNINGS AND SPECIAL PRECAUTIONS: Clinical worsening of depressive symptoms, unusual changes in behaviour, and suicidality: Patients with major depressive disorder may experience worsening of their depression and/ or the emergence of suicidal ideation and remission occurs. Patients being treated with EXSIRA should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy or at any time of dose changes, either increases or decreases. Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorders should be observed when treating patients with other psychiatric and non-psychiatric disorders. The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania. Although a causal link between the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing EXSIRA in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision is made to discontinue treatment, EXSIRA should be tapered (see DOSAGE AND DIRECTIONS FOR USE). Shortterm trials did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 years and older. There have been reports of hostility, suicidal ideation and self-harm with use of SSRIs in children under the age of 18 years. Paediatric use: Safety and

EXSIRA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered (see DOSAGE AND DIRECTIONS FOR USE and SIDE EFFECTS). Abnormal bleeding: Medicines that inhibit serotonin uptake in platelets may lead to abnormalities of platelet aggregation. As with other agents that inhibit serotonin-reuptake, EXSIRA should be used cautiously in patients predisposed to bleeding.

Hyponatraemia: Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion have been described with SNRIs and SSRIs, including EXSIRA, usually in volumedepleted or dehydrated patients, including elderly patients and patients taking diuretics (see SIDE EFFECTS). Geriatric use: No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of EXSIRA should be considered when determining dose (see DOSAGE AND DIRECTIONS FOR USE). In the short-term placebo-controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients treated with EXSIRA who were ≥ 65 years of age (8 %) compared to patients < 65 years of age (0,9 %). Effects on ability to drive and use machines: EXSIRA may impair judgement, thinking and motor skills. Therefore, patients should be cautioned about their ability to drive or operate hazardous machinery. INTERACTIONS: Monoamine oxidase inhibitors (MAOI): Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on antidepressants with pharmacological properties similar to EXSIRA (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, neuroleptic malignant syndrome, seizures and death. Concomitant use of EXSIRA in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS AND SPECIAL PRECAUTIONS and CONTRAINDICATIONS). Central nervous system (CNS)-active agents: The risk of using EXSIRA in combination with other CNS-active medicines has not been systematically evaluated. Consequently, caution is advised when EXSIRA is taken in combination with other CNS-active medicines. Serotonin syndrome: Serotonin syndrome, a potentially life-threatening condition, may occur with EXSIRA treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, lithium, sibutramine, tramadol, St. John’s Wort [Hypericum perforatum ], pethidine), with medicines that impair metabolism of serotonin (such as MAOIs, including linezolid [an antibiotic which is a reversible non-selective MAOI], see CONTRAINDICATIONS), or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms (see WARNINGS AND SPECIAL PRECAUTIONS). Ethanol: Patients should be advised to avoid alcohol consumption while taking EXSIRA. Potential for other medicines to affect EXSIRA: Inhibitors of CYP3A4: CYP3A4 is involved in EXSIRA elimination. In a clinical trial, ketoconazole (200 mg twice daily) increased the area under the concentration vs. time curve (AUC) of EXSIRA (400 mg single dose) by approximately 43 %, a weak interaction and Cmax by about 8 %.

Concomitant use of EXSIRA with potent inhibitors of CYP3A4 may result in higher exposure to EXSIRA. Inhibitors of other CYP enzymes: Based on in vitro

I am unique My depression is unique too.

S5 EXSIRA 50 mg and 100 mg extended–release tablets (Reg. nos.: 42/1.2/0935, 41/1.2/0427). Each tablet contains desvenlafaxine succinate equivalent to 50 mg and 100 mg desvenlafaxine respectively.

PHARMACOLOGICAL CLASSIFICATION: A 1.2 Psychoanaleptics (antidepressants). INDICATIONS: Major depressive disorder: EXSIRA tablets are indicated for the treatment of major depressive disorder (MDD). CONTRAINDICATIONS: Hypersensitivity to EXSIRA, venlafaxine hydrochloride or to any excipients in the EXSIRA formulation. EXSIRA is an inhibitor of both norepinephrine and serotonin reuptake. EXSIRA must not be used in combination with a monoamine oxidase inhibitor (MAOI), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of EXSIRA, at least 7 days should be allowed after stopping EXSIRA before starting an MAOI. Severe adverse reactions have been reported when therapy is initiated with SSRI/SNRI medicines such as EXSIRA soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of SSRI/SNRI medicines. These

hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death (see

(see WARNINGS AND SPECIAL PRECAUTIONS and SIDE EFFECTS). Pregnancy and lactation (see PREGNANCY AND LACTATION). WARNINGS AND SPECIAL PRECAUTIONS: Clinical worsening of depressive symptoms, unusual changes in behaviour, and suicidality: Patients with major depressive disorder may experience worsening of their depression and/ or the emergence of suicidal ideation and

remission occurs. Patients being treated with EXSIRA should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy or at any time of dose changes, either increases or decreases. Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorders should be observed when treating patients with other psychiatric and non-psychiatric disorders. The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania. Although a causal link between the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing EXSIRA in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision is made to discontinue treatment, EXSIRA should be tapered (see DOSAGE AND DIRECTIONS FOR USE). Shortterm trials did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 years and older. There have been reports of hostility, suicidal ideation and self-harm with use of SSRIs in children under the age of 18 years. Paediatric use: Safety and

S5 EXSIRA 50 mg and 100 mg extended–release tablets (Reg. nos.: 42/1.2/0935, 41/1.2/0427). Each tablet contains desvenlafaxine succinate equivalent to 50 mg and 100 mg desvenlafaxine respectively.

