RIMEGEPANT: 9,175 Adverse Event Reports & Safety Profile

NURTEC ODT contains rimegepant sulfate, a calcitonin gene-related peptide receptor antagonist. Rimegepant sulfate is described chemically as (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate sesquihydrate and its structural formula is: Its empirical formula is C 28 H 28 F 2 N 6 O 3 0.5 H 2 SO 4 1.5 H 2 O, representing a molecular weight of 610.63. Rimegepant free base has a molecular weight of 534.56. Rimegepant sulfate is a white to off-white, crystalline solid that is slightly soluble in water. NURTEC ODT (orally disintegrating tablets) is for sublingual or oral use and contains 85.7 mg rimegepant sulfate, equivalent to 75 mg rimegepant free base, and the following inactive ingredients: benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin.

Chemical

Structure

AND USAGE NURTEC ODT is a calcitonin gene-related peptide receptor antagonist indicated for the:

• acute treatment of migraine with or without aura in adults ( 1.1 )
• preventive treatment of episodic migraine in adults ( 1.2 )

1.1 Acute Treatment of Migraine NURTEC ODT is indicated for the acute treatment of migraine with or without aura in adults .

1.2 Preventive Treatment of Episodic Migraine NURTEC ODT is indicated for the preventive treatment of episodic migraine in adults.

AND ADMINISTRATION

• Recommended dosage for acute treatment of migraine: 75 mg taken orally, as needed. ( 2.1 )
• The safety of using more than 18 doses in a 30-day period has not been established. ( 2.1 )
• Recommended dosage for preventive treatment of episodic migraine: 75 mg taken orally every other day. ( 2.2 )
• The maximum dose in a 24-hour period is 75 mg. ( 2.1 )

2.1 Recommended Dosing for Acute Treatment of Migraine The recommended dose of NURTEC ODT is 75 mg taken orally, as needed. The maximum dose in a 24-hour period is 75 mg. The safety of using more than 18 doses in a 30-day period has not been established.

2.2 Recommended Dosing for Preventive Treatment of Episodic Migraine The recommended dosage of NURTEC ODT is 75 mg taken orally every other day.

2.3 Administration Information Instruct the patient on the following administration instructions:

• Use dry hands when opening the blister pack.
• Peel back the foil covering of one blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil.
• As soon as the blister is opened, remove the ODT and place on the tongue; alternatively, the ODT may be placed under the tongue.
• The ODT will disintegrate in saliva so that it can be swallowed without additional liquid.
• Take the ODT immediately after opening the blister pack. Do not store the ODT outside the blister pack for future use.

2.4 Concomitant Administration with Strong or Moderate CYP3A4 Inhibitors Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]</span>.

2.5 Concomitant Administration with Strong or Moderate CYP3A Inducers Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A, which may lead to loss of efficacy of NURTEC ODT <span class="opacity-50 text-xs">[see Drug Interactions (7.2) , Clinical Pharmacology (12.3) ]</span> .

2.6 Concomitant Administration with Potent Inhibitors of P-gp Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with potent inhibitors of P-gp <span class="opacity-50 text-xs">[see Drug Interactions (7.3) , Clinical Pharmacology (12.3) ]</span>.

NURTEC ODT is contraindicated in patients with a history of hypersensitivity reaction to rimegepant, NURTEC ODT, or any of its components. Reactions have included anaphylaxis and delayed serious hypersensitivity [see Warnings and Precautions (5.1) ] . Patients with a history of hypersensitivity reaction to rimegepant, NURTEC ODT, or to any of its components. ( 4 )

REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1) ]
• Hypertension [see Warnings and Precautions (5.2) ]
• Raynaud’s Phenomenon [see Warnings and Precautions (5.3) ] Acute treatment of migraine: the adverse reaction reported in ≥ 1% of patients treated with NURTEC ODT is nausea. ( 6.1 ) Preventive treatment of episodic migraine: adverse reactions reported in ≥ 2% for rimegepant and ≥ 1% higher than placebo are nausea and abdominal pain/dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Acute

Treatment of Migraine The safety of NURTEC ODT for the acute treatment of migraine in adults has been evaluated in a randomized, double-blind, placebo-controlled trial (Study 1) in 682 patients with migraine who received one 75 mg dose of NURTEC ODT [see Clinical Studies (14) ] .

Approximately

85% were female, 74% were White, 21% were Black, and 17% were Hispanic or Latino. The mean age at study entry was 40 years (range 18-75 years of age). Long-term safety was assessed in an open-label extension study using a different oral dosage form of rimegepant. That study evaluated 1,798 patients, dosing intermittently for up to one year, including 1,131 patients who were exposed to rimegepant 75 mg for at least 6 months, and 863 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month. The most common adverse reaction in Study 1 was nausea (2% in patients who received NURTEC ODT compared to 0.4% of patients who received placebo). Hypersensitivity, including dyspnea and severe rash, occurred in less than 1% of patients treated with NURTEC ODT [see Contraindications (4) and Warnings and Precautions (5.1) ] .

