Naratriptan

Naratriptan is a an Antimigraine agent belonging to Serotonin 5-HT1B, 1D Receptor Agonist

Naratriptan is approved for the treatment of Migraine, moderate to severe, acute treatment

Naratriptan isRapidly and well absorbed. Bioavailability: Approx 70%. Time to peak plasma concentration: 2-3 hours with Volume of distribution: of 170 L. and get Metabolised in the liver by CYP450 enzymes.It gets excreted Via urine (50% as unchanged drug, 30% as inactive metabolites). Elimination half-life: 6 hours.

The common side effects associated with Naratriptan include Sensation of pressure, pain and tightness in the chest, throat, jaw or neck; peripheral vascular ischaemia, colonic ischaemia, gastrointestinal vascular ischaemia and infarction, splenic infarction

Naratriptan is available in the form of oral solid.

The molecule is available in India, USA, Germany, Japan.

Selective agonist for serotonin (5-HT1B and 5-HT1D receptors) in cranial arteries; causes vasoconstriction and reduces sterile inflammation associated with antidromic neuronal transmission correlating with relief of migraine

Onset of action of Naratriptan was within 1`-2 hours

Tmax of Naratriptan was about 2- 3hours.

Naratriptan is available in Tablets

Oral: Administer higher doses preferably at late afternoon or as bedtime doses to minimize daytime sedation.

Naratriptan can be used in the treatment of Migraine, moderate to severe, acute treatment. It is also used to treat Menstrual migraine prevention.

Naratriptan is a selective agonist for serotonin (5-HT1B and 5-HT1D) receptors in intracranial blood vessels which causes cranial vasoconstriction and inhibition of neuropeptide release. This activity reduces inflammation associated with antidromic neuronal transmission which is correlated with migraine relief.

Naratriptan is approved for use in the following clinical indications

• Migraine, moderate to severe, acute treatment: Acute treatment of migraine attacks with or without aura in adults.
• Although not approved there have been certain off labelled uses documented for Naratriptan which include:

Menstrual migraine prevention.

Menstrual migraine prevention (off-label use):

Oral: 1 mg twice daily beginning 2 to 3 days prior to expected onset of symptoms; continue for a total of 5 to 6 days.

Migraine, moderate to severe, acute treatment

Note: Administration early in the course of a migraine attack, at the first sign of pain, may improve response to treatment. When attack is complicated by severe nausea or vomiting, a nonoral medication may be more effective.

Oral: 2.5 mg as a single dose; if symptoms persist or return, may repeat dose after ≥4 hours. Maximum: 2.5 mg/dose; 5 mg per 24 hours

(Naratriptan can be administered orally before/ after meals. The dosage and duration of treatment should be as per the clinical judgement of the treating physician)

(The dosage and duration of treatment should be as per the clinical judgement of the treating physician).

1 mg, 2.5 mg.

Tablets

• Dose Adjustment in Kidney Patient:

Mild to moderate renal impairment: Initial: 1 mg; maximum dose: 2.5 mg per 24 hours.

Severe renal impairment (CrCl <15 mL/minute): Use is contraindicated.

• Dose Adjustment in Hepatic Impairment Patient:

Mild to moderate hepatic impairment (Child-Pugh grade A or B): Initial: 1 mg; maximum dose: 2.5 mg per 24 hours.

Severe hepatic impairment (Child-Pugh grade C): Use is contraindicated

Naratriptan should be used in the treatment of (approved indications) along with appropriate dietary restrictions

The dietary restriction should be individualized as per patient requirements.

Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction [MI], or documented silent ischemia); coronary artery vasospasm, including Prinzmetal’s angina; Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders; history of stroke, transient ischemic attack (TIA), or history of hemiplegic migraine or migraine with brainstem aura; peripheral vascular disease; ischemic bowel disease; uncontrolled hypertension; recent use (within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, or ergot-type medication (eg, dihydroergotamine or methysergide); severe renal impairment (CrCl <15 mL/minute) or severe hepatic impairment; hypersensitivity to naratriptan or any component of the formulation.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Anaphylactic reactions: Anaphylaxis and hypersensitivity reactions (including angioedema) have occurred; may be life-threatening or fatal. Use is contraindicated in patients with known hypersensitivity to naratriptan.

• Cardiac events: Coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia/fibrillation, cardiac arrest, and death have been reported with 5-HT₁ agonist administration; some events have occurred within a few hours of administration. Discontinue if these events occur. Patients who experience sensations of chest pain/pressure/tightness or symptoms suggestive of angina following dosing should be evaluated for coronary artery disease (CAD) or Prinzmetal's angina before receiving additional doses; if dosing is resumed and similar symptoms recur, monitor with ECG. Use is contraindicated in patients with ischemic or vasospastic CAD and Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

• Cerebrovascular events: Cerebral/subarachnoid hemorrhage and stroke (some fatal) have been reported with 5-HT₁ agonist administration. Use is contraindicated in patients with a history of stroke or transient ischemic attack.

CNS depression: May cause CNS depression, such as dizziness, weakness, or drowsiness, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Elevated blood pressure: Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension. Monitor blood pressure; use is contraindicated in patients with uncontrolled hypertension.

• Headaches: Acute migraine agents (eg, triptans, opioids, ergotamine, or a combination of the agents) used for 10 or more days per month may lead to worsening of headaches (medication overuse headache); withdrawal treatment may be necessary in the setting of overuse.

• Vasospasm-related events: Peripheral vascular ischemia and colonic ischemia, gastrointestinal vascular ischemia and infarction, splenic infarction, and Raynaud syndrome have been reported with 5-HT1 agonist administration.

