Prescription Drug Information: Rizatriptan (Page 3 of 6)

7 DRUG INTERACTIONS

7.1 Propranolol

The dose of rizatriptan benzoate should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70% [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

7.2 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 rizatriptan benzoate within 24 hours is contraindicated [see Contraindications (4)].

7.3 Other 5-HT1 Agonists

Because their vasospastic effects may be additive, co-administration of rizatriptan benzoate and other 5-HT1 agonists within 24 hours of each other is contraindicated [see Contraindications (4)].

7.4 SSRIs/SNRIs and Serotonin Syndrome

Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7)].

7.5 Monoamine Oxidase Inhibitors

Rizatriptan benzoate is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors. A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite [see Contraindications (4) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
Available human data on the use of rizatriptan benzoate 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 [see Animal Data].
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.

Clinical Considerations
Disease-Associated 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 rizatriptan benzoate did not identify any pattern of congenital anomalies or other adverse birth outcomes over the period of 1998 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 rizatriptan benzoate. Additionally, there was significant loss to follow-up in the prospective pregnancy reports, further complicating this assessment of an association between rizatriptan benzoate 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.

Animal Data
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.

8.2 Lactation

Risk Summary
There are no data on the presence of rizatriptan or any active metabolites in human milk, or on the effects of rizatriptan on the breastfed infant, or on milk production.
Rizatriptan was excreted in rat milk, with levels in milk approximately 6 times those in maternal plasma.
The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for rizatriptan benzoate tablets and any potential adverse effects on the breastfed infant from rizatriptan benzoate tablets or from the underlying maternal condition.
Data
Following oral administration of rizatriptan to lactating rats at a dose of 100 mg/kg/day, drug
concentrations of rizatriptan in milk samples exceeded maternal plasma drug concentrations by approximately 6-fold.

8.4 Pediatric Use

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

The efficacy and safety of riztriptan benzoate tablets in the acute treatment of migraine in patients aged 6 to 17 years was established in an adequate and well-controlled study [see Clinical Studies (14.2) ]. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received riztriptan benzoate tablets to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

8.5 Geriatric Use

Clinical studies of rizatriptan benzoate did not include sufficient numbers of subjects aged 65 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 rizatriptan benzoate [see Warnings and Precautions (5.1)].

10 OVERDOSAGE

No overdoses of rizatriptan benzoate were reported during clinical trials in adults.

Some adult patients who received 40 mg of rizatriptan benzoate either a single dose or as two doses with a 2-hour interdose interval had dizziness and somnolence.

In a clinical pharmacology study in which 12 adult subjects received rizatriptan benzoate, at total cumulative doses of 80 mg (given within four hours), two of the subjects experienced syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence.

In the long-term, open label study, involving 606 treated pediatric migraineurs 12 to 17 years of age (of which 432 were treated for at least 12 months), 151 patients (25%) took two 10-mg doses of rizatriptan benzoate orally disintegrating tablets within a 24-hour period. Adverse reactions for 3 of these patients included abdominal discomfort, fatigue, and dyspnea.

In addition, based on the pharmacology of rizatriptan benzoate, hypertension or myocardial ischemia could occur after overdosage. Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with rizatriptan benzoate. 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.

11 DESCRIPTION

Rizatriptan benzoate tablets, USP contain rizatriptan benzoate, USP a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D ) receptor agonist.

Rizatriptan benzoate, USP is described chemically as: N,N -dimethyl-5-(1H -1,2,4-triazol-1-ylmethyl)-1H -indole-3-ethanamine monobenzoate and its structural formula is:

1
(click image for full-size original)

Its molecular formula is C15 H19 N5 C7 H6 O2 , representing a molecular weight of the free base of 269.4. Rizatriptan benzoate, USP is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.

Rizatriptan benzoate tablets, USP are available for oral administration in strengths of 5 mg and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively). Each compressed tablet contains the following inactive ingredients:

lactose monohydrate, microcrystalline cellulose, pregelatinized maize starch, ferric oxide (red), and magnesium stearate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Rizatriptan presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.