PHARMACOLOGICAL CLASSIFICATION: A 1.2 Psychoanaleptics (antidepressants). INDICATIONS: Major depressive disorder: EXSIRA tablets are indicated for the treatment of major depressive disorder (MDD). CONTRAINDICATIONS: Hypersensitivity to EXSIRA, venlafaxine hydrochloride or to any excipients in the EXSIRA formulation. EXSIRA is an inhibitor of both norepinephrine and serotonin reuptake. EXSIRA must not be used in combination with a monoamine oxidase inhibitor (MAOI), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of EXSIRA, at least 7 days should be allowed after stopping EXSIRA before starting an MAOI. Severe adverse reactions have been reported when therapy is initiated with SSRI/SNRI medicines such as EXSIRA soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of SSRI/SNRI medicines. These

hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death (see (see WARNINGS AND SPECIAL PRECAUTIONS and SIDE EFFECTS). Pregnancy and lactation (see PREGNANCY AND LACTATION). WARNINGS AND SPECIAL PRECAUTIONS: Clinical worsening of depressive symptoms, unusual changes in behaviour, and suicidality: Patients with major depressive disorder may experience worsening of their depression and/ or the emergence of suicidal ideation and remission occurs. Patients being treated with EXSIRA should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy or at any time of dose changes, either increases or decreases. Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorders should be observed when treating patients with other psychiatric and non-psychiatric disorders. The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania. Although a causal link between the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing EXSIRA in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision is made to discontinue treatment, EXSIRA should be tapered (see DOSAGE AND DIRECTIONS FOR USE). Shortterm trials did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 years and older. There have been reports of hostility, suicidal ideation and self-harm with use of SSRIs in children under the age of 18 years. Paediatric use: Safety and EFFECTS). Mania/hypomania: In clinical trials, mania was reported for 0,03 % of patients treated with EXSIRA. EXSIRA should be used cautiously in patients with a history or family history of mania or hypomania (see SIDE EFFECTS). Serotonin syndrome: The development of a potentially life-threatening serotonin syndrome may occur with EXSIRA treatment, particularly with concomitant use of other serotonergic medicines (including SSRIs, SNRIs and triptans) and with medicines that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, and coma), autonomic instability (e.g. tachycardia, labile blood pressure, and symptoms (e.g. nausea, vomiting, and diarrhoea) (see INTERACTIONS). The concomitant use of EXSIRA with serotonin precursors (such as tryptophan supplements) is not recommended. Narrow-angle

EFFECTS). Mania/hypomania: In clinical trials, mania was reported for 0,03 % of patients treated with EXSIRA. EXSIRA should be used cautiously in patients with a history or family history of mania or hypomania (see SIDE EFFECTS). Serotonin syndrome: The development of a potentially life-threatening serotonin syndrome may occur with EXSIRA treatment, particularly with concomitant use of other serotonergic medicines (including SSRIs, SNRIs and triptans) and with medicines that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g.

EXSIRA. gradual reduction in the autonomic dose ratherinstability than abrupt is labile recommended whenever agitation,Ahallucinations, and coma), (e.g. cessation tachycardia, blood pressure, and possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of resumingvomiting, the previously prescribed dose may be considered (see DOSAGE AND treatment, symptoms then (e.g. nausea, and diarrhoea) (see INTERACTIONS).

The concomitant use of EXSIRA DIRECTIONS USE and(such SIDEasEFFECTS).

Abnormal bleeding: Medicines that inhibit serotonin with serotoninFOR precursors tryptophan supplements) is not recommended.

Narrow-angle uptake in platelets mayhas leadbeen to abnormalities of platelet aggregation.

Astherefore, with otherpatients agents that glaucoma: Mydriasis reported in association with EXSIRA; with inhibit raised serotonin-reuptake, EXSIRA be used cautiously in patients predisposed to bleeding. intraocular pressure or those atshould risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be Hyponatraemia: CasesEFFECTS). of hyponatraemia and/or the Syndrome Inappropriate Antidiuretic Hormone monitored (see SIDE Ischaemic cardiac adverseofevents: In clinical trials, there were (SIADH) secretion have been described SNRIsevents, and SSRIs, including EXSIRA, usually inmyocardial volumeuncommon reports of ischaemic cardiacwith adverse including myocardial ischaemia, depleted dehydrated patients and patients taking SIDE infarction,orand coronary patients, occlusionincluding requiring elderly revascularisation; these patients haddiuretics multiple (see underlying EFFECTS). dosageexperienced adjustment these is required solely on the basistreatment of age; however, possible as compared to cardiac riskGeriatric factors. use: MoreNo patients events during EXSIRA reduced clearance of EXSIRA should Adverse be considered whenreported determining (see DOSAGE AND placebo.renal Discontinuation symptoms: reactions in dose association with abrupt DIRECTIONS FOR USE).

In the short-term placebo-controlled trials, there was a higher incidence of discontinuation, dose reduction or tapering of treatment in MDD clinical trials at a rate of ≥ 2 % include: systolic orthostatic hypotension patients withInEXSIRA were ≥ 65 years of age (8 %) dizziness, withdrawal syndrome, in nausea andtreated headache. general,who discontinuation symptoms occurred compared to patients 65 years of ageof(0,9 %). Effects on ability to drive and use FOR machines: EXSIRA more frequently with <longer duration therapy (see DOSAGE AND DIRECTIONS USE). Adverse may impair leading judgement, thinking and motor Therefore, patients should be cautioned their reactions to discontinuation of skills. therapy: The most common adverse reactionabout leading to ability to drive orin operate INTERACTIONS: oxidasetrials, inhibitors discontinuation at leasthazardous 2 % of machinery. the EXSIRA-treated patients Monoamine in the short-term up to (MAOI): Adverse reactions, which were serious, have been no reported patients who have 12 weeks, was nausea (2 %);some in the of long-term studies, up to 11 months, events in lead to discontinuation recently been discontinued a monoamine oxidase inhibitor (MAOI) and started 41/1.2/0427). on antidepressants S5 in at least 250 % of the at a rate greater than placebo in the double-blind phase. Adverse EXSIRA mg andpatients 100from mgand extended–release tablets (Reg. nos.: 42/1.2/0935, Each with pharmacological properties similar to EXSIRAgastrointestinal (SNRIs or SSRIs), ormg who have recently respectively. had or reactions reported with othersuccinate SNRIs: Although is not considered anSNRI adverse tablet contains desvenlafaxine equivalent to 50 mg andbleeding 100 desvenlafaxine SSRI therapy discontinued prior to reaction initiation ofother an MAOI. These reactions have tremor, reaction for EXSIRA, it is an adverse SNRIs and may also occur withincluded EXSIRA. Effects PHARMACOLOGICAL CLASSIFICATION: A for 1.2 Psychoanaleptics (antidepressants).

INDICATIONS:

EFFECTS). Mania/hypomania: In clinical trials, mania was reported for 0,03 % of patients treated with EXSIRA. EXSIRA should be used cautiously in patients with a history or family history of mania or hypomania (see SIDE EFFECTS). Serotonin syndrome: The development of a potentially life-threatening serotonin syndrome may occur with EXSIRA treatment, particularly with concomitant use of other serotonergic medicines (including SSRIs, SNRIs and triptans) and with medicines that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g.

EXSIRA. hallucinations, A gradual reduction in the dose rather than abrupt cessation is recommended whenever agitation, and coma), autonomic instability (e.g. tachycardia, labile blood pressure, and possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment,(e.g. thennausea, resuming the previously prescribed dose may be The considered (see use DOSAGE AND symptoms vomiting, and diarrhoea) (see INTERACTIONS). concomitant of EXSIRA DIRECTIONS USE and SIDE bleeding: that inhibit serotonin with serotonin FOR precursors (such as EFFECTS). tryptophan Abnormal supplements) is not Medicines recommended.

Narrow-angle uptake in platelets may lead to abnormalities of platelet aggregation.

As with other agents that inhibit glaucoma: Mydriasis has been reported in association with EXSIRA; therefore, patients with raised serotonin-reuptake, should be narrow-angle used cautiously in patients predisposed to should bleeding. intraocular pressure or EXSIRA those at risk of acute glaucoma (angle-closure glaucoma) be the Syndrome of Inappropriate Hormone Hyponatraemia: Cases of hyponatraemia and/or monitored (see SIDE EFFECTS).

Ischaemic cardiac adverse events: In clinicalAntidiuretic trials, there were (SIADH) secretion been described with SNRIs and including SSRIs, including EXSIRA, usuallymyocardial in volumeuncommon reports have of ischaemic cardiac adverse events, myocardial ischaemia, depleted and or dehydrated patients, requiring includingrevascularisation; elderly patients and diureticsunderlying (see SIDE infarction, coronary occlusion thesepatients patientstaking had multiple EFFECTS).

Geriatric use: No dosage adjustment is required solely on the basis of age; however, possible cardiac risk factors. More patients experienced these events during EXSIRA treatment as compared to reduced renal clearance of symptoms: EXSIRA should be considered when determining dose (see DOSAGE AND placebo.

Discontinuation Adverse reactions reported in association with abrupt DIRECTIONS FOR In the trials, there was a higher discontinuation, doseUSE). reduction or short-term tapering of placebo-controlled treatment in MDD clinical trials at a rate of ≥ 2 incidence % include:of systolic orthostatic in patients treated with EXSIRA discontinuation who were ≥ 65symptoms years of age (8 %) dizziness, withdrawal hypotension syndrome, nausea and headache.

In general, occurred compared to patients < 65 years of age (0,9 %).(see Effects on ability drive and use machines: EXSIRA more frequently with longer duration of therapy DOSAGE ANDtoDIRECTIONS FOR USE). Adverse may impair judgement, thinking and motor skills.

Therefore, patients should be cautioned about reactions leading to discontinuation of therapy: The most common adverse reaction leading their to ability to drive inor at operate machinery.