Preventive

Treatment of Episodic Migraine The safety of NURTEC ODT for the preventive treatment of episodic migraine in adults has been established in a randomized, double-blind, placebo-controlled trial with an open-label extension (Study 2) using a different oral dosage form of rimegepant [see Clinical Studies (14) ] . In the 12-week, double-blind treatment period, 370 patients with migraine received one 75 mg dose of rimegepant every other day .

Approximately

81% were female, 80% were White, 17% were Black, and 28% were Hispanic or Latino. The mean age at study entry was 41 years (range 18-74 years of age). Long-term safety was assessed in an open-label extension study that included 603 patients who were treated for up to one year. Overall, 527 patients were exposed to rimegepant 75 mg for at least 6 months, and 311 were exposed for at least one year. The most common adverse reactions (occurring in at least 2% of rimegepant-treated patients and at a frequency of at least 1% higher than placebo) in Study 2 were nausea (2.7% in patients who received rimegepant compared with 0.8% of patients who received placebo) and abdominal pain/dyspepsia (2.4% in patients who received rimegepant compared with 0.8% of patients who received placebo).

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of NURTEC ODT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System

Disorders : Hypersensitivity (e.g., anaphylaxis) [see Contraindications (4) and Warnings and Precautions (5.1) ]

Vascular

Disorders : Hypertension [see Warnings and Precautions (5.2) ] , Raynaud’s phenomenon [see Warnings and Precautions (5.3) ]

AND PRECAUTIONS

• Hypersensitivity Reactions: If a serious hypersensitivity reaction occurs, discontinue NURTEC ODT and initiate appropriate therapy. Severe hypersensitivity reactions have included anaphylaxis, dyspnea, and rash, and can occur days after administration. ( 5.1 )
• Hypertension: New-onset or worsening of pre-existing hypertension may occur. ( 5.2 )
• Raynaud’s Phenomenon: New-onset or worsening of pre-existing Raynaud’s phenomenon may occur. ( 5.3 )

5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis , dyspnea, and rash, have occurred in patients treated with NURTEC ODT. Hypersensitivity reactions can occur days after administration, and delayed serious hypersensitivity has occurred. If a hypersensitivity reaction occurs, discontinue NURTEC ODT and initiate appropriate therapy <span class="opacity-50 text-xs">[see Contraindications (4) and Adverse Reactions (6.1 , 6.2) ]</span>.

5.2 Hypertension Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including NURTEC ODT, in the postmarketing setting. Some of the patients who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension and, in some cases, hospitalization. Hypertension may occur at any time during treatment, but was most frequently reported within 7 days of therapy initiation. NURTEC ODT was discontinued in many of the reported cases. Monitor patients treated with NURTEC ODT for new-onset hypertension or worsening of pre-existing hypertension, and consider whether discontinuation of NURTEC ODT is warranted if evaluation fails to establish an alternative etiology or blood pressure is inadequately controlled.

5.3 Raynaud’s Phenomenon Development of Raynaud’s phenomenon and recurrence or worsening of pre-existing Raynaud’s phenomenon have been reported in the postmarketing setting following the use of CGRP antagonists, including NURTEC ODT. In reported cases with small molecule CGRP antagonists, symptom onset occurred a median of 1.5 days following dosing. Many of the cases reported serious outcomes, including hospitalizations and disability, generally related to debilitating pain. In most reported cases, discontinuation of the CGRP antagonist resulted in resolution of symptoms. NURTEC ODT should be discontinued if signs or symptoms of Raynaud’s phenomenon develop, and patients should be evaluated by a healthcare provider if symptoms do not resolve. Patients with a history of Raynaud’s phenomenon should be monitored for, and informed about the possibility of, worsening or recurrence of signs and symptoms.

INTERACTIONS

• Strong CYP3A4 Inhibitors: Avoid concomitant administration. ( 7.1 )
• Moderate CYP3A4 Inhibitors: Avoid another dose within 48 hours when administered with a moderate CYP3A4 inhibitor. ( 7.1 )
• Strong and Moderate CYP3A Inducers: Avoid concomitant administration. ( 7.2 )
• Potent Inhibitors of P-gp: Avoid another dose of NURTEC ODT within 48 hours when administered with a potent P-gp inhibitor. ( 7.3 )

7.1 CYP3A4 Inhibitors Concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 results in a significant increase in rimegepant exposure. Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Concomitant administration of NURTEC ODT with moderate inhibitors of CYP3A4 may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.2 CYP3A Inducers Concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A can result in a significant reduction in rimegepant exposure, which may lead to loss of efficacy of NURTEC ODT. Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 7.3 P-gp Inhibitors Concomitant administration of NURTEC ODT with potent inhibitors of P-gp (e.g., amiodarone, cyclosporine, lapatinib, quinidine, ranolazine) may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with potent inhibitors of P-gp <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .