Naratriptan: Package Insert and Label Information

NARATRIPTAN- naratriptan hydrochloride tablet, film coated
OrchidPharma, Inc

1 INDICATIONS AND USAGE

Naratriptan tablets are indicated for the acute treatment of migraine with or without aura in adults.

Limitations of Use:

  • Use only if a clear diagnosis of migraine has been established. If a patient has no response to the first migraine attack treated with naratriptan tablets, reconsider the diagnosis of migraine before naratriptan tablets are administered to treat any subsequent attacks.
  • Naratriptan tablets are not indicated for the prevention of migraine attacks.
  • Safety and effectiveness of naratriptan tablets have not been established for cluster headache.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

The recommended dose of naratriptan tablets is 1 mg or 2.5 mg.

If the migraine returns or if the patient has only partial response, the dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24 hour period.

The safety of treating an average of more than 4 migraine attacks in a 30 day period has not been established.

2.2 Dosage Adjustment in Patients with Renal Impairment

Naratriptan tablets are contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug [see Contraindications (4), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

In patients with mild to moderate renal impairment, the maximum daily dose should not exceed 2.5 mg over a 24‑hour period and a 1 mg starting dose is recommended [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.3 Dosage Adjustment in Patients with Hepatic Impairment

Naratriptan tablets are contraindicated in patients with severe hepatic impairment (Child-Pugh Grade C) because of decreased clearance [see Contraindications (4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

In patients with mild or moderate hepatic impairment (Child-Pugh Grade A or B), the maximum daily dose should not exceed 2.5 mg over a 24 hour period and a 1 mg starting dose is recommended [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

1 mg white to off-white tablets, capsule shaped, film-coated, and debossed with “N” on one side and “1” on the other side

2.5 mg green tablets, capsule shaped, film-coated, and debossed with “N” on one side and “2.5” on the other side

4 CONTRAINDICATIONS

Naratriptan tablets are contraindicated in patients with:

  • Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal’s angina [see Warnings and Precautions (5.1)]
  • Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.2)]
  • History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because such patients are at a higher risk of stroke [s ee Warnings and Precautions (5.4)]
  • Peripheral vascular disease [see Warnings and Precautions (5.5)]
  • Ischemic bowel disease [see Warnings and Precautions (5.5)]
  • Uncontrolled hypertension [see Warnings and Precautions (5.8)]
  • Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide) [see Drug Interactions (7.1, 7.2)]
  • Hypersensitivity to naratriptan tablets (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.9)]
  • Severe renal or hepatic impairment [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)]

5 WARNINGS AND PRECAUTIONS

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina

Naratriptan tablets are contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of naratriptan tablets. Some of these reactions occurred in patients without known CAD. Naratriptan tablets may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD.

Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving naratriptan tablets. If there is evidence of CAD or coronary artery vasospasm, naratriptan tablets are contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of naratriptan tablets in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of naratriptan tablets. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of naratriptan tablets.

5.2 Arrhythmias

Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue naratriptan tablets if these disturbances occur. Naratriptan tablets are contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure

Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with naratriptan tablets and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. 5-HT1 agonists, including naratriptan tablets, are contraindicated in patients with CAD and those with Prinzmetal’s variant angina.

5.4 Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue naratriptan tablets if a cerebrovascular event occurs.

Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, exclude other potentially serious neurological conditions. Naratriptan tablets are contraindicated in patients with a history of stroke or TIA.

5.5 Other Vasospasm Reactions

Naratriptan tablets may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional doses of naratriptan tablets.

Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.

5.6 Medication Overuse Headache

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

5.7 Serotonin Syndrome

Serotonin syndrome may occur with naratriptan tablets, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors [see Drug Interactions (7.3)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue naratriptan tablets if serotonin syndrome is suspected.

5.8 Increase in Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with naratriptan tablets. Naratriptan tablets are contraindicated in patients with uncontrolled hypertension.

5.9 Anaphylactic Reactions

There have been reports of anaphylaxis and hypersensitivity reactions, including angioedema, in patients receiving naratriptan tablets. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Naratriptan tablets are contraindicated in patients with a history of hypersensitivity reaction to naratriptan tablets.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the prescribing information:

  • Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina [see Warnings and Precautions (5.1)]
  • Arrhythmias [see Warnings and Precautions (5.2)]
  • Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3)]
  • Cerebrovascular events [see Warnings and Precautions (5.4)]
  • Other vasospasm reactions [see Warnings and Precautions (5.5)]
  • Medication overuse headache [see Warnings and Precautions (5.6)]
  • Serotonin syndrome [see Warnings and Precautions (5.7)]
  • Increase in blood pressure [see Warnings and Precautions (5.8)]
  • Hypersensitivity reactions [see Contraindications (4), Warnings and Precautions (5.9)]

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a long-term open-label trial where patients were allowed to treat multiple migraine attacks for up to 1 year, 15 patients (3.6%) discontinued treatment due to adverse reactions.

In controlled clinical trials, the most common adverse reactions were paresthesias, dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms, which occurred at a rate of 2% and at least 2 times placebo rate.

Table 1 lists the adverse reactions that occurred in 5 placebo-controlled clinical trials of approximately 1,752 exposures to placebo and naratriptan tablets in adult patients with migraine. Only reactions that occurred at a frequency of 2% or more in groups treated with naratriptan tablets 2.5 mg and that occurred at a frequency greater than the placebo group in the 5 pooled trials are included in Table 1.

Table 1. Adverse Reactions Reported by at Least 2% of Patients Treated With Naratriptan Tablets and at a Frequency Greater Than Placebo

Adverse Reaction

Percent of Patients Reporting

Naratriptan Tablets 1 mg

(n = 627)

Naratriptan Tablets 2.5 mg

(n = 627)

Placebo

(n = 498)

Atypical sensation

2

4

1

Paresthesias (all types)

1

2

<1

Gastrointestinal

6

7

5

Nausea

4

5

4

Neurological

4

7

3

Dizziness

1

2

1

Drowsiness

1

2

<1

Malaise/fatigue

2

2

1

Pain and pressure sensation

2

4

2

Throat/neck symptoms

1

2

1

The incidence of adverse reactions in controlled clinical trials was not affected by age or weight of the patients, duration of headache prior to treatment, presence of aura, use of prophylactic medications, or tobacco use. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

7 DRUG INTERACTIONS

7.1 Ergot-Containing Drugs

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and naratriptan tablets within 24 hours of each other is contraindicated.

7.2 Other 5-HT1 Agonists

Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of treatment with naratriptan tablets is contraindicated because the risk of vasospastic reactions may be additive.

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