INTERACTIONS: oxidase inhibitors discontinuation least hazardous 2 % of the EXSIRA-treated patients inMonoamine the short-term trials, up to (MAOI): reactions, of whichstudies, were serious, been in patients who have 12 weeks, Adverse was nausea (2 %); insome the long-term up to 11have months, noreported events lead to discontinuation recently a at monoamine oxidase (MAOI) and started41/1.2/0427). onphase. antidepressants S5 mgthe andpatients 100 from mgand extended–release tablets (Reg. nos.: 42/1.2/0935, Each in atEXSIRA leastbeen 2 50 % discontinued of a rate greater thaninhibitor placebo in the double-blind Adverse with pharmacological properties similarAlthough to EXSIRA (SNRIs or and SSRIs), who have recentlyrespectively. had SNRI or tablet contains desvenlafaxine equivalent to 50 mg 100ormg reactions reported with othersuccinate SNRIs: gastrointestinal bleeding isdesvenlafaxine not considered an adverse SSRI therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, PHARMACOLOGICAL 1.2other Psychoanaleptics INDICATIONS: reaction for EXSIRA, it isCLASSIFICATION: an adverse reactionAfor SNRIs and may(antidepressants). also occur with EXSIRA. Effects

Major depressive disorder: EXSIRA tablets indicated for the treatment with cognitive and motor on activities requiring concentration andare performance: Interference neuroleptic malignant syndrome, seizures andthat death.

Concomitant use of taking performance: The results of a clinical trial assessed the effects of EXSIRA EXSIRA inonpatients behavioural monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS AND SPECIAL PRECAUTIONS CONTRAINDICATIONS).

CentralHowever, nervous since system (CNS)-active The riskimpair of using EXSIRA in orand complex behaviour performance. any CNS-active agents: medicine may judgement, combination with other CNS-active medicines has not been systematically evaluated.

Consequently, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including caution is advised when is taken in that combination with other CNS-active medicines.

Serotonin automobiles, until they are EXSIRA reasonably certain EXSIRA therapy does not adversely affect their ability syndrome, potentially life-threatening may occurdependence: with EXSIRA tosyndrome: engage in Serotonin such activities.

Abusea and dependence: Physicalcondition, and psychological treatment, particularly use of other agents or that may trials affect serotonergic Although EXSIRA has notwith beenconcomitant systematically studied in preclinical clinical for the its potential for neurotransmitter system (including triptans, SSRIs, other SNRIs, lithium, sibutramine, tramadol, St. John’s abuse, no indication of drug-seeking behaviour was seen in the clinical trials. Co-administration of Wort [Hypericum perforatum ], pethidine), with medicines impair of serotonin (such as medicines containing venlafaxine and/or EXSIRA: EXSIRAthat is the majormetabolism active metabolite of venlafaxine, including [andepressive, antibiotic generalised which is anxiety, a reversible non-selective see aMAOIs, medication used to linezolid treat major social anxiety and panicMAOI], disorders.

CONTRAINDICATIONS), or concomitantly with serotoninwith precursors as tryptophan products (such containing venlafaxinesupplements). hydrochloride Serotonin or other EXSIRA should not be used syndrome symptoms mayEffects includeonmental status changes, autonomic instability, neuromuscular products containing EXSIRA. blood pressure: Increased blood pressure: Increases in blood aberrations and/or gastrointestinal symptoms (see WARNINGS AND SPECIAL PRECAUTIONS).

Ethanol: pressure were observed in some patients in clinical trials, particularly with higher doses. Pre-existing Patients should be be advised to avoid consumption while takingreceiving EXSIRA.EXSIRA Potential for have other hypertension should controlled beforealcohol treatment with EXSIRA. Patients should medicines to affect EXSIRA: Inhibitors is involved in EXSIRA elimination.

In a regular monitoring of blood pressure.

CasesofofCYP3A4: elevatedCYP3A4 blood pressure requiring immediate treatment clinical trial, ketoconazole (200 mg twice daily) increased area under the concentration vs. time curve have been reported with EXSIRA. Sustained blood pressurethe increases could have adverse consequences.

(AUC) of EXSIRA (400 mg single dose) byincrease approximately 43pressure %, a weak interaction Cmax byeither aboutdose 8 %.

For patients who experience a sustained in blood while receivingand EXSIRA, of CYP3A4 mayberesult in higher exposure to EXSIRA. Concomitant use of EXSIRAshould with potent inhibitors Caution reduction or discontinuation be considered. should exercised in treating patients with Inhibitors of other CYP enzymes: Based on in vitro underlying conditions that might be compromised by increases in blood pressure (see SIDE EFFECTS).

Postural hypotension (see Geriatric use). Cardiovascular/cerebrovascular: Caution is advised in forwith EXSIRA to affect cerebrovascular, other medicines: metabolised by administering EXSIRAPotential to patients cardiovascular, or Medicines lipid metabolism disorders.

CYP2D6:inClinical haveand shown EXSIRA is a weakininhibitor CYP2D6 at a doseEXSIRA of 100 mg Increases blood trials pressure heartthat rate were observed clinicalof trials with EXSIRA. has daily. not Concomitant of EXSIRAin with a medicine metabolised CYP2D6 infarction, may result in increased been evaluateduse systematically patients with a recent history ofbymyocardial unstable heart concentrations of that medicine and concentrations of its CYP2D6 metabolites.

Medicines disease, uncontrolled hypertension, or decreased cerebrovascular disease. Patients with these diagnoses, except metabolised by CYP3A4: In vitro, EXSIRA does not inhibit or induce the CYP3A4 isozymes.

Concomitant for cerebrovascular disease, were excluded from clinical trials (see SIDE EFFECTS). Serum lipids: Doseuse of EXSIRA with medicine metabolised

by CYP3A4 may(low result in lower exposurescholesterol, to that medicine. related elevations in afasting serum total cholesterol, LDL density lipoprotein) and Medicines metabolised byina combination both CYP2D6 CYP3A4 (tamoxifen and aripiprazole): triglycerides were observed clinical trials. of Measurement of and serum lipids should be considered during Clinical studies have shown thatEFFECTS).

