23 minute read
New Microbiota Research Could Lift the Fog on Chemobrain
Cancer is the second-leading cause of death in Europe and imposes significant human and economic costs. Research in recent decades has primarily focused on reducing mortality and relapse rates, leading to considerable improvements to established treatment regimens as well as the advent of new therapies, specifically the development of immunotherapies and more targeted anti-cancer agents. These advancements in treatment options have dramatically improved patient care and survival for several cancers and have also exposed a number of issues around the long-term side effects of cancer therapies that impact quality of life.
What is chemobrain?
A large subset of cancer patients and survivors frequently report neuropsychiatric symptoms and impairments during and following cancer treatment, including impaired cognition, increased incidence of mood and anxiety disorders, and increased pain and fatigue which collectively resembles “brain fog” and has been termed “chemobrain”. These impairments are most frequent during and immediately following therapy, although some cancer survivors experience these symptoms for decades after the resolution of their cancer, interfering with their well-being and return to normal life. These neuropsychiatric impairments are often difficult to quantify: while patients’ subjective reports indicate sluggish thinking and poorer cognitive performance following therapy, these are often not well captured by standard neuropsychological testing utilised in the majority of studies to date. This is most likely because standard neuropsychological tests were originally designed for diagnosis of focal lesions of the central and peripheral nervous systems, rather than diffuse damage throughout the brain. Approaches using methods from cognitive psychology, which are designed to assess cognitive performance within healthy populations, have identified that cancer patients and survivors suffer from difficulties with concentration and attention, short-term memory and executive function.
Written by Dr Sarah-Jane Leigh, Government of Ireland Postdoctoral Fellow at APC Microbiome Ireland, an SFI Research Centre headquartered at University College Cork
What the Research Tells us
While most research so far has shown that these neuropsychiatric symptoms and impairments are associated with traditional cytotoxic chemotherapy regimens in cancer
patients and survivors, there is emerging evidence that newer immunotherapies1 and targeted cancer therapies2 may have similar impacts on brain health and function. The mechanisms underpinning these chemobrain symptoms are poorly understood, posing a serious impediment to their clinical management. Similarly to cancer patients and survivors, in vivo experiments with chemotherapeutic agents induce impairments in cognition and increased anxiety-like and pain behaviours. These experiments have shown that chemotherapeutic agents increase neuroinflammation, reduce neurogenesis and neurotransmitter availability, and alter neuronal morphology throughout the central and peripheral nervous systems when administered in both healthy animals and those with cancerous tumours.
The gut microbiota, cancer and chemobrain
The human gastrointestinal tract is populated by an ecosystem of bacteria and other micro-organisms, collectively known as the gut microbiota, that have co-evolved alongside humans to produce a complex symbiotic relationship. The gut microbiota supports host physiology through improved energy harvest, strengthened gut integrity and barrier function, protection from infection, immune modulation3, and brain health and function.4 A healthy gut microbiota is thought to reduce the risk of cancer development, while altered gut microbiota community as well as specific gut microbes can increase the likelihood of developing gastrointestinal cancers5 (for example, Helicobacter pylori causes stomach ulcers and increases the prevalence of stomach and small intestine cancers while Fusobacterium nucleatum promotes colorectal cancer development). Furthermore, the gut microbiota can modulate cancer therapy effectiveness through direct and indirect interactions with cancer drugs: chemotherapies can transiently shift gut microbiota composition and microbial metabolite production, and baseline
microbiota composition and exposure to antibiotics influences patient responses to immunotherapy.6 The gut microbiota also appears to be involved in cancer therapy side effects involving the gut (diarrhoea and nausea), infection risk as well as changes in the central and peripheral nervous systems. A recent systematic review assessing the role of the microbiota in side effects reported by cancer patients concluded that microbiota composition was associated with fatigue, anxiety, depression, sleep quality, cognitive impairment and peripheral neuropathy in patients undergoing chemotherapy.7 These results are in line with emerging evidence from experiments in vivo where chemotherapy-related fatigue8 and peripheral neuropathy9 are related to microbiota composition and can be modified through interventions targeting the microbiota. So far, only a few drugs and neuropsychological symptoms have been examined and several experts in the field have identified the microbiota as a potential site for intervention in chemobrain.
What is the role of drug-microbiota and brain-microbiota interactions in chemobrain?
