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ISSUE 4 AUGUST
New drug

Rimegepant for migraine

Approved indications: acute treatment of migraine with or without aura in adults, and prophylactic treatment of episodic migraine in adults who have at least 4 migraine attacks per month
Nurtec ODT (Pfizer)
75 mg orally disintegrating tablets

Migraine is a complex neuronal disorder that can be difficult to treat. Stimulation of the trigeminal ganglion during migraine causes the release of several vasoactive neuropeptides including calcitonin gene-related peptide (CGRP), which is thought to play a key role in mediating inflammation and pain.1 A number of monoclonal antibodies targeting CGRP or its receptor are approved in Australia for prevention of migraine (eptinezumab, erenumab, fremanezumab, galcanezumab); these are administered intravenously or subcutaneously. Rimegepant is the first orally administered, small-molecule CGRP antagonist available in Australia, approved for both prevention and acute treatment of migraine.

For acute treatment of migraine, rimegepant provides modest benefit compared with placebo. Efficacy was evaluated in 4 similar randomised, double-blind, placebo-controlled phase 3 studies (total n=4847, mean age 37.8 to 42 years, majority female, approximately 30% with aura, most had at least 4 attacks per month).2,3 All 4 studies assessed rimegepant 75 mg versus placebo, with (standard) tablets used in 2 studies and orally disintegrating tablets used in 2 studies. The co-primary endpoints in all studies were freedom from pain, and freedom from the person’s most bothersome symptom (nausea, photophobia or phonophobia) 2 hours post-dose. Rimegepant was statistically more effective than placebo in all studies for both primary endpoints; however, the differences were fairly small. For freedom from pain at 2 hours, the difference between rimegepant and placebo ranged from 4.9 to 10.4% across the 4 studies. The highest absolute chance of being pain-free at 2 hours was 21%. For freedom from the most bothersome symptom at 2 hours, the difference between rimegepant and placebo ranged from 8.3 to 14.8% across the 4 studies. The highest absolute chance of being free from the most bothersome symptom was 50%.3

For migraine prophylaxis, rimegepant was assessed in a randomised, placebo-controlled phase 2/3 trial of people who experienced between 4 and 18 (median = 8) moderate to severe migraine attacks per month.2,4 The primary endpoint was change in the mean number of migraine days per month in the 12-week double-blind phase of the study compared with the initial 4-week observation phase. The 747 participants (median age 40, 83% female) were randomised to receive rimegepant 75 mg orally disintegrating tablet or placebo every other day. Data were analysed for 695 participants. Rimegepant was superior to placebo, with a mean difference of −0.8 migraine days per month: rimegepant −4.3 days (95% confidence interval [CI] −4.8 to −3.9) versus placebo −3.5 days (95% CI −4.0 to −3.0). There was no statistically significant difference in rescue medication use between the 2 arms; however, there was a trend towards reduced use with rimegepant.

Most adverse events in the prophylaxis and acute treatment trials were mild, with a similar incidence in the rimegepant and placebo arms. Nausea, and abdominal pain or dyspepsia, occurred in around 2% of participants receiving rimegepant. Hypersensitivity, including dyspnoea and severe rash, occurred in less than 1% of patients. Drowsiness has been reported (although migraines can also cause drowsiness), so caution is recommended in patients driving or using machines during a migraine attack, including after treatment. There is no evidence to date that rimegepant use leads to medication overuse headache.2,5

Safety data for rimegepant in patients with cardiovascular disease are lacking (clinical trials generally excluded people with new or unstable cardiovascular disease, uncontrolled hypertension and uncontrolled diabetes), but there is a theoretical risk that long-term suppression of CGRP could impede the CGRP-mediated vasodilatory response to ischaemic events.2,6 Cautious use of CGRP antagonists in patients with cardiovascular disease is prudent.

Rimegepant is metabolised by the cytochrome P450 enzyme CYP3A4 and should not be used concomitantly with strong CYP3A4 inhibitors, nor strong or moderate CYP3A4 inducers, which increase or decrease rimegepant concentrations respectively. When rimegepant is used concomitantly with moderate inhibitors of CYP3A4 or with strong inhibitors of P-glycoprotein, a further dose of rimegepant should not be taken within 48 hours.5

Rimegepant is classified as category B1 in pregnancy. A small study of a single dose of rimegepant 75 mg taken by breastfeeding women found that transfer of rimegepant into breastmilk is low; however, there are no data on the effects of the drug on the infant or on milk production.5

Rimegepant is available as an orally disintegrating tablet that can be placed on or under the tongue; it can be taken without liquid. The patient should use dry hands when removing the tablet from its packaging (as it may start to disintegrate in the presence of moisture). For acute treatment of migraine, the recommended dose is rimegepant 75 mg as needed, with a maximum of 75 mg in 24 hours. For prophylaxis of migraine, the recommended dose is rimegepant 75 mg every other day (if rimegepant is also required for acute treatment, the total maximum dose is 75 mg in 24 hours). No dosage adjustment is required in mild, moderate or severe renal impairment, but avoid use in patients with end-stage renal disease (creatinine clearance less than 15 mL/min). Rimegepant should not be used in patients with severe hepatic impairment.5

Rimegepant offers modest benefit compared with placebo for acute treatment or prophylaxis of migraine. It may serve as an alternative option when other migraine therapies are ineffective, contraindicated or not tolerated; however, its role in therapy in Australia is not yet clear.7

This new drug comment was finalised on 24 June 2024.

🅃 🅃 manufacturer provided additional useful information. The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA, the European Medicines Agency and the Therapeutic Goods Administration.

 

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References

  1. Pescador Ruschel M, De Jesus O. Migraine Headache. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. [cited 2024 Jun 17]
  2. Therapeutic Goods Administration. Australian Public Assessment Report for Nurtec ODT. Department of Health and Aged Care; 2024. [cited 2024 Jun 19]
  3. Yu S, Kim BK, Guo A, Kim MH, Zhang M, Wang Z, et al. Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2023;22:476-84.
  4. Croop R, Lipton RB, Kudrow D, Stock DA, Kamen L, Conway CM, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet 2021;397:51-60.
  5. Therapeutic Goods Administration. Australian Product Information - NURTEC ODT rimegepant (as sulfate) 75 mg orally disintegrating tablet blister pack. Department of Health and Aged Care; 2023. [cited 2024 Jun 19]
  6. Loder EW, Burch RC. Who Should Try New Antibody Treatments for Migraine? JAMA Neurol 2018;75:1039-40.
  7. Lipton RB, Blumenfeld A, Jensen CM, Croop R, Thiry A, L'Italien G, et al. Efficacy of rimegepant for the acute treatment of migraine based on triptan treatment experience: Pooled results from three phase 3 randomized clinical trials. Cephalalgia 2023;43.

 The new drug commentaries in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Advisory Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

 
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