Kaporiza^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmfirma Sotex, CJSC (Russia)

Manufactured By

Emcure Pharmaceuticals, Ltd. (India)

Contact Information

PharmFirma Sotex ZAO (Russia)

ATC Code

N02CC04 (Rizatriptan)

Active Substance

Rizatriptan (Rec.INN WHO registered)

Dosage Form

Kaporiza®

Orodispersible tablets, 10 mg: 2 or 6 pcs.

Dosage Form, Packaging, and Composition

Orodispersible tablets, white, round, flat-cylindrical, with a bevel and engraving “HP” on one side, “239” on the other, with a mint odor.

Excipients: mannitol (E421) – 91.62 mg, crospovidone, calcium silicate, sodium stearyl fumarate, aspartame – 2 mg, colloidal silicon dioxide, mint flavor.

2 pcs. – blister packs (1) – cardboard boxes.
6 pcs. – blister packs (1) – cardboard boxes.

Clinical-Pharmacological Group

Serotonin 5-HT₁ receptor agonist. Agent with antimigraine activity

Pharmacotherapeutic Group

Antimigraine agent. Selective 5-HT₁ receptor agonist

Pharmacological Action

Mechanism of action

Rizatriptan has high affinity and selectively binds to 5-HT_1B and 5-HT_1D receptors; it has little or no pharmacological activity on 5-HT₂, 5-HT₃; adrenergic α₁, α₂ or β; dopaminergic D₁, D₂; histamine H₁; M-cholinergic receptors; benzodiazepine receptors.

The therapeutic activity of rizatriptan in the treatment of migraine headache may be related to its agonistic action on 5-HT_1B and 5-HT_1D receptors located in extracerebral intracranial blood vessels, which are thought to dilate during an attack, and on the sensory nerves of the trigeminal nerve that innervate them. Activation of these 5-HT_1B and 5-HT_1D receptors leads to constriction of pain-causing intracranial blood vessels and inhibition of neuropeptide release, which causes a reduction in inflammation in sensitive tissues and a reduction in pain signal transmission in the central trigeminal nerve.

Pharmacodynamic effects

Adults

The efficacy of rizatriptan in the treatment of acute migraine attacks has been studied in 4 multicenter placebo-controlled studies involving more than 2000 patients treated with Rizatriptan at doses of 5 mg or 10 mg for up to 1 year. Headache relief occurred as early as 30 minutes after the first dose. The efficacy rate in patients receiving Rizatriptan 5 mg and 10 mg at 2 hours after administration was 60-63% and 67-77%, respectively, compared with 23-40% in the placebo group.

Although patients who did not respond to the initial use of rizatriptan were not re-administered for the same attack, they were still likely to respond to treatment in a subsequent attack.

Rizatriptan also relieves the discomfort, nausea, photophobia, and phonophobia associated with migraine.

Based on studies with oral rizatriptan tablets, it is effective in treating menstrual migraine, i.e., migraine that occurs within 3 days before or after the onset of menstruation.

Adolescents (12-17 years)

The efficacy of orally disintegrating rizatriptan in children (12 to 17 years) was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study (n=570).

The study population was required to be non-responsive to early therapy with NSAIDs and paracetamol. Within the first 30 minutes of the onset of the episode, patients with migraine initially received placebo or Rizatriptan. After 15 minutes, subjects with placebo who did not respond to treatment received placebo or rizatriptan for the same migraine attack. A weight-based dosing approach was used: patients weighing 20 to 40 kg received 5 mg of rizatriptan, and patients weighing 40 kg or more received 10 mg of rizatriptan.

In this study, conducted with a carefully selected population, a 9% difference was noted between active treatment and placebo for the primary efficacy endpoint of pain relief (moderate or severe pain reduced to mild or none) at 2 hours after treatment (31% for rizatriptan versus 22% for the placebo group (p=0.025)). No significant differences were found for the secondary endpoint of pain relief (reduction of pain from moderate or severe to mild or none).

Children (6-11 years)

The efficacy of rizatriptan orodispersible tablets was also evaluated in sick children aged 6 to 11 years in a placebo-controlled clinical study for the treatment of acute attacks (n=200). The number of patients who achieved pain relief at 2 hours after treatment was not statistically different between patients receiving Rizatriptan orodispersible tablets at doses of 5 mg and 10 mg compared with patients receiving placebo (39.8% vs. 30.4%, p=0.269).

Rizatriptan orodispersible tablets allow patients suffering from migraine to treat headache attacks without the need to drink the medication with liquid. As a result, patients can receive treatment at any time and under any conditions, for example, in the absence of liquid to drink. In addition, this dosage form avoids the unpleasant gastrointestinal sensations that may occur when swallowing liquid.

Pharmacokinetics

Absorption

Rizatriptan is rapidly and completely absorbed after oral administration.