Professors Gerard Clarke, John Cryan, and I at APC Microbiome Ireland, a Science Foundation Ireland funded research centre dedicated to the study of host-microbe interactions, are combining behavioural neuroscience and neuropharmacology approaches to address how traditional and novel cancer drugs may induce chemobrain through modulation of the gut microbiota, in collaboration with a multidisciplinary team spanning pharmacy, pharmacomicrobiomics (the study of drugmicrobiota interactions), microbiology and oncology. Our current project is grounded in the hypothesis that host-microbiota and drug-microbiota interactions underlie cancer-therapy associated behavioural impairment. Specifically, we propose that different cancer therapies will present unique drug-microbiota interactions that will modify host-microbiota interactions and subsequently behaviour. The lived experience of cancer treatment means people often take longer than they anticipated to get back on their feet and fully engaged in life, and this is often due in part to chemobrain. Understanding the mechanisms at play can help find some much-needed solutions to this problem and deliver potential interventions for these behavioural impairments. The study of how microbiota-drug interactions alter drug benefits and side effects is a relatively new avenue of research with substantial scope to yield impactful new discoveries. The development of microbiota-targeted therapies holds promise for the management of these troublesome side effects that cloud quality of life for cancer patient and survivor.
Twitter @SarahJane_Leigh Linkedin Sarah-Jane Leigh Twitter @Pharmabiotic Linkedin APC Microbiome Ireland Facebook Pharmabiotic Instagram microbiomeireland
References:
1. Joly F, Castel H, Tron L, Lange M, Vardy J.
Potential Effect of Immunotherapy Agents on Cognitive Function in Cancer Patients.
J Natl Cancer Inst. 2020;112(2):123-127. doi:10.1093/jnci/djz168 2. Abdel-Aziz AK, Mantawy EM, Said RS,
Helwa R. The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating
VEGFR signaling, apoptotic and autophagic machineries. Exp Neurol. 2016 Sep;283(Pt A):129-41. doi: 10.1016/j. expneurol.2016.06.004. 3. Sekirov I, Russell SL, Antunes LCM et al.
Gut Microbiota in Health and Disease.
Physiological Reviews. 2010;90(3):859-904. doi: 10.1152/physrev.00045.2009. 4. Cryan, J., Dinan, T. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat
Rev Neurosci. 2012 13, 701–712. https://doi. org/10.1038/nrn3346 5. Helmink, B.A., Khan, M.A.W., Hermann, A. et al. The microbiome, cancer, and cancer therapy. Nat Med 25, 377–388 (2019). https:// doi.org/10.1038/s41591-019-0377-7 6. Leigh SJ, Lynch CMK, Bird BRH, et al. Gut microbiota-drug interactions in cancer pharmacotherapies: implications for efficacy and adverse effects. Expert Opin Drug
Metab Toxicol. 2022 Jan;18(1):5-26. doi: 10.1080/17425255.2022.2043849. 7. Song BC, Bai J. Microbiome-gut-brain axis in cancer treatment-related psychoneurological toxicities and symptoms: a systematic review. Support Care Cancer. 2021
Feb;29(2):605-617. doi: 10.1007/s00520-02005739-9. 8. Grant CV, Loman BR, Bailey MT, Pyter LM.
Manipulations of the gut microbiome alter chemotherapy-induced inflammation and behavioral side effects in female mice. Brain
Behav Immun. 2021 Jul;95:401-412. doi: 10.1016/j.bbi.2021.04.014. 9. Ramakrishna, C., Corleto, J., Ruegger, P.M. et al. Dominant Role of the Gut Microbiota in Chemotherapy Induced Neuropathic
Pain. Sci Rep 9, 20324 (2019). https://doi. org/10.1038/s41598-019-56832-x
Strength of Balance
Indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or are intolerant to one or more disease modifying anti-rheumatic drugs.1 May be used as monotherapy or in combination with methotrexate.1
Refer to Summary of Product Characteristics (SmPC) before prescribing, and for full prescribing information.
