MITRIPTAN

Rizatriptan is a second-generation triptan and a selective 5-HT 1B and 5-HT1D receptor agonist.

Used in the treatment of migraines, rizatriptan was first approved in the US in 1998.

Rizatriptan is available in oral tablets, Oral disintegrating tablets (wafers), and oral film formulations.

Rizatriptan is indicated for the acute treatment of diagnosed migraine with or without aura. 9, 10, 12, 13 Rizatriptan is not indicated for the prophylactic therapy of migraine nor the treatment of cluster headache.

In Canada, rizatriptan is approved in adults. 12, 13 In the US, the oral tablet formulations are used in patients six years of age and older and the oral film formation is approved for patients 12 years of age and older weighing 40 kg or more.

Rizatriptan, in combination with Meloxicam is indicated for the acute treatment of migraine with or without aura in adults.

Rizatriptan relieves migraine-associated symptoms. 1, 5, 9 Rizatriptan is reported to reach the maximum plasma concentrations more quickly and produces a more rapid onset of pain relief than other triptans, such as sumatriptan; 2, 3, 5 however, it has a relatively shorter elimination half-life than other triptans.

Rizatriptan causes transient increases in blood pressure to some extent.

In vitro, rizatriptan was shown to contract isolated human coronary arteries; however, since the EC for this effect is high, rizatriptan is not expected to cause myocardial ischemia at therapeutic plasma concentrations in patients with normal coronary circulation.

Rizatriptan has a weak affinity for other 5-HT1 receptor subtypes (5-HT 1A, 5-HT 1E, 5-HT 1F ) and the 5-HT 7 receptor but has no significant activity at 5-HT 2, 5-HT 3, alpha.

• and beta-adrenergic, dopaminergic, histaminergic, muscarinic or benzodiazepine receptors.

5-hydroxytryptamine receptor 1B Agonist 5-hydroxytryptamine receptor 1D Agonist 5-hydroxytryptamine receptor 1F Agonist + 1 more target.

Rizatriptan is readily absorbed (approximately 90%) following oral administration; 1 however, the mean oral absolute bioavailability of the rizatriptan tablet is about 45%, owing to extensive first-pass metabolism.

T max is approximately one to 1.5 hours.

The presence of a migraine headache did not appear to affect the absorption or pharmacokinetics of rizatriptan.

Food has no significant effect on the bioavailability of rizatriptan but delays the time to reach peak concentration by an hour.

In clinical trials, rizatriptan was administered without regard to food.

The bioavailability and

C max of rizatriptan were similar following the administration of rizatriptan tablets and rizatriptan Oral disintegrating tablets.

Still, the absorption rate is somewhat slower with Oral disintegrating tablets, with T max delayed by up to 0.7 hours.

AUC of rizatriptan is approximately 30% higher in females than males.

The mean volume of distribution is approximately 140 L in male subjects and 110 L in female subjects.

Rizatriptan primarily undergoes oxidative deamination mediated by monoamine oxidase-A (MAO-A) to form triazolomethyl-indole-3-acetic acid, which is not pharmacologically active.

N-monodesmethyl-rizatriptan is a minor metabolite with a pharmacological activity comparable to the parent compound's.

Plasma concentrations of

N-monodesmethyl-rizatriptan are approximately 14% of those of the parent compound, which is eliminated at a similar rate.

Other pharmacologically inactive minor metabolites include the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite. 1, 6, 9 Hover over products below to view reaction partners Rizatriptan N-Monodesmethyl Rizatriptan Triazolomethyl-indole-3-acetic acid Rizatriptan N10-oxide 6-Hydroxy rizatriptan 6-Hydroxy rizatriptan sulfate.

Following oral administration of a single 10 mg of 14 C-rizatriptan, the total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively.

Following oral administration of 14C-rizatriptan, rizatriptan accounted for about 17% of circulating plasma radioactivity.

Approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan, while 51% is excreted as indole acetic acid metabolite, indicating substantial first-pass metabolism.

The plasma half-life of rizatriptan in males and females ranges from two to three hours.

An early study involving healthy subject reported plasma clearance of 1042 mL/min in males and 821 mL/min in females; however, this difference in clearance rates is not thought to be clinically relevant. 3, 4.

