Rizatriptan

Rizatriptan is a an Antimigraine Agent belonging to pharmacology class of Serotonin 5-HT1B, 1D Receptor Agonist Class

Rizatriptan can be used in the treatment of Migraine, moderate to severe, acute treatment.

Rizatriptan is readily absorbed (approximately 90%) following oral administration;however, the mean oral absolute bioavailability of the rizatriptan tablet is about 45%, owing to extensive first-pass metabolism. 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. Following oral administration of a single 10 mg of ¹⁴C-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 common side effects associated with Rizatriptan include Angioedema, peripheral vascular ischemia, colonic ischemia, gastrointestinal ischemia or infarction, splenic infarction.

Rizatriptan is available in the form of tablets.

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

Selective agonist for serotonin (5-HT_1B and 5-HT_1D receptors) in cranial arteries; causes vasoconstriction and reduces sterile inflammation associated with antidromic neuronal transmission correlating with relief of migraine

The Tmax of Rizatriptan was about 1-1.5 hours.

Onset of Action: Most patients have response to treatment within 2 hours.

Rizatriptan is available in tablet.

Oral: May administer without regard to meals.

Rizatriptan can be used in the treatment of Migraine, moderate to severe, acute treatment.

Rizatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Rizatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Rizatriptan is approved for use in the following clinical indications

Migraine, moderate to severe, acute treatment: Acute treatment of migraine with or without aura in adults and pediatric patients ≥6 years of age (orally disintegrating tablet, tablet) or in adults and pediatric patients ≥12 years of age weighing ≥40 kg (oral film).

Migraine, moderate to severe, acute treatment:

Note: Do not use within 24 hours of an ergotamine preparation or a different triptan. Limit use to <10 days per month to avoid medication-overuse headache. Administration early in the course of a migraine attack, at the first sign of pain, may improve response to treatment. A large initial dose may be more effective than multiple smaller doses. When attack is complicated by severe nausea or vomiting, a non-oral medication may be more effective.

Oral: 5 to 10 mg (orally disintegrating tablet, tablet) or 10 mg (oral film) as a single dose; if symptoms persist or return, may repeat dose after ≥2 hours. The manufacturer’s labeling recommends a maximum daily dose of 30 mg per 24 hours; however, some experts recommend a maximum of 20 mg per 24 hours; efficacy data are not available for doses exceeding 20 mg in a 24-hour period.

Tablet:

5mg, 10 mg.

Tablet

Dose Adjustment in Kidney impairment patient:

There are no dosage adjustments provided in the manufacturer's labeling; however, the AUC was 44% greater in patients on hemodialysis.

Dose Adjustment in Hepatic Patient:

There are no dosage adjustments provided in the manufacturer's labeling; however, plasma concentrations are increased by 30% in patients with moderate hepatic dysfunction.

Dose Adjustment in Pediatric Patient:

Migraine, acute treatment:

Children ≥6 years and Adolescents: Oral: Note: Safety and efficacy of multiple rizatriptan doses in a 24-hour period has not been established for pediatric patients.

<40 kg: 5 mg as a single dose.

≥40 kg: 10 mg as a single dose.

The dietary restriction should be individualized as per patient requirements.

Rizatriptan may be contraindicated in the following conditions:

Hypersensitivity to rizatriptan or any component of the formulation; ischemic coronary artery disease (e.g, angina pectoris, history of myocardial infarction, or documented silent ischemia) or other significant cardiovascular disease; coronary artery vasospasm (including Prinzmetal angina); history of stroke or transient ischemic attack; peripheral vascular disease; ischemic bowel disease; uncontrolled hypertension; hemiplegic migraine or migraine with brainstem aura; during or within 2 weeks of monoamine oxidase inhibitor use; during or within 24 hours of treatment with another 5-HT₁ agonist, or an ergotamine-containing or ergot-type medication (e.g, methysergide, dihydroergotamine); concurrent use with propranolol (oral film only); Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders (oral film only).

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

Concerns related to adverse effects:

• Cardiac events: Coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia/fibrillation, cardiac arrest, and death have been reported with 5-HT₁ agonist administration. Patients who experience sensations of chest pain/pressure/tightness or symptoms suggestive of angina following dosing should be evaluated for coronary artery disease or Prinzmetal's angina before receiving additional doses; if dosing is resumed and similar symptoms recur, monitor with ECG.

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

• Elevated blood pressure: Significant elevation in blood pressure, including hypertensive crisis, has also been reported on rare occasions in patients with and without a history of hypertension.

• Headaches: Acute migraine agents (e.g, 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 ischemia/infarction, splenic infarction, and Raynaud syndrome have been reported with 5-HT₁ agonist.

• Visual effects: Rarely, partial vision loss and blindness (transient and permanent) have been reported with 5-HT₁ agonist.

There is no sufficient scientific evidence traceable regarding use and safety of Rizatriptan in concurrent use with alcohol.

Rizatriptan is present in breast milk.

