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December 2016

clinical initiatives, research and current updates in treatment

Insulin Rachel Taylor, Epic Pharmacy Port Macquarie

Insulin is used for treatment of patients with diabetes mellitus type 1 and type 2 when optimal blood glucose control was not achieved with diet, exercise and other medications. In 2014 there were 29,436 people who began using insulin to treat their diabetes in Australia—66% had type 2 diabetes, 23% had gestational diabetes, 9% had type 1 diabetes and 2% had other forms of diabetes.1 Insulin is a high risk medication and incidents causing serious harm have been reported at all stages of the medication management pathway, with 61% of incidents occurring during administration, 17% during prescribing and 10% during dispensing.2 The top three error types were wrong dose, omitted or delayed dose and wrong insulin product. The leading causes of medication errors were incorrect prescriptions, use of dangerous abbreviation IU instead of “units” and incorrect monitoring of blood glucose and dose adjustments. The major contributing factors were “look alike, sound alike” nature of the proprietary names, poor documentation of dose administration on inpatient charts and failure to prescribe the correct insulin preparation.2 Insulin is available in forms that have different pharmacokinetic profiles featuring different time to onset, peak and duration of action. Table 1 (page 4) lists types of insulin and their pharmacokinetic characteristics.

All insulins are provided as 100 units per mL except for the concentrated insulins Toujeo® and Humulin R® U-500. Toujeo® is a concentrated insulin that contains 300 units per mL of long acting insulin glargine. Toujeo® is not interchangeable with Lantus® which contains insulin glargine 100 units per mL.4 Humulin R® U-500 is a short acting concentrated insulin human injection for subcutaneous use in patients with diabetes mellitus requiring more than 200 units of insulin per day. Do not confuse this product with Humulin R® which contains 100 units per mL.5 Concentrated insulins should be discontinued whilst the patient is in hospital and an alternative standard treatment prescribed. However, if the decision is made to continue using concentrated Humulin R® U-500 as inpatient therapy the following risk mitigation strategies are recommended:5,6 ¬¬ Annotate the orders clearly i.e. “Concentrated insulin Humulin

R® U-500” for identification and administration. Place safety alerts on the patient’s charts or notes ¬¬ As a syringe with U-500 scale is not available, to address common dosing confusion when using tuberculin syringe or standard U-100 syringe, the conversion information table5 must be provided to assist with dose selection and indication of required volumes ¬¬ Clearly mark the product and store separately from other insulin preparations ¬¬ Ensure use of uncommon insulin is discussed as part of clinical handover to alert staff of the potential risk ¬¬ Provide clear guidance to the patient on discharge on any decision to change or continue treatment In a hospital setting, consideration should be given to independent double checking before administration of insulin. In addition, steps should be taken to ensure that each insulin pen is used for one patient only3. Extra care should be taken in ensuring that the correct type of insulin and the correct dose is used for each patient to maximise safety and effectiveness of this high risk medication. References available on request.


What’s new Anti-PD-1: a snapshot of current therapy and rationale Anthony Chiu, Icon River City Pharmacy

The field of immunotherapy in oncology (coined immunooncology) has been re-invigorated in the past decade with the emergence of the immune checkpoint inhibitors, powerful anti-cancer agents that can awaken and re-harness the immune system to fight advanced cancers. Two of the most successful immune checkpoint inhibitors — nivolumab and pembrolizumab — target the Programmed Death-1 (PD-1) pathway. These agents have been approved for use worldwide for a variety of cancers, with more anti-PD-1 agents in development. PD-1 is a key inhibitory receptor expressed on the surface of activated cytotoxic T-cells and other immune cells. When PD-1 is activated by either of its two ligands — PD-L1 and the less ubiquitously expressed PD-L2 — it causes down-regulation of the activity of the immune cell. As such, PD-1 and its ligands are normally involved in controlling and suppressing active T-cell mediated immune response in a negative feedback loop fashion, acting as an ‘immune checkpoint’ that prevents excessive inflammation and autoimmune conditions.1,2,3

renal cell carcinoma (nivolumab), recurrent head and neck cancer (pembrolizumab) and Hodgkin’s lymphoma (nivolumab).5,6 To date these indications are for advanced disease settings with disease progression following prior established first-line therapies.