• Visual effects: Partial vision loss and blindness (transient and permanent) have been reported with use of 5-HT1 agonists; a causal relationship between these events and 5-HT1 agonist administration has not been clearly determined.

May enhance the sedative effect of alcohol.

Naratriptan and the metabolite nortriptyline are present in breast milk.

Pregnancy

Pregnancy Category (FDA): C

There are no adequate and well-controlled trials in pregnant women. Naratriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In reproductive toxicity studies in rats and rabbits, oral administration of naratriptan was associated with developmental toxicity (embryolethality, fetal abnormalities, pup mortality, offspring growth retardation) at doses producing maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 5 mg.

May increase the incidence of undesirable effects with St John’s wort.

The adverse reactions related to Naratriptan can be categorized as

Common

Sensation of pressure, pain and tightness in the chest, throat, jaw or neck; peripheral vascular ischemia, colonic ischemia, gastrointestinal vascular ischemia and infarction, splenic infarction.

Less Common

Raynaud’s syndrome; exacerbation of headache or medication overuse headache (frequent/prolonged use); CNS depression (e.g. dizziness, drowsiness, weakness), significant partial vision loss, transient or permanent blindness.

Rare

Significant blood pressure elevation, including hypertensive crisis with acute organ systems impairment.

The clinically relevant drug interactions of Naratriptan is briefly summarized here

Oral contraceptives may reduce the total clearance of naratriptan.

Potentially Fatal: Increased risk of coronary vasospasm with ergotamine, ergotamine derivatives (including dihydroergotamine or methysergide), and other 5-HT₁ receptor agonists. Increased risk of serotonin syndrome with MAOIs, SSRIs, TCAs and serotonin norepinephrine reuptake inhibitors (SNRIs).

The common side of Naratriptan include the following

Sensation of pressure, pain and tightness in the chest, throat, jaw or neck; peripheral vascular ischemia, colonic ischemia, gastrointestinal vascular ischemia and infarction, splenic infarction

Pregnancy

Pregnancy Category (FDA): C

There are no adequate and well-controlled trials in pregnant women. Naratriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In reproductive toxicity studies in rats and rabbits, oral administration of naratriptan was associated with developmental toxicity (embryolethality, fetal abnormalities, pup mortality, offspring growth retardation) at doses producing maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 5 mg.

When naratriptan was administered to pregnant rats during the period of organogenesis at doses of 10, 60, or 340 mg/kg/day, there was a dose-related increase in embryonic death; incidences of fetal structural variations (incomplete/irregular ossification of skull bones, sternebrae, ribs) were increased at all doses. The maternal plasma exposures (AUC) at these doses were approximately 11, 70, and 470 times the exposure in humans at the MRDD. The high dose was maternally toxic, as evidenced by decreased maternal body weight gain during gestation. A no-effect dose for developmental toxicity in rats exposed during organogenesis was not established.

When naratriptan was administered orally (1, 5, or 30 mg/kg/day) to pregnant Dutch rabbits throughout organogenesis, the incidence of a specific fetal skeletal malformation (fused sternebrae) was increased at the high dose, and increased incidences of embryonic death and fetal variations (major blood vessel variations, supernumerary ribs, incomplete skeletal ossification) were observed at all doses (4, 20, and 120 times, respectively, the MRDD on a body surface area basis). Maternal toxicity (decreased body weight gain) was evident at the high dose in this study. In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day throughout organogenesis), decreased fetal weights and increased incidences of fetal skeletal variations were observed at all doses (maternal exposures equivalent to 2.5, 19, and 140 times exposure in humans receiving the MRDD), while maternal body weight gain was reduced at 5 mg/kg or greater. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established.

When female rats were treated orally with naratriptan (10, 60, or 340 mg/kg/day) during late gestation and lactation, offspring behavioral impairment (tremors) and decreased offspring viability and growth were observed at doses of 60 mg/kg or greater, while maternal toxicity occurred only at the highest dose. Maternal exposures at the no-effect dose for developmental effects in this study were approximately 11 times the exposure in humans receiving the MRDD.

There is no FDA guidance on the use of Naratriptan with respect to specific gender populations.

Race

There is no FDA guidance on the use of Naratriptan with respect to specific racial populations.

Renal Impairment

The use of Naratriptan is contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug. In patients with mild to moderate renal impairment, the recommended starting dose is 1 mg, and the maximum daily dose should not exceed 2.5 mg over a 24-hour period.

Hepatic Impairment

The use of Naratriptan is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) because of decreased clearance. In patients with mild or moderate hepatic impairment (Child-Pugh grade A or B), the recommended starting dose is 1 mg, and the maximum daily dose should not exceed 2.5 mg over a 24-hour period.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Naratriptan in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Naratriptan in patients who are immunocompromised.

Symptoms: Increased blood pressure resulting in light-headedness, neck tension, tiredness, loss of coordination and ischemic ECG changes.

Management: Supportive treatment. Monitor the patient for at least 24 hours.

Pharmacodynamics

Naratriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (including substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of Naratriptan for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Pharmacokinetics

Absorption: Rapidly and well absorbed. Bioavailability: Approx 70%. Time to peak plasma concentration: 2-3 hours.

Distribution: Volume of distribution: 170 L. Plasma protein binding: 28-31%.

Metabolism: Metabolized in the liver by CYP450 enzymes.

Excretion: Via urine (50% as unchanged drug, 30% as inactive metabolites). Elimination half-life: 6 hours.

1. https://www.uptodate.com/contents/Naratriptan-drug-information?search=Naratriptan&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F23890541
2. https://www.mims.com/india/drug/info/Naratriptan?type=full
3. https://www.ncbi.nlm.nih.gov/books/NBK537225/
4. https://go.drugbank.com/drugs/DB00321
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/071297s030lbl.pdf