EXSIRA (100 mg daily) does not have a clinically effect on treatment with EXSIRA (see SIDE Seizures: Cases of seizure were reported relevant in pre-marketing medicines a combination of both CYP2D6 evaluated and CYP3A4 enzymes. clinical trials metabolised with EXSIRA.by EXSIRA has not been systematically in patients with Medicines a seizure metabolised by CYP1A2, 2A6, 2C8, 2C9 and 2C19: In vitro, EXSIRA does not inhibit CYP1A2, 2A6, 2C8, disorder. Patients with a history of seizures were excluded from pre-marketing clinical trials. EXSIRA 2C9, and 2C19 isozymes and would not be with expected to affect the (see pharmacokinetics of medicines that are should be prescribed with caution in patients a seizure disorder SIDE EFFECTS).

Discontinuation metabolised bymarketing these CYPofisozymes.

P-glycoprotein transporter: In Reuptake vitro, EXSIRA is not a and substrate effects: During SNRIs (Serotonin and Norepinephrine Inhibitors), SSRIsor an inhibitor for the P-glycoprotein transporter.

Electroconvulsive therapy: are no clinical (Selective Serotonin Reuptake Inhibitors) such as EXSIRA, there have beenThere spontaneous reportsdata of EXSIRA treatment for adverse events occurring upon discontinuation of these medicines, particularly when abrupt, including MDD. PREGNANCY LACTATION: EXSIRA dizziness, must not sensory be administered to pregnant or lactating the following: dysphoricAND mood, irritability, agitation, disturbances (e.g. paraesthesias women.

Safety during human anxiety, pregnancy and headache, lactation lethargy, has not been lability, established (see such as electric shock sensations), confusion, emotional insomnia, CONTRAINDICATIONS).DOSAGE ANDthese DIRECTIONS USE: Major depressive The hypomania, tinnitus, and seizures. While events are FOR generally self-limiting, there havedisorder: been reports dose for EXSIRA is 50Patients mg onceshould daily, with or withoutwhen food,discontinuing with a maximum dose ofwith 100 ofrecommended serious discontinuation symptoms. be monitored treatment mg per day. The dose increase should occur gradually and at an interval of not less than 7 days. Use in patientsAwith renal impairment: starting dose inispatients with severe renal EXSIRA. gradual reduction in the The doserecommended rather than abrupt cessation recommended whenever impairment (24-hr CrClsymptoms < 30ml/min)occur or end-stage disease (ESRD) is 50 mg every discontinuation other day. Because possible.

If intolerable followingrenal a decrease in the dose or upon of of individual variability in the clearance in these patients, individualisation of dosage be desirable. treatment, then resuming previously prescribed dose may be considered (seemay DOSAGE AND should not be given to Abnormal patients after dialysis.Medicines Use in patients withserotonin hepatic SupplementalFOR doses USE and SIDE EFFECTS). bleeding: that inhibit on activities requiring concentration and Interference cognitive and motor DIRECTIONS Major depressive disorder: EXSIRA tablets areperformance: indicated for the treatment ofwith major depressive disorder FA 3987M_Exsira API (A4).indd 1 neuroleptic malignant syndrome, seizures and that death.

Concomitant use of of EXSIRA in patients impairment: No dosage adjustment is necessary for patients with hepatic impairment.

Paediatric use: uptake in platelets may lead to abnormalities of platelet aggregation.

As with other agents that inhibit performance: The results of a Hypersensitivity clinical trial the effects EXSIRA on or behavioural (MDD).

CONTRAINDICATIONS: toassessed EXSIRA, venlafaxine hydrochloride totaking any monoamineinoxidase inhibitors (MAOIs) isEXSIRA contraindicated (see WARNINGS AND SPECIAL PRECAUTIONS elderly serotonin-reuptake, EXSIRA should be used cautiously in patients predisposed Use to in bleeding. excipients the EXSIRA formulation. is an inhibitor of both norepinephrine and serotonin and CONTRAINDICATIONS). system (CNS)-active agents: The risk ofimpair using judgement, EXSIRA in patients: No dosage adjustment is required solelythe on Syndrome the basis of however, possible reduced renal Hyponatraemia: Cases of hyponatraemia and/or ofage; Inappropriate Antidiuretic Hormone or complex behaviour performance.

However, since CNS-active medicine may reuptake.

EXSIRA must not beCentral used innervous combination withany a monoamine oxidase inhibitor (MAOI), or within combination with other medicines notabout been operating systematically evaluated.

Consequently, clearance of EXSIRA should considered determining dose.

Discontinuing (SIADH) secretion have been be described withwhen SNRIs and SSRIs, including EXSIRA, EXSIRA: usually inSymptoms volumethinking, motor skills,CNS-active patients should be hazardous machinery, at least 14or days of discontinuing treatment withcautioned anhas MAOI. Based on the half-life of EXSIRA, at leastincluding 7 days caution is allowed advised whenstopping EXSIRA is taken in combination other CNS-active medicines.

Serotonin associated discontinuation of including EXSIRA, other SNRIs and SSRIs have been reported.

Patients or with dehydrated patients, elderly patients and patients taking diuretics (see should SIDE automobiles, until after they are reasonably certain that EXSIRA therapy does not adversely affect have their been ability depleted should be EXSIRA before starting anwith MAOI. Severe adverse reactions syndrome: Serotonin a potentially life-threatening condition, may after occurdiscontinuation with EXSIRA be monitored for these when discontinuing treatment.