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The acute oral toxicity (LD 50 ) was 2,227 mg/kg in rats and 700-1,631 mg/kg in mice.

No overdoses of rizatriptan were reported in clinical trials.

Some adult patients who received 40 mg of rizatriptan either a single dose or as two doses with a two-hour interdose interval had dizziness and somnolence.

Syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence were experienced by two adults who received a total cumulative doses of 80 mg (given within four hours) in a clinical pharmacology study.

Some adolescent patients (aged 12-17 years old) receiving two 10-mg doses of Oral disintegrating tablets of rizatriptan experienced abdominal discomfort, fatigue, and dyspnea.

Based on the pharmacological properties of rizatriptan, hypertension and myocardial ischemia are possible after overdosage.

Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with rizatriptan.

Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed.

The effects of hemo.

• or peritoneal dialysis on serum concentrations of rizatriptan are unknown.

is contraindicated in patients with: Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease.

Coronary artery vasospasm including

Prinzmetal's angina.

History of stroke or transient ischemic attack (TIA) .

Peripheral vascular disease (PVD) .

Ischemic bowel disease.

Uncontrolled hypertension.

Recent use (i.e., within 24 hours) of another 5-HT 1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) .

Hemiplegic or basilar migraine.

Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor.

Hypersensitivity to rizatriptan or any of the excipients (angioedema and anaphylaxis seen) .

History of ischemic heart disease or coronary artery vasospasm History of stroke or transient ischemic attack Peripheral vascular disease Ischemic bowel disease Uncontrolled hypertension Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan), or of an ergotamine-containing medication Hemiplegic or basilar migraine MAO-A inhibitor used in the past 2 weeks Hypersensitivity to rizatriptan or any of the excipients.

Although rizatriptan benzoate 5 mg tablets and orally disintegrating tablets are available in the marketplace, MAXALT Tablets and MAXALT-MLT Orally Disintegrating Tablets are no longer marketed in the 5 mg strength.

Adults: 5 or 10 mg single dose; separate repeat doses by at least two hours; maximum dose in a 24-hour period: 30 mg Pediatric patients to 17 years: 5 mg single dose in patients less than 40 kg (88 lb); 10 mg single dose in patients 40 kg (88 lb) or more Adjust dose if co-administered with propranolol 2.1 Dosing Information in Adults The recommended starting dose of rizatriptan benzoate is either 5 mg or 10 mg for the acute treatment of migraines in adults.

The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions.

Although the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose.

The maximum daily dose should not exceed 30 mg in any 24-hour period.

The safety of treating, on average, more than four headaches in a 30-day period has not been established. 2.2 Dosing Information in Pediatric Patients (Age to 17 Years) Dosing in pediatric patients is based on the patient's body weight.

The recommended dose of rizatriptan benzoate is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more.

The efficacy and safety of treatment with more than one dose of rizatriptan benzoate within 24 hours in pediatric patients to 17 years of age have not been established. 2.3 Administration of MAXALT-MLT Orally Disintegrating Tablets For MAXALT-MLT Orally Disintegrating Tablets, administration with liquid is not necessary.

Orally disintegrating tablets are packaged in a blister within an outer aluminum pouch and patients should not remove the blister from the outer pouch until just prior to dosing.

The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva. 2.4 Dosage Adjustment for Patients on Propranolol Adult Patients In adult patients taking propranolol, only the 5-mg dose of rizatriptan benzoate is recommended, up to a maximum of 3 doses in any 24-hour period (15 mg) .

For pediatric patients weighing 40 kg (88 lb) or more, taking propranolol, only a single 5-mg dose of rizatriptan benzoate is recommended (maximum dose of 5 mg in a 24-hour period).

Rizatriptan benzoate should not be prescribed to propranolol-treated pediatric patients who weigh less than 40 kg (88 lb) .

Tablets, 10 mg, are pale pink, capsule-shaped, compressed tablets coded MAXALT on one side and MRK on the other: NDC 78206-142-01, carton of 18 tablets.

Tablets, 10 mg, are white to off-white, round lyophilized orally disintegrating tablets debossed with a modified square on one side, and measuring 12.0-13.8 mm (side-to-side) with a peppermint flavor.