12.3 Pharmacokinetics

Absorption
Rizatriptan is completely absorbed following oral administration. The mean oral absolute bioavailability of the rizatriptan benzoate tablet is about 45%, and mean peak plasma concentrations (Cmax ) are reached in approximately 1 to 1.5 hours (Tmax ). 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 benzoate was administered without regard to food.

The bioavailability and Cmax of rizatriptan were similar following administration of rizatriptan benzoate tablets and rizatriptan benzoate orally disintegrating tablets, but the rate of absorption is somewhat slower with rizatriptan benzoate orally disintegrating tablets, with Tmax delayed by up to 0.7 hour. AUC of rizatriptan is approximately 30% higher in females than in males. No accumulation occurred on multiple dosing.

Distribution
The mean volume of distribution is approximately 140 liters in male subjects and 110 liters in female subjects. Rizatriptan is minimally bound (14%) to plasma proteins.

Metabolism
The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not active at the 5-HT1B/1D receptor. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT1B/1D receptor, is formed to a minor degree. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites, the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT1B/1D receptor.

Elimination
The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following a single 10-mg oral administration of 14 C-rizatriptan. Following oral administration of 14 C-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 averages 2 to 3 hours.

Cytochrome P450 Isoforms
Rizatriptan is not an inhibitor of the activities of human liver cytochrome P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1; rizatriptan is a competitive inhibitor (Ki = 1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations.

Special Populations
Geriatric: Rizatriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65 to 77 years) were similar to those in younger non-migraineur volunteers (age 18 to 45 years).

Pediatric: The pharmacokinetics of rizatriptan was determined in pediatric migraineurs 6 to 17 years of age. Exposures following single dose administration of 5 mg rizatriptan orally disintegrating tablets to pediatric patients weighing 20 to 39 kg (44-87 lb) or 10 mg rizatriptan orally disintegrating tablets to pediatric patients weighing ≥40 kg (88 lb) were similar to those observed following single dose administration of 10 mg rizatriptan orally disintegrating tablets to adults.

Gender: The mean AUC0-∞ and Cmax of rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while Tmax occurred at approximately the same time.

Hepatic impairment: Following oral administration in patients with hepatic impairment caused by mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar in patients with mild hepatic insufficiency compared to a control group of subjects with normal hepatic function; plasma concentrations of rizatriptan were approximately 30% greater in patients with moderate hepatic insufficiency.

Renal impairment: In patients with renal impairment (creatinine clearance 10 to 60 mL/min/1.73 m2), the AUC0-∞ of rizatriptan was not significantly different from that in subjects with normal renal function. In hemodialysis patients, (creatinine clearance < 2 mL/min/1.73 m2), however, the AUC for rizatriptan was approximately 44% greater than that in patients with normal renal function.

Race: Pharmacokinetic data revealed no significant differences between African American and Caucasian subjects.

Drug Interactions
[See also Drug Interactions (7).]

Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, ‘A’ subtype (MAO-A). Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In a drug interaction study, when rizatriptan 10 mg was administered to subjects (n = 12) receiving concomitant therapy with the selective, reversible MAO-A inhibitor, moclobemide 150 mg t.i.d., there were mean increases in rizatriptan AUC and Cmax of 119% and 41% respectively; and the AUC of the active N-monodesmethyl metabolite of rizatriptan was increased more than 400%. The interaction would be expected to be greater with irreversible MAO inhibitors. No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors [see Contraindications (4) and Drug Interactions (7.5)].

Propranolol: In a study of concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg in healthy adult subjects (n = 11), mean plasma AUC for rizatriptan was increased by 70% during propranolol administration, and a four-fold increase was observed in one subject. The AUC of the active N-monodesmethyl metabolite of rizatriptan was not affected by propranolol [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

Nadolol/Metoprolol: In a drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of a single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12). No pharmacokinetic interactions were observed.

Paroxetine: In a study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of rizatriptan 10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptan nor its safety profile were affected by paroxetine [see Warnings and Precautions (5.7), Drug Interactions (7.4), and Patient Counseling Information (17)].

Oral contraceptives: In a study of concurrent administration of an oral contraceptive during 6 days of administration of rizatriptan (10 to 30 mg/day) in healthy female volunteers (n=18), rizatriptan did not affect plasma concentrations of ethinyl estradiol or norethindrone.

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