Importantly some tumours may also express PD-L1 and possibly PD-L2, which bind to PD-1 on T-cells and lead to inhibition of the immune system’s anti-tumour response. This allows these tumours to escape the immune system (see Figure 1). Therefore PD-1 is a crucial therapeutic target and has led to the development of immune checkpoint inhibiting monoclonal antibodies that either bind to and inhibit PD-1 directly (PD-1 inhibitor) or bind to PD-L1 thereby preventing its activation of PD-1 (PD-L1 inhibitor) (see Figure 2).1,2,3

The only exception for frontline use being in unresectable or advanced melanoma, where these agents demonstrated improved response rates in phase 3 trials compared to classical chemotherapy (nivolumab 40% vs dacarbazine 13.9%, pembrolizumab 23% vs investigator’s choice 4%).7,8 A further groundbreaking result was the lasting duration of response under the immune checkpoint inhibitors (dacarbazine median response 6 months vs nivolumab median response not reached at 12 months + 7% complete responses).7 There were responses which lasted past cessation of treatment, thus demonstrating how the immune checkpoint inhibitors may re-awaken the immune system’s natural anti-tumour response after previous dormancy.

Nivolumab and pembrolizumab are both PD-1 inhibitors. Within only the last 3 years these two agents have received accelerated approvals in the US among other continents for unresectable or advanced melanoma (both agents), metastatic nonsmall cell lung cancer (both agents),

The PD-1 inhibitors were also associated with better patient tolerability compared to traditional chemotherapy. In advanced melanoma, whilst the overall rate of treatmentrelated adverse events (AEs) was similar between the two groups (nivolumab 74.3% vs dacarbazine

75.6%), serious AEs (grade 3 & 4) were less common in the nivolumab group (nivolumab 11.7% vs dacarbazine 17.6%). The most common adverse events related to nivolumab were fatigue (19.9% of patients), pruritus (17%), nausea (16.5%) and infusionrelated reactions (6.4%). Better tolerability of nivolumab was further demonstrated by less AE-associated treatment discontinuation (6.8%) compared to dacarbazine (11.7%).7 Particular immune mediated AEs have also been noted. These present as immune-related overactivity in a range of organs, such as the lungs, colon, liver, kidneys and hormone-producing glands (e.g. thyroid). Results from the above trial showed serious (grade 3–4) immune-related AE’s were infrequent (<2% in any category).5,7

Figure 1. Tumour cell escape using PD-L1 ligand4

T-cell receptor

T-cell OFF

PD-1


Whilst individual product guidelines should be referred to in specific circumstances, the management of AEs for the current anti-PD-1 agents is generally consistent. No premedications or specific precautions for infusion reactions or nausea are required. In mild or moderate infusion reactions, it is recommended to interrupt or slow the infusion rate. There are no dosage adjustments required.5 For low grade (1) AEs, treatment schedule can continue if symptoms are managed with conventional symptom relief plus supplementation with topical or oral corticosteroids if required. For grade 2 AEs, treatment may be withheld and AEs managed with intravenous corticosteroids until symptoms subside (to ≤ grade 1), in which case treatment can resume as normal. For grade 3 AEs, patients are managed similarly or may escalate to permanent treatment discontinuation depending on organ/area of immune overactivity. Life-threatening (grade 4) AEs necessitate more intensive management and intravenous corticosteroids plus permanent treatment discontinuation in all cases. With early intervention the majority of AEs are resolved or controlled quickly

with low risk of mortality.5,7 The PD-L1 inhibitors have been more recently developed and a number of agents are in the development pipeline. Atezolizumab is the only agent approved so far (by the FDA), being granted accelerated approval for advanced urothelial bladder cancer after disease progression following platinum-containing chemotherapy.9 It is speculated that due to the selective blocking of PD-L1, PD-L1 inhibitors compared to PD-1 inhibitors may have less incidence of immunemediated AEs but whether this also translates into less efficacy is still also to be determined.3 Many cancers have been reported to have significant PD-L1 and/or PD-L2 expression, including melanoma, non-small cell lung cancer (NSCLC), colorectal cancer, breast cancer, ovarian cancer, renal cell carcinoma, glioblastoma, multiple myeloma and certain B-cell lymphomas.1,10 Even so, PD-L1 is not uniformly expressed by all these cancer types and actual individual expression can vary. In actuality, in the melanoma trials, the percentage of tumours that expressed PD-L1, at a level equal to or higher than 5%, ranged from 17%

to 33%.11,12 This has led to interest in how tumour PD-L1 levels may be a determinant for efficacy of antiPD-1 treatment. Reviews have found that PD-L1 expression is significantly associated with better clinical response to anti-PD-1 treatments in melanoma and NSCLC plus decreased mortality in melanoma.13,14 However, patients considered PD-L1 negative have also been found to experience benefit and long durations of response, therefore the role of PD-L1 as a potential predictive or prognostic biomarker is still uncertain.15 PD-1 targeted therapy has been a major contributor to the exciting revival of immuno-oncology and produced amazing results to date. There remains great potential with further investigation into the role PD-1 has in tumour response and how it may crossover with other immune checkpoints and therapeutic targets to maximise patient response.12,15 We look forward to what further development and research into the anti-PD-1 target brings in our fight against cancer. References available on request.