Each orally disintegrating tablet is individually packaged in a blister inside an aluminum pouch (sachet).

They are supplied as follows

NDC 78206-143-01, 6 × unit of use carrying case of 3 orally disintegrating tablets (18 tablets total).

Tablets at room temperature, 15°C-30°C (59°F-86°F).

Tablets at room temperature, 15°C-30°C (59°F-86°F).

Risk Summary Available human data on the use of MAXALT in pregnant women are not sufficient to draw conclusions about drug-associated risk for major birth defects and miscarriage.

In animal studies, developmental toxicity was observed following oral administration of rizatriptan during pregnancy (decreased fetal body weight in rats) or throughout pregnancy and lactation (increased mortality, decreased body weight, and neurobehavioral impairment in rat offspring) at maternal plasma exposures greater than that expected at therapeutic doses in humans.

In the

U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The reported rate of major birth defects among deliveries to women with migraine range from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which are similar to rates reported in women without migraine.

Maternal and/or Embryo/Fetal Risk In women with migraine, there is an increased risk of adverse perinatal outcomes in the mother, including pre-eclampsia and gestational hypertension.

Data Human Data The Pregnancy Registry for MAXALT did not identify any pattern of congenital anomalies or other adverse birth outcomes over the period of to 2018.

However, the lack of identification of any pattern should be viewed with caution, as the number of prospective reports with outcome information was low and did not provide sufficient power to detect an increased risk of individual birth defects associated with the use of MAXALT.

Additionally, there was significant loss to follow-up in the prospective pregnancy reports, further complicating this assessment of an association between MAXALT and any pattern of congenital anomalies or other adverse birth outcomes.

In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not.

Of the 157 births with first-trimester exposure to rizatriptan, 7 infants were born with malformations (relative risk 1.01 [95% CI: 0.40 to 2.08]).

A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for triptans before pregnancy only, compared with a population control group.

Of the 310 women who redeemed prescriptions for rizatriptan during the first trimester, 10 had infants with major congenital malformations (OR 1.03 [95% CI: 0.55 to 1.93]), while for the 271 women who redeemed prescriptions for rizatriptan before, but not during, pregnancy, 12 had infants with major congenital malformations (OR 1.48 [95% CI: 0.83 to 2.64]), each compared with the population comparison group.

When rizatriptan (0, 2, 10, or 100 mg/kg/day) was administered orally to pregnant rats throughout organogenesis, a decrease in fetal body weight was observed at the highest doses tested.

At the mid dose (10 mg/kg/day), which was a no-effect dose for adverse effects on embryofetal development, plasma exposure (AUC) was approximately 15 times that in humans at the maximum recommended human dose (MRHD) of 30 mg/day. When rizatriptan (0, 5, 10, or 50 mg/kg/day) was administered orally to pregnant rabbits throughout organogenesis, no adverse fetal effects were observed.

Plasma exposure (AUC) at the highest dose tested was 115 times that in humans at the MRHD.

Placental transfer of drug to the fetus was demonstrated in both species.

Oral administration of rizatriptan (0, 2, 10, or 100 mg/kg/day) to female rats prior to and during mating and continuing throughout gestation and lactation resulted in reduced body weight in offspring from birth and throughout lactation at all but the lowest dose tested (2 mg/kg/day).

Plasma exposure (AUC) at the no-effect dose (2 mg/kg/day) for adverse effects on postnatal development was similar to that in humans at the MRHD.

Oral administration of rizatriptan (0, 5, 100, or 250 mg/kg/day) throughout organogenesis and lactation resulted in neonatal mortality, reduced body weight (which persisted into adulthood), and impaired neurobehavioral function in offspring at all but the lowest dose tested.

Plasma exposure (AUC) at the no-effect dose for adverse effects on postnatal development (5 mg/kg/day) was approximately 8 times that in humans at the MRHD.

Safety and effectiveness in pediatric patients under 6 years of age have not been established.

The efficacy and safety of

MAXALT in the acute treatment of migraine in patients aged to 17 years was established in an adequate and well-controlled study.

The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received MAXALT to those who received placebo.

The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

Clinical studies of

MAXALT did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Although the pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range.

This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving MAXALT.