New Medicines Profile February 2010

Issue No. 10/01

Fentanyl nasal spray (Instanyl®)

Concise evaluated information to support the managed entry of new medicines in the NHS Introduction

Summary •

Fentanyl nasal spray (Instanyl®) is licensed for breakthrough pain in adults receiving maintenance opioid therapy for chronic cancer pain. There are several other immediate release fentanyl products already on the market for this indication. Instanyl® is the first intranasal formulation available. There are two published randomised controlled trials of Instanyl®. Its use resulted in significantly superior pain reduction at 10 minutes compared to placebo, and provided analgesia around 5 minutes faster than oral transmucosal fentanyl (Actiq®).

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The safety profile of Instanyl® appears comparable to that of other fentanyl containing products indicated in the treatment of breakthrough cancer pain. Typical opioid adverse reactions have been reported. The most common adverse reactions are somnolence, dizziness, headache, vertigo, flushing, throat irritation, hyperhidrosis, nausea and vomiting.

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Instanyl® is currently the most expensive immediate release fentanyl preparation on the market. It is significantly more expensive than immediate release morphine.

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As with other immediate release fentanyl products, Instanyl® treatment must be initiated and supervised by physicians experienced in opioid therapy in cancer patients.

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Instanyl® bypasses the oral/gastrointestinal route and may offer advantages to patients with nausea or vomiting, oral mucositis, dry mouth and impaired gastrointestinal function.

Brand Name, (Manufacturer): Instanyl®, (Nycomed Danmark ApS) BNF Therapeutic Class: Opioid analgesics 4.7.2 Licensed Indications: Breakthrough pain in adults already receiving maintenance opioid therapy for chronic cancer pain. Dosage and Administration: 50 micrograms in one nostril, titrating upwards as necessary, as described in the Summary of Product Characteristics, through the range of available strengths (50, 100, and 200 micrograms). A second dose of the same strength can be administered after at least 10 minutes if required. A maximum of four breakthrough pain episodes may be treated per day, providing they are at least 4 hours apart. Marketed: October 2009 Cost Comparisons: Cost for one dose (prices from eMIMs February 2010. For each fentanyl preparation the cost was the same regardless of strength.

 

 

 

NB: Prices are shown for general comparison and do not imply therapeutic equivalence.

Breakthrough pain (BTP) is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain.1 A typical BTP episode reaches peak intensity after three to five minutes and has an average duration of 15 to 30 minutes.2 There are several immediate release fentanyl products licensed for the management of BTP in patients already receiving maintenance opioid therapy for chronic cancer pain. Instanyl® is a new product licensed for this indication. Benefits include its nasal route of administration, which avoids first-pass metabolism of the active substance and provides quick onset of analgesic action.1

Evidence Full results from individual studies can be found in Appendices 1 to 3. There are two published comparative studies of Instanyl® in the treatment of BTP in adult cancer patients, one versus placebo and the other versus Actiq®. The placebo controlled study was of a double-blind crossover design and enrolled 120 patients from two previous studies; these patients may be considered as responders.3, 4 Ninety-four percent of patients were titrated to an effective dose during the titration phase.4 This is higher than the rate found with other rapidly absorbed fentanyl preparations, which is likely to be because patients had received Instanyl® as part of previous studies.4 Therefore, they may be considered as responders and tolerant (in terms of safety to Instanyl®) which may have biased the results.4 Patients were titrated to an Instanyl® dose of 50, 100 or 200micrograms during the initial phase of the study.3 They received this dose, or placebo, in a randomised double-blind sequence for eight BTP episodes. The primary endpoint was the pain intensity difference at 10 minutes (PID10) after the first actuation, assessed using an 11 point numerical scale. An effect size of 0.5 PID10 was considered clinically relevant. It was not clear how the study designers decided upon this figure. All three strengths of Instanyl® were superior to placebo (Appendix 1).3 The mean response rate (defined as a PID10 > 2) was 51.1% versus 20.9%, respectively (confidence interval not provided). 3 Secondary endpoints, which included the sum of normalised PIDs over 0-60 minutes and the general impression score also favoured Instanyl®.3 In the active comparative trial Instanyl® was compared with Actiq® in an openlabel, crossover treatment of six episodes

Fentanyl nasal spray (Instanyl®) of BTP in 139 opioid-tolerant patients with cancer (Appendix 2).5 In total 85.1% and 87.9% of patients initiating titration reached an effective dose of Instanyl® and Actiq®, respectively. The proportion of treated BTP episodes which required rescue medication with another agent (not defined) was 7.8% with Instanyl® compared with 4.9% for Actiq®. The primary endpoint of the study was the time to onset of meaningful pain relief. A statistically significant proportion of patients reported faster pain relief with Instanyl® (65.7 %, p 15 minutes and an intensity that required treatment with an analgesic Œ Receiving stable chronic opioid therapy equivalent to 60-500mg of oral morphine/day for ≥ 1 month to control background pain to a mild intensity Œ History of at least partial relief of BTP with the use of a strong immediate release opioid Œ Ability to use intranasal drugs Exclusion criteria Œ pregnant/breastfeeding Œ experiencing psychiatric, severe hepatic or respiratory impairment Œ treated with a monoamine oxidase inhibitor within the 14 days before the study Œ using methadone or buprenorphine Œ using intranasal drugs or had a nasopharyngeal probe. Œ conditions that might have increased the risk of elevated intracranial pressure or impaired consciousness, or prevented administration or normal absorption of Instanyl®

Results Primary Outcome Pain intensity difference at 10 minutes (PID10) after first actuation. Assessed using an 11 point numerical scale (0=no pain to 10=worst pain imaginable) Instanyl® dose, micrograms

Instanyl®) Pooled doses (n=111)

Placebo (n=110)

2.56 (0.131)

1.28 (0.138)

Least Squares (LS) Mean (95% confidence interval [CI])

2.36 (2.16-2.56)

1.10 (0.841.36)

LS Mean versus placebo (95% CI)

1.26 (1.03-1.48); p