Figure 2. Effect of anti-PD-1 agents4

Antigen

Tumour cell

T-cell receptor

Antigen

T-cell ON

Tumour cell

PD-1 PD-L1

Anti PD-1

PD-L1 Anti PD-L1


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Nivolumab Anthony Chiu, Icon River City Pharmacy EGFR or ALK genomic aberrations that progress on/after prior chemotherapy, and for combination therapy with ipilimumab in metastatic melanoma.2

The immune checkpoint inhibitor nivolumab (Opdivo®) is a monoclonal antibody that binds to and blocks the activation of the Programmed Death-1 (PD-1) receptor (refer to article “Anti-PD-1 Therapy” in this issue for more details). Nivolumab became available from May 2016 on the Australian Pharmaceutical Benefits Scheme (PBS) for monotherapy in patients with unresectable or metastatic (with no prior ipilimumab or PD-1 inhibitor treatment).1

There is an Australian Opdivo Patient Access Program currently available for these indications.3

Nivolumab is also registered for use in Australia as monotherapy in locally advanced or metastatic non-small cell lung cancer (NSCLC) with or without

Nivolumab as monotherapy is dosed at 3mg/kg and infused over 60 minutes every fortnight. Combination therapy with ipilimumab starts with a nivolumab dose of 1mg/kg infused over 90 minutes every three weeks for 4 doses and then continues on as per monotherapy. Nivolumab doesn’t require premedication and is administered via intravenous infusion

through a low protein binding line with an in-line filter.2 Common side-effects (SEs)are fatigue, pruritus and nausea while serious SEs are immune-mediated. Management of immune-mediated SEs involve symptom management, withholding or discontinuing treatment, corticosteroids and potentially other systemic immunosuppressants, such as infliximab, depending on severity of the immune-mediated adverse event. There are no dose adjustments for nivolumab (refer to article “Anti‑PD-1 Therapy” for more details).2 References available on request.

Table 1. Insulin types, onset, peak and duration of action3 (from page 1) Name Of Insulin

Onset

Peak

Duration

Rapid acting

Name Of Insulin

Onset

Peak

Duration

Rapid premixes (rapid acting + immediate acting)

Insulin aspart (Novorapid) 15–20 min

1–3 hr

3–5 hr

NovoMix 30 (30% insulin aspart+70% protamine aspart)

10–20 min

1–4 hr

up to 24 hr

Insulin glulisine (Apidra)

15–30 min

1.6–2.8 hr

3–4 hr

Insulin lispro (Humalog)

15–30 min

0.5 — 3 hr

≤ 5 hr

Humalog Mix 25 (25% lispro + 75% protamine)

0–15 min

1 hr

16–18 hr

Neutral (Actrapid)

30 min

1–3 hr

8 hr

Rapid (Humulin R)

30 min

2–4 hr

Humalog Mix 50 (50% lispro + 50% protamine )

0–15 min

2 hr

16–18 hr

6–8 hr

Neutral (Hypurin)

30–60 min

2–3 hr

6–8 hr

Short premixes (short acting + immediate acting)

Short acting

Intermediate acting Isophane (Protaphane)

1.5 hr

4–12 hr

up to 24 hr

Isophane (Humulin NPH)

1 hr

4–10 hr

16–18 hr

Isophane (Hypurin Isophane)

2 hr

6–12 hr

18 hr

Insulin glargine (Lantus)

3–4 hrs

none

24 hr

Insulin detemir (Levemir)

3–4 hrs

3–9 hr

6–23 hr

Mixtard 30 (30% neutral + 30 min 70% isophane)

2–8 hrs

up to 24 hrs

Mixtard 50 (50% neutral + 30 min 50% isophane)

2–8 hrs

up to 24 hrs

Humulin 30/70 (30% regular + 70% isophane)

2–12 hrs

16–18 hrs

< 1 hour

Long acting

If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: circuit.editor@epicpharmacy.com.au Every effort has been made to ensure this newsletter is free from error or omission.

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Epic Pharmacy Circuit Newsletter December 2016  

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