A gradual reduction in the dose rather EFFECTS).

Geriatric use:symptoms No dosage adjustment is required solely on the basis of age; however, possible to engage in such activities.

Abuse and dependence: and psychological dependence: reported when therapy issyndrome, initiated with SSRI/SNRI medicinesPhysical such as EXSIRA soon treatment, particularly with concomitant use studied of other agents that may affect theitsserotonergic than abrupt whenever possible.

If intolerable symptoms following renalcessation clearanceisofrecommended EXSIRA should be considered when determining dose (seeoccur DOSAGE ANDa Although has an not been systematically in preclinical orofclinical trials for potential for reduced of an MAOIEXSIRA and when MAOI is initiated soon after discontinuation SSRI/SNRI medicines.

These neurotransmitter system triptans, SSRIs, was otherseen SNRIs, sibutramine, tramadol, St. John’s decrease in the dose or upon discontinuation of treatment, then resuming thewas previously prescribed FOR USE).

In the short-term placebo-controlled trials, there a higher incidencedose of abuse, no indication of (including drug-seeking behaviour in lithium, the clinical trials. Co-administration of DIRECTIONS Wort [Hypericum perforatum ],resembling pethidine), with medicines thatisimpair metabolism of serotonin (such as may beorthostatic considered.hypotension Subsequently, the medical practitioner may continue decreasing theof dose systolic in patients treated with EXSIRA who were ≥ 65 years agebut (8 at %)a medicines containing venlafaxine and/or EXSIRA: EXSIRA thesyndrome, major active metabolite venlafaxine, hyperthermia with features neuroleptic malignant seizures andof death (see MAOIs, including linezolid [an depressive, antibiotic generalised which is aanxiety, reversible MAOI], see more gradual rate (see SPECIAL and and SIDE EFFECTS).

Switching compared to patients < 65WARNINGS years of ageAND (0,9 %).

EffectsPRECAUTIONS on ability to drive use machines: EXSIRA a medication used to treat major social non-selective anxiety and panic disorders.

CONTRAINDICATIONS), or with serotonin with precursors (such as tryptophan supplements).

Serotonin Discontinuation symptoms have been reported patients other antidepressants to EXSIRA: may impairfrom judgement, thinking and motor skills. Therefore, patients should be cautioned about when their be SPECIAL used concomitantly products containing venlafaxine hydrochloride or other EXSIRA should not (see WARNINGS AND PRECAUTIONS and SIDE EFFECTS).

Pregnancy and lactation (see syndrome symptoms may include mental changes, autonomic instability, neuromuscular switching patients from other antidepressants, including venlafaxine,Monoamine to EXSIRA. Tapering the initial ability to drive or operate hazardous machinery.

INTERACTIONS: oxidase ofinhibitors products containing EXSIRA. Effects on bloodstatus pressure: Increased blood pressure: Increases in blood PREGNANCY AND LACTATION).

WARNINGS AND SPECIAL PRECAUTIONS: Clinical worsening of aberrations and/or gastrointestinal symptoms (see WARNINGS AND SPECIAL PRECAUTIONS).

Ethanol: antidepressant be necessary discontinuation symptoms.

SIDE EFFECTS: Verywho common: (MAOI): Adversemay reactions, sometoofminimise which were serious, have been reported in patients have pressure were observed in some patientsininbehaviour, clinical trials, with higher depressive symptoms, unusual changes and particularly suicidality: Patients withdoses. major Pre-existing depressive Patients should be advised to avoid consumption while taking EXSIRA. Potential for other ≥ 10 %,been Common: ≥ 1 % and < 10 %, Uncommon: ≥ 0,1inhibitor % and <(MAOI) 1 %, Rare: ≥ 0,01 % < 0,1 %, Very oxidase and started onand antidepressants recently discontinued from a monoamine hypertension should be controlled before treatment withand/ EXSIRA. Patients receiving EXSIRAideation should have disorder may experience worsening of alcohol their depression or the emergence of suicidal and medicines to affectofEXSIRA: Inhibitors of CYP3A4: CYP3A4 is involved in EXSIRA elimination.

In a rare:pharmacological < 0,01 %. Cardiac disorders: Palpitations, tachycardia. andrecently labyrinth disorders with properties similarCommon: to EXSIRA (SNRIs or SSRIs), or whoEar have had SNRI or : regular monitoring blood pressure.

Cases of elevated blood pressure requiring immediate treatment clinical trial, ketoconazole (200 mgSustained twice daily) increased theincreases areanevertheless, under the concentration vs.closely time curve Common: Tinnitus.

Eye disorders Gastrointestinal disorderstremor, : Very SSRI therapy discontinued prior :toCommon: initiationBlurred of an vision, MAOI. mydriasis.

These reactions have included have been reported with EXSIRA. blood pressure could have consequences. remission occurs.

Patients being treated with EXSIRA should, beadverse observed for (AUC) of EXSIRA mg single dose) by approximately 43 %, interaction and Cmax about 8dose %. common: Nausea, dry mouth, constipation. Common: Diarrhoea, vomiting. General disorders and For patients who(400 experience a sustained increase in blood pressure while receiving either clinical worsening and suicidality, especially at the beginning of aa weak course of therapy or EXSIRA, at anybytime of dose CYP3A4 may result higherinexposure to EXSIRA. Concomitant useincreases of EXSIRAorwith potent inhibitors administration site conditions : Common: Fatigue, chills, Concomitant asthenia, feeling irritability.