The mean bioavailability of the orodispersible tablet is 40-45%, and mean C_max in plasma is reached in approximately 1.58 h. T_max in plasma after administration of rizatriptan in the orodispersible tablet form is approximately 30-60 minutes longer than after administration of rizatriptan in the oral tablet form.

Effect of food

When rizatriptan is taken as an oral tablet on a full stomach, T_max increases by approximately 1 h. For rizatriptan orodispersible tablets, T_max occurs 1 h later when administered in the fed state. A further delay in the absorption of rizatriptan occurs when rizatriptan is administered after a meal.

Distribution

Rizatriptan is minimally (14%) bound to plasma proteins. V_d is 140 L in men and 110 L in women.

Metabolism

The main pathway of rizatriptan metabolism is oxidative deamination by monoamine oxidase A (MAO-A) to indoleacetic acid, which is not pharmacologically active. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of the parent compound at 5-HT_1B/1D receptors, is formed to a minor extent and does not contribute significantly to the pharmacodynamic activity of rizatriptan. The plasma concentration of N-monodesmethyl-rizatriptan is about 14% of the parent compound concentration, and it is eliminated at the same rate. Other metabolites (N-oxide, 6-hydroxy compound, and sulfate conjugate of the 6-hydroxy metabolite) are not pharmacologically active. After oral administration of ¹⁴C-labeled rizatriptan, Rizatriptan accounts for about 17% of the circulating plasma radioactivity.

Excretion

After IV administration, AUC increases proportionally in men and nearly proportionally in women over the dose range of 10-60 mcg/kg. After oral administration, AUC increases nearly proportionally with dose over the dose range of 2.5-10 mg. The T_1/2 of rizatriptan from plasma in men and women averages 2-3 h. The plasma clearance of rizatriptan averages about 1000-1500 ml/min in men and about 900-1100 ml/min in women; about 20-30% of this is renal clearance. After oral administration of ¹⁴C-labeled rizatriptan, about 80% of the radioactivity is excreted in the urine and about 10% of the dose is excreted in the feces. This shows that metabolites are excreted primarily via the kidneys.

In accordance with first-pass metabolism, approximately 14% of an oral dose is excreted in the urine as unchanged rizatriptan, and 51% is excreted as the indoleacetic acid metabolite. No more than 1% is excreted in the urine as the active N-monodesmethyl metabolite.

When rizatriptan is taken daily at the maximum dosage, Rizatriptan does not accumulate in the blood plasma.

Preclinical safety data

Preclinical study data indicate no risk to humans, based on studies of repeated toxic doses, genotoxicity, carcinogenic potential, reproductive toxicity and developmental toxicity, pharmacological safety, pharmacokinetics and metabolism.

Indications

• Treatment of an attack of migraine with or without aura.

ICD codes

Dosage Regimen

The recommended dose is 10 mg.

When a migraine headache occurs, Kaporiza^® should be taken as early as possible; however, the drug is also effective at a later stage of the migraine attack.

Repeated administration: at least 2 hours should pass between doses; no more than 2 doses should be taken per day.

In case of headache recurrence within 24 hours: if after relief of the initial attack, the headache recurs, another dose can be taken. The above dosage limits should be observed.

After no response: the efficacy of a second dose for treating the initial attack, in case the first dose is ineffective, has not been studied in controlled trials. Therefore, if a patient does not respond to the first dose, a second dose should not be taken during the same attack.

Clinical studies have shown that patients who do not respond to treatment of the current attack may respond to treatment of subsequent attacks.

Patients over 65 years of age

The safety and efficacy of rizatriptan in patients over 65 years of age have not been evaluated.

Patients with renal impairment

Patients with mild or moderate renal impairment should take a lower dose of rizatriptan – 5 mg.

Patients with hepatic impairment

Patients with mild and moderate hepatic impairment should take a lower dose of rizatriptan – 5 mg.

Patients taking propranolol

Patients taking propranolol should use Rizatriptan at a dose of 5 mg. At least 2 hours should pass between taking rizatriptan and taking propranolol (see section “Drug Interactions”).

Children

The safety and efficacy of Kaporiza^® in children and adolescents under 18 years of age have not been established.

Method of administration

Kaporiza^® should not be used for the prevention of migraine attacks.

Orodispersible tablets should not be taken with liquid.

If it is necessary to use the drug at a dose of less than 10 mg, Rizatriptan in the appropriate dosage should be used.

The orodispersible tablet should be removed from the blister pack with dry hands. Place the tablet on the tongue, wait for it to dissolve and swallow with saliva.

Patients should be instructed not to remove the orodispersible tablet from the blister pack until immediately before taking the tablet. Orodispersible tablets can be used in situations where taking liquid is not possible, or to avoid nausea and vomiting that may accompany taking tablets with liquid.