Data related to the presence of 5-HT_1B/1D agonists (triptans) in breast milk is available from a study of 19 lactating women (6 weeks to 30 months postpartum) treated for migraine headaches. During the study, infants were fed previously expressed breast milk. Breast milk was sampled prior to and at intervals up to 24 hours after the dose in 5 patients taking rizatriptan 10 mg. Using the average breast milk concentration observed, authors of the study calculated the estimated exposure of rizatriptan to the breastfed infant to be 0.4 to 2.2 mcg/kg/day, providing a relative infant dose (RID) of 0.3% to 1.4% based on the weight-adjusted maternal dose. Using the maximum breast milk concentration, the RID of rizatriptan was calculated to be 1.7% to 9.7%. In 3 samples, rizatriptan was not detectable in breast milk 24 hours after the dose. A large interindividual variability among breast milk concentrations was found with all the triptans in the study, even when considering dose and dosage form.

Pregnancy

AU TGA pregnancy category B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.

Increased risk of adverse effects with St. John’s wort.

The adverse reactions related to Rizatriptan can be categorized as:

• Common Adverse effects: Angioedema, peripheral vascular ischemia, colonic ischemia, gastrointestinal ischemia or infarction, splenic infarction
• Less Common Adverse effects: sensation of pain, pressure or tightness in the precordium throat, neck, and jaw; worsening of headache or medication overuse headache.
• Rare Adverse effects: Significant blood pressure elevation, including hypertensive crisis; partial vision loss, transient or permanent blindness.

The clinically relevant drug interactions of Rizatriptan is briefly summarized here:

Plasma concentrations may be increased by propranolol.

Potentially Fatal: Increased risk of coronary vasoconstriction and hypertensive effects with ergotamine, ergot derivatives (including dihydroergotamine or methysergide), and other 5-HT_1B/_1D receptor agonists (e.g. Rizatriptan, zolmitriptan). Increased risk of serotonin syndrome with MAOIs, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or TCAs.

The common side of Rizatriptan include the following:

Pregnancy Risk Summary

Available human data on the use of rizatriptan 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 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 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. Additionally, there was significant loss to follow-up in the prospective pregnancy reports, further complicating this assessment of an association between rizatriptan 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 the drug to the fetus was demonstrated in both species.

Oral administration of rizatriptan (0, 2, 10, or 100 mg/kg/day) to female rats before 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.

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 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 and any potential adverse effects on the breastfed infant from Rizatriptan or the underlying maternal condition. Data Following oral administration of rizatriptan to lactating rats at a dose of 100 mg/kg/day, the drug concentrations of rizatriptan in milk samples exceeded maternal plasma drug concentrations by approximately 6-fold.

Pediatric Use

The safety and effectiveness of Rizatriptan for the acute treatment of migraine have been established in pediatric patients 12 years of age and older weighing 40 kg or more based on an adequate and well controlled study with rizatriptan benzoate tablets. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received rizatriptan benzoate tablets to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults. Safety and effectiveness of Rizatriptan in pediatric patients under 12 years of age and weighing less than 40 kg have not been established.

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. The pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and younger adults (n=17)

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

Symptoms: Dizziness, somnolence, hypertension and other serious CV symptoms.

Management: Gastrointestinal decontamination (e.g. gastric lavage followed by activated charcoal) may be considered. Clinical and electrocardiographic monitoring must be continued for at least 12 hours (even if symptoms are not observed).

Pharmacodynamics:

Rizatriptan is a selective agonist at the 5-HT_1B and 5-HT_1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system. It binds to these receptors with high affinity. The exact mechanism of action of rizatriptan has not been fully elucidated; however, several documented pharmacological actions of rizatriptan may contribute to its antimigraine effects. Rizatriptan causes vasoconstriction of intracranial extracerebral blood vessels, which is thought to occur primarily via 5-HT_1B receptors. Rizatriptan also inhibits nociceptive neurotransmission in trigeminal pain pathways. It attenuates the release of vasoactive neuropeptides by the trigeminal nerve, which is thought to occur via neurogenic and central 5-HT_1D receptors

Pharmacokinetics:

• Absorption:

Rizatriptan is readily absorbed (approximately 90%) following oral administration; however, the mean oral absolute bioavailability of the rizatriptan tablet is about 45%, owing to extensive first-pass metabolism. The 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 orally disintegrating tablets. Still, the absorption rate is somewhat slower with orally disintegrating tablets, with T_max delayed by up to 0.7 hours. The AUC of rizatriptan is approximately 30% higher in females than males. No accumulation occurred on multiple dosing.

• Distribution: The mean volume of distribution is approximately 140 L in male subjects and 110 L in female subjects
• Metabolism: 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
• Excretion: Following oral administration of a single 10 mg of ¹⁴C-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.

1. https://www.uptodate.com/contents/Rizatriptan -drug-information?search=Rizatriptan &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Rizatriptan _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Rizatriptan ?type=full&mtype=generic#mechanism-of-action