Immune system malignant syndrome, seizures and death. usejittery, of EXSIRA in patients taking reductioneither or discontinuation should be considered. should be exercised treating patients with neuroleptic changes, decreases.

BecauseofCaution of the possibility of inco-morbidity between major Inhibitors other CYP enzymes: Based on innon-psychiatric vitro by increases disorders : Uncommon: Hypersensitivity.

Investigations :(see Common: Increased weight, PRECAUTIONS increased blood monoamine oxidase inhibitors (MAOIs) is contraindicated WARNINGS AND SPECIAL underlyingof conditions might be compromised in bloodthe pressure (see SIDE EFFECTS). depressive disorder andthat other psychiatric and disorders, same precautions observed pressure, decreased weight.Central Uncommon: Increased blood cholesterol, increased blood CONTRAINDICATIONS). nervous system (CNS)-active agents: The risk of usingtriglycerides, EXSIRA in Postural hypotension (seemajor Geriatric use). Cardiovascular/cerebrovascular: advised when treating patients with depressive disorders should be observed whenCaution treating is patients within and for EXSIRA to affect other medicines: Medicines metabolised by abnormal liver function test, increased blood prolactin. and nutritional disorders : Common: combination with other CNS-active medicines has not Metabolism been systematically evaluated.

Consequently, administering EXSIRA to patients with cardiovascular, cerebrovascular, or lipid metabolism other psychiatric andPotential non-psychiatric disorders.

The following symptoms have been reported indisorders. patients CYP2D6: Clinical have shown that EXSIRA isobserved a weakdisorder inhibitor of CYP2D6 atEXSIRA. a doseindications, of 100 mg daily.

Decreased appetite.

Rare: Hyponatraemia.

Musculoskeletal, tissue and bone disorders: is advised when EXSIRA is taken in combination with connective other CNS-active medicines.

Serotonin Increases in blood pressure and heart rate were in clinical trials with EXSIRA has not caution being treated withtrials antidepressants for major depressive as well as for other both Concomitant usesystematically of EXSIRA in with a medicine metabolised by CYP2D6 may result in increased Common: Musculoskeletal stiffness.

Nervous system disorders: condition, Very common: Serotonin syndrome, a potentially life-threatening may Dizziness, occur withheadache.

EXSIRA been evaluated patients with a recent historyattacks, of myocardial infarction, unstable heart syndrome: psychiatric and non-psychiatric: anxiety, agitation, panic insomnia, irritability, hostility, concentrations ofimpulsivity, that hypertension, medicine and or decreased concentrations its CYP2D6 metabolites.

Medicines Common: Somnolence, tremor, paraesthesia, attention, Uncommon: treatment, particularly with concomitant usedysgeusia, of other disturbance agents thatin may affectvertigo. the serotonergic disease, uncontrolled cerebrovascular Patients with these diagnoses, except aggressiveness, akathisia, hypomania, and disease. mania. ofAlthough a causal link between the metabolised CYP3A4: In vitro, does not inhibittrials or induce the CYP3A4 isozymes.

Concomitant Syncope. Rare: system Convulsion, dystonia.

Psychiatric : Very common: Insomnia.

Common: neurotransmitter (including triptans, SSRIs,disorders other SNRIs, lithium, sibutramine, tramadol, St.Anxiety, John’s for cerebrovascular disease, were excluded from clinical (see SIDE EFFECTS).

Serum lipids: Doseemergence of by suicidal impulses hasEXSIRA not been established, consideration should be given to changing the use of EXSIRA with ainincluding medicine metabolised

by CYP3A4 may in lower exposures tocholesterol, that medicine. abnormal dreams, nervousness, decreased libido, anorgasmia.

[Hypericum perforatum ], pethidine), with medicines that impairUncommon: metabolism Withdrawal of serotoninsyndrome, (such as related elevations fasting possibly serum total cholesterol, LDL result (low density and Wort therapeutic regimen, discontinuing EXSIRA in patients forlipoprotein) whom such symptoms are

Potential for EXSIRA to affect other medicines: Medicines metabolised by CYP2D6: Clinical trials have shown that EXSIRA is a weak inhibitor of CYP2D6 at a dose of 100 mg daily.

Concomitant use of EXSIRA with a medicine metabolised by CYP2D6 may result in increased concentrations of that medicine and decreased concentrations of its CYP2D6 metabolites. Medicines metabolised by CYP3A4: In vitro, EXSIRA does not inhibit or induce the CYP3A4 isozymes. Concomitant use of EXSIRA with a medicine metabolised by CYP3A4 may result in lower exposures to that medicine.

Medicines metabolised by a combination of both CYP2D6 and CYP3A4 (tamoxifen and aripiprazole): Clinical studies have shown that EXSIRA (100 mg daily) does not have a clinically relevant effect on medicines metabolised by a combination of both CYP2D6 and CYP3A4 enzymes. Medicines metabolised by CYP1A2, 2A6, 2C8, 2C9 and 2C19: In vitro, EXSIRA does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of medicines that are metabolised by these CYP isozymes. P-glycoprotein transporter: In vitro, EXSIRA is not a substrate or an inhibitor for the P-glycoprotein transporter. Electroconvulsive therapy: There are no clinical data EXSIRA treatment for MDD. PREGNANCY AND LACTATION: EXSIRA must not be administered to pregnant or lactating women. Safety during human pregnancy and lactation has not been established (see CONTRAINDICATIONS).DOSAGE AND DIRECTIONS FOR USE: Major depressive disorder: The recommended dose for EXSIRA is 50 mg once daily, with or without food, with a maximum dose of 100 mg per day. The dose increase should occur gradually and at an interval of not less than 7 days. Use in patients with renal impairment: The recommended starting dose in patients with severe renal impairment (24-hr CrCl < 30ml/min) or end-stage renal disease (ESRD) is 50 mg every other day. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable.