JYSELECA® filgotinib 100 mg or 200 mg film-coated tablets. Indication: Jyseleca is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti rheumatic drugs (DMARDs). Jyseleca may be used as monotherapy or in combination with methotrexate (MTX). Dosage: Adults: 200 mg once daily. Taken orally with/without food. It is recommended that tablets are swallowed whole. Laboratory Monitoring: Refer to the SmPC for information regarding laboratory monitoring and dose initiation or interruption. Elderly: A starting dose of 100 mg once daily is recommended for patients aged 75 years and older as clinical experience is limited. Renal impairment: No dose adjustment required in patients with estimated creatinine clearance (CrCl) ≥ 60 mL/min. A dose of 100 mg of filgotinib once daily is recommended for patients with moderate or severe renal impairment (CrCl 15 to < 60 mL/min). Not recommended in patients with CrCl < 15 mL/min. Hepatic impairment: Mild/moderate hepatic impairment: no dose adjustment required. Severe hepatic impairment: not recommended. Children (< 18years): Safety and efficacy not yet established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active tuberculosis (TB) or active serious infections. Pregnancy. Warnings/Precautions: See SmPC for full information. Immunosuppression: Combination use, with immunosuppressants e.g. azathioprine, ciclosporin, tacrolimus, or biologic DMARDs (bDMARDs) or other Janus kinase (JAK) inhibitors is not recommended as a risk of additive immunosuppression cannot be excluded. Infections: Infections, including serious infections such as pneumonia and opportunistic infections e.g. tuberculosis (TB), oesophageal candidiasis, and cryptococcosis have been reported. Risk benefit should be assessed prior to initiating in patients with risk factors for infections (see SmPC). Patients should be closely monitored for the development of signs and symptoms of infections during and after filgotinib treatment. Treatment should be interrupted if the patient is not responding to antimicrobial therapy, until infection is controlled. There is a higher incidence of serious infections in the elderly aged 75 years and older, caution should be used when treating this population. Tuberculosis: Patients should be screened for TB before initiating filgotinib, and filgotinib should not be administered to patients with active TB. Viral reactivation: Cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies (see SmPC). If a patient develops herpes zoster, filgotinib treatment should be temporarily interrupted until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed. Malignancy: Immunomodulatory medicinal products may increase the risk of malignancies. Malignancies were observed in clinical studies (see SmPC). Fertility: In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed (see SmPC). The potential effect of filgotinib on sperm production and male fertility in humans is currently unknown. Haematological abnormalities: Do not start therapy, or temporarily stop, if Absolute Neutrophil Count (ANC) <1 × 109 cells/L, ALC <0.5 × 109 cells/L or haemoglobin <8 g/dL. Temporarily stop therapy if these values are observed during routine patient
JYSELECA – a preferential JAK1 inhibitor for moderate to severe RA1
JYSELECA shows more than 5x greater potency for JAK1 over JAK2/3 and TYK21* Balancing sustained efficacy2-6 with acceptable tolerability1,7
*This is based on biochemical assays, the clinical consequence of this is unknown. Common adverse events (≥1/100 to <1/10) include: nausea, upper respiratory tract infection, urinary tract infection, dizziness.1
Visit strengthofbalance.co.uk to learn more
management. Vaccinations: Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. Lipids: Treatment with filgotinib was associated with dose dependent increases in lipid parameters, including total cholesterol, and high-density lipoprotein (HDL) levels, while low density lipoprotein (LDL) levels were slightly increased (see SmPC). Cardiovascular risk: Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care. Venous thromboembolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. Caution should be used in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery, and prolonged immobilisation. Lactose content: Contains lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take filgotinib. Pregnancy/ Lactation: Filgotinib is contraindicated in pregnancy. Filgotinib should not be used during breast-feeding. Women of childbearing potential must use effective contraception during and for at least 1 week after cessation of treatment. Driving/Using machinery: No or negligible influence, however dizziness has been reported. Side effects: See SmPC for full information. Common (≥1/100 to <1/10): nausea, upper respiratory tract infection, urinary tract infection and dizziness. Uncommon (≥1/1000 to <1/100): herpes zoster, pneumonia, neutropenia, hypercholesterolaemia and blood creatine phosphokinase increase. Serious side effects: See SmPC for full information Legal category: POM Pack: 30 film-coated tablets/bottle Price: UK Basic NHS cost: £863.10; Ireland: POA Marketing authorisation number(s): Jyseleca 100mg film-coated tablets EU/1/20/1480/001 EU/1/20/1480/002 Jyseleca 200mg film-coated tablets EU/1/20/1480/003 EU/1/20/1480/004 Further information: Galapagos UK, Belmont House, 148 Belmont Road, Uxbridge UB8 1QS, United Kingdom 00800 7878 1345 medicalinfo@glpg.com Jyseleca® is a trademark. Date of Preparation: January 2022 IE-RA-FIL-202112-00003
Additional monitoring required
Adverse events should be reported. For Northern Ireland, reporting forms and information can be found at yellowcard.mhra.gov.uk or via the Yellow Card app (download from the Apple App Store or Google Play Store). Adverse events should also be reported to Galapagos via email to Drug.safety.UK.Ireland@glpg.com or 00800 7878 1345 Adverse events should be reported. For Ireland, reporting forms and information can be found at www.hpra.ie and can be reported to HPRA on +353 1 6764971. Adverse events should also be reported to Galapagos via email to Drug.safety.UK.Ireland@glpg.com or 00800 7878 1345
References: 1. JYSELECA SPC. Available at: www.medicines.org.uk / www.medicines.ie. Last accessed: January 2022. 2. Combe B, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219214. 3. Genovese MC, et al. JAMA 2019;322 (4):315–325. 4. Westhovens R, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219213. 5. Combe B, et al. Poster presented virtually at ACR, November 3–10, 2021. 6. Buch MH, et al. Poster presented virtually at ACR, November 3–10, 2021. 7. Genovese MC, et al. Poster presented virtually at the European League Against Rheumatism (EULAR) 2020 E-Congress, June 3–6, 2020.
Survival results from KEYNOTE-006
An open-label, multicentre, randomised, controlled, phase 3 study of KEYTRUDA monotherapy vs Ipilimumab for patients with advanced Melanoma.1-3
7-Year Overall Survival in the intention-to-treat population* In participants who completed 2 years of KEYTRUDA and achieved Stable Disease or better*
KEYTRUDA 37.8% vs Ipilimumab 25.3% HR 0.70 (95 % CI 0.58 to 0.83)
5-year Overall Survival was 92.9% 5-year Progression Free Survival was 70.1% 103/556 (18.5%) of patients obtained stable disease or better In the as-treated population, any grade adverse events of any cause occurred in 442 (80%) of 555 participants in the pembrolizumab group and 190 (74%) of 256 participants in the Ipilimumab group. Grade 3 or worse adverse events of any cause occurred in 96 (17%) in the pembrolizumab group and 50 (20%) in the Ipilimumab group.
*This is a 7-year follow-up post-hoc analysis and no statistical conclusions can be drawn from these results
KEYTRUDA® (pembrolizumab)
ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION KEYTRUDA 25 mg/mL: One vial of 4 mL of concentrate contains 100 mg of pembrolizumab. INDICATIONS KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection. KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD L1 with a combined positive score (CPS) ≥ 10. KEYTRUDA as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1. KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy. KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma (RCC) in adults. KEYTRUDA, in combination with lenvatinib, is indicated for the first line treatment of advanced renal cell carcinoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. KEYTRUDA as monotherapy is indicated for the first line treatment of metastatic microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in adults. KEYTRUDA as monotherapy is indicated for the treatment of the following MSI H or dMMR tumours in adults with (a) unresectable or metastatic colorectal cancer after previous fluoropyrimidine based combination therapy, (b) advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation, (c) unresectable or metastatic gastric, small intestine, or biliary cancer, who have disease progression on or following at least one prior therapy. KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 10. KEYTRUDA, in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, is indicated for the treatment of adults with locally advanced, or early stage triple negative breast cancer at high risk of recurrence. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumours express PD L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease. KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation. KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD L1 with a CPS ≥ 1. DOSAGE AND ADMINISTRATION See SmPC for full details. Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer. The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes. For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitant therapies. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first. Treat patients until disease progression or unacceptable toxicity (and up to maximum duration of therapy if specified for an indication). For the adjuvant treatment of melanoma or RCC, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year. Refer to the SmPC for dosing in neoadjuvant and adjuvant treatment of locally advanced, or early stage triple-negative breast cancer at high risk of recurrence. KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued (a) For Grade 4 toxicity except for: endocrinopathies that are controlled with replacement hormones; or haematological toxicity, only in patients with cHL in which KEYTRUDA should be withheld until adverse reactions recover to Grade 0-1; (b) If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks; (c) If a treatment-related toxicity does not resolve to Grade 0 1 within 12 weeks after last dose of KEYTRUDA; (d) If any event occurs a second time at Grade ≥ 3 severity. Patients must be given the Patient Alert Card and be informed about the risks of KEYTRUDA. Special populations Elderly: No dose adjustment necessary. Renal impairment: No dose adjustment needed for mild or moderate renal impairment. No studies in severe renal impairment. Hepatic impairment: No dose adjustment needed for mild hepatic impairment. No studies in moderate or severe hepatic impairment. Paediatric population: Safety and efficacy in children below 18 years of age not established except in paediatric patients with cHL. CONTRAINDICATIONS Hypersensitivity to the active substance or to any excipients. PRECAUTIONS AND WARNINGS Assessment of PD-L1 status When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations. Immune-related adverse reactions Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously. Immune-related adverse reactions are immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis, immune-related endocrinopathies (including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism), Immune-related skin adverse reactions (also including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)), Refer to SmPC for more information and management of immune-related adverse reactions. Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Infusion-related reactions: Grades 1, 2, 3 or 4 infusion reactions including hypersensitivity and anaphylaxis, could be seen with pembrolizumab treatment. Refer to SmPC for more information and management of infusion-related reactions. Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab. Breast-feeding It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded. Fertility No clinical data available. SIDE EFFECTS Refer to SmPC for complete information on side effects. Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For additional lenvatinib safety information related to advanced RCC see the SmPC for Kisplyx and for advanced EC see the SmPC for Lenvima. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, pruritus, rash, fatigue. Common: pneumonia, thrombocytopenia, neutropenia, lymphopenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, dermatitis, myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, increase in blood alkaline phosphatase, hypercalcaemia, blood bilirubin increased, blood creatinine increased, infusion related reaction. In combination with chemotherapy: Very Common: neutropenia, anaemia, thrombocytopenia, leukopenia, hypothyroidism, hypokalaemia, decreased appetite, insomnia, neuropathy peripheral, headache, dizziness, dysgeusia, dyspnoea, cough, nausea, diarrhoea, vomiting, abdominal pain, constipation, alopecia, rash, pruritus, arthralgia, musculoskeletal pain, myositis, pyrexia, fatigue, asthenia, oedema, ALT increase, AST increased. Common: pneumonia, febrile neutropenia, lymphopenia, infusion related reaction, adrenal insufficiency, thyroiditis, hyperthyroidism, hyponatraemia, hypocalcaemia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, pneumonitis, colitis, gastritis, dry mouth, hepatitis, severe skin reactions, erythema, dermatitis acneiform, dermatitis, dry skin, eczema, pain in extremity, arthritis, acute kidney injury, influenza-like illness, chills, blood creatinine increased, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased. In combination with axitinib or lenvatinib: Very Common: urinary tract infection, anaemia, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, diarrhoea, abdominal pain, nausea, vomiting, constipation, rash, pruritus, arthralgia, musculoskeletal pain, myositis, pain in extremity, fatigue, asthenia, oedema, pyrexia, lipase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, infusion-related reaction, adrenal insufficiency, hyperthyroidism, thyroiditis, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, dizziness, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, pancreatitis, gastritis, dry mouth, hepatitis, severe skin reactions, dermatitis, dry skin, erythema, dermatitis acneiform, alopecia, arthritis, nephritis, influenza like illness, chills, amylase increased, blood bilirubin increased, blood alkaline phosphatase increased, hypercalcaemia. PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers EU/1/15/1024/002 Marketing Authorisation holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: May 2022. © 2022 Merck & Co., Inc., Rahway, NJ, USA and its affiliates.. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin, D18 X5K7 or from www.medicines.ie. II109_II117_II110
Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to MSD (Tel: 01-2998700)
References
1. KEYTRUDA (pembrolizumab) SmPC. Available at: www.medicines.ie. Accessed June 2022 2. Robert C, Carlino MS, McNeil C, et al. 7-Year Follow-Up of KEYNOTE-006: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. Poster 104. Presented at the 18th International Congress of the Society for Melanoma Research; October 28-31, 2021; Virtual. 3. C. Robert, A. Ribas, J. Schachter et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019; 20: 1239-1251