Supplemental doses should not be given to patients after dialysis. Use in patients with hepatic impairment: No dosage adjustment is necessary for patients with hepatic impairment. Paediatric use: Use in elderly patients: No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of EXSIRA should be considered when determining dose. Discontinuing EXSIRA: Symptoms associated with discontinuation of EXSIRA, other SNRIs and SSRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the medical practitioner may continue decreasing the dose but at a more gradual rate (see WARNINGS AND SPECIAL PRECAUTIONS and SIDE EFFECTS). Switching patients from other antidepressants to EXSIRA: Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to EXSIRA. Tapering of the initial antidepressant may be necessary to minimise discontinuation symptoms. SIDE EFFECTS: Very common: ≥ 10 %, Common: ≥ 1 % and < 10 %, Uncommon: ≥ 0,1 % and < 1 %, Rare: ≥ 0,01 % and < 0,1 %, Very rare: < 0,01 %. Cardiac disorders: Common: Palpitations, tachycardia. Ear and labyrinth disorders : Common: Tinnitus. Eye disorders : Common: Blurred vision, mydriasis. Gastrointestinal disorders : Very common: Nausea, dry mouth, constipation. Common: Diarrhoea, vomiting. General disorders and administration site conditions : Common: Fatigue, chills, asthenia, feeling jittery, irritability. Immune system disorders : Uncommon: Hypersensitivity. Investigations : Common: Increased weight, increased blood pressure, decreased weight. Uncommon: Increased blood cholesterol, increased blood triglycerides, abnormal liver function test, increased blood prolactin. Metabolism and nutritional disorders : Common: Decreased appetite. Rare: Hyponatraemia. Musculoskeletal, connective tissue and bone disorders: Common: Musculoskeletal stiffness. Nervous system disorders: Very common: Dizziness, headache.

Common: Somnolence, tremor, paraesthesia, dysgeusia, disturbance in attention, vertigo. Uncommon: Syncope. Rare: Convulsion, dystonia. Psychiatric disorders : Very common: Insomnia. Common: Anxiety, abnormal dreams, nervousness, decreased libido, anorgasmia. Uncommon: Withdrawal syndrome, abnormal orgasm, depersonalisation. Rare: Hypomania, hallucinations. Renal and urinary disorders : Uncommon: Urinary hesitation, proteinuria, urinary retention. Reproductive system and breast disorders : Common: Erectile dysfunction*, delayed ejaculation*, ejaculation failure*. Uncommon: Ejaculation disorder*, sexual dysfunction. Respiratory, thoracic and mediastinal disorders: Common: Yawning.

Uncommon: Epistaxis. Skin and subcutaneous tissue disorders: Very common: Hyperhidrosis. Common: Rash. Uncommon: Alopecia. Rare: Photosensitivity reaction, angioedema. Not known: Stevens-Johnson syndrome**. Vascular disorders: WARNINGS AND SPECIAL PRECAUTIONS), peripheral coldness. *Frequency is calculated based on LICENCE HOLDER: (Pty) Ltd. Reg. No. 1954/000781/07. 85 Bute Lane, Sandton, 2196, South Africa. Tel. No.: 0860 PFIZER (734937). Please refer to detailed package insert for full prescribing information. PI Ref.: 06/03/2014.

Breakthroughs that change patients’ lives

2018/11/12 09:25

HER NEXT STEP AFTER FRAGILITY FRACTURE IS NEW BONE FOR PATIENTS WITH OSTEOPOROSIS AT RISK OF ANOTHER FRACTURE

1, 2

*

Treatment of osteoporosis patients with FORTEO®:1* • decreases the risk of vertebral and nonvertebral fractures1* • increases vertebral, femoral and total-body bone mineral density1*

CONSIDER FORTEO® AND HELP BUILD NEW BONE2 *Fracture Prevention Trial: Multicenter, prospective, double-blind trial of FORTEO® 20 mcg/day (n = 541) vs. placebo (n = 544). 1,637 postmenopausal women with osteoporosis, of whom 90 % had a prevalent vertebral fracture at baseline, were evaluated. Mean age: 69. Median duration of exposure to therapy: 19 months (maximum 24 months). All received 1,000 mg/day of calcium and 400 – 1,200 IU/day of vitamin D. References: 1. Neer RM, Arnaud CD, Zanchetta JR et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441. 2. McClung MR, San Martin J, Miller PD et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med 2005;165:1762-1768.

S4 FORTEO®. Each 2.4 ml FORTEO® cartridge contains 250 μg/ml of teriparatide (rDNA origin). Reg. No. 36/21.4/0334. For full prescribing information please refer to the package insert currently approved by the medicine regulatory authority.

Eli Lilly (S.A.) (Pty) Ltd. Reg. No. 1957/000371. 1st Floor, Suite 15, Golden Oak House, Ballyoaks Office Park, 35 Ballyclare Drive, Bryanston, 2021. Private Bag X119, Bryanston, 2021. Telephone: (011) 510 9300. PP-TE-ZA-0048 October 2018