Adverse Reactions

Summary of the safety profile

The use of rizatriptan has been evaluated in more than 8630 adult patients for up to one year in controlled clinical trials. The most frequent adverse effects assessed in clinical trials were dizziness, drowsiness and asthenia/fatigue.

Summary of adverse reactions

The following adverse effects have been assessed in clinical trials and/or reported in the post-marketing period. The frequency of adverse reactions was determined according to the WHO classification: common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Immune system disorders: rare – hypersensitivity, anaphylactic/anaphylactoid reaction.

Psychiatric disorders: common – insomnia; uncommon – disorientation, nervousness.

Nervous system disorders: common – dizziness, drowsiness, paresthesia, headache, hypesthesia, decreased mental activity; uncommon – ataxia, tremor, vertigo, dysgeusia/unpleasant taste, syncope; frequency unknown – seizures, serotonin syndrome.

Eye disorders: uncommon – blurred vision.

Cardiac disorders: common – palpitations; uncommon – arrhythmia, tachycardia; rare – cerebrovascular accident (most of these adverse reactions were reported in patients with risk factors predictive of coronary artery disease), bradycardia; frequency unknown – myocardial ischemia or infarction (most of these adverse reactions were reported in patients with risk factors predictive of coronary artery disease).

Vascular disorders: uncommon – hypertension, flushing, paroxysmal sensation of heat; frequency unknown – peripheral vascular ischemia.

Respiratory, thoracic and mediastinal disorders: common – throat discomfort; uncommon – dyspnea; rare – wheezing.

Gastrointestinal disorders: common – nausea, dry mouth, vomiting, diarrhea, dyspepsia, abdominal pain; frequency unknown – ischemic colitis.

Skin and subcutaneous tissue disorders: common – flushing; uncommon – pruritus, urticaria, angioedema (see section “Special Precautions”), rash, sweating; frequency unknown – toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: common – heaviness in limbs, neck pain, stiffness; uncommon – muscle tension, muscle weakness, myalgia.

General disorders and administration site conditions: common – asthenia/fatigue, chest pain; uncommon – thirst, facial pain.

Investigations: uncommon – ECG abnormalities.

Contraindications

• Hypersensitivity to rizatriptan or to any of the excipients;
• Concomitant use of MAO inhibitors or use of rizatriptan within 2 weeks after discontinuation of MAO inhibitor therapy (see section “Drug Interactions”);
• Severe hepatic impairment;
• Severe renal impairment;
• Patients with a history of cerebrovascular accident (CVA) or transient ischemic attack (TIA);
• Moderately severe or severe hypertension, or untreated mild hypertension;
• Established coronary heart disease (CHD), including CHD (angina, history of myocardial infarction or documented silent/painless ischemia), signs and symptoms of CHD or Prinzmetal’s angina;
• Peripheral vascular disease;
• Concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide) or other 5-HT_1B/1D receptor agonists (see section “Drug Interactions”);
• Children and adolescents under 18 years of age (safety and efficacy have not been established).

Use in Pregnancy and Lactation

Pregnancy

The safety of rizatriptan use during pregnancy has not been established. Animal studies have not shown harmful effects on embryonic development, pregnancy, childbirth and postnatal development when using doses exceeding therapeutic doses.

Since animal studies do not always predict the effect in humans, Rizatriptan should be used during pregnancy only if absolutely necessary.

Breastfeeding

Studies in rats have shown that Rizatriptan passes into breast milk. There is no information on the passage of rizatriptan (metabolites) into human breast milk.

Caution should be exercised when prescribing rizatriptan to women who are breastfeeding. Exposure to infants should be minimized by avoiding breastfeeding for 24 hours after treatment.

Fertility

The effect on human fertility has not been investigated. Animal studies revealed only a minimal effect on fertility at plasma concentrations much higher than human therapeutic concentrations (more than 500 times).

Use in Hepatic Impairment

Patients with mild and moderate hepatic impairment should take a lower dose of rizatriptan – 5 mg.

Use in Renal Impairment

Patients with mild or moderate renal impairment should take a lower dose of rizatriptan – 5 mg.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age (safety and efficacy have not been established).

Geriatric Use

The safety and efficacy of rizatriptan in patients over 65 years of age have not been evaluated.

Special Precautions

Kaporiza^® should be prescribed only to patients in whom a diagnosis of migraine has been established. Kaporiza^® should not be prescribed to patients with basilar or hemiplegic migraine.

Kaporiza^® is not used to treat “atypical” headaches, i.e., those that may be associated with potentially serious conditions (e.g., CVA, ruptured aneurysm) in which cerebrovascular vasoconstriction may be dangerous.

Taking rizatriptan may be accompanied by transient symptoms, including chest pain and tightness, which may be intense and involve the throat (see section “Adverse Reactions”). If such symptoms are suspected to indicate coronary artery disease, the drug should be discontinued and the patient should be examined.

Like other 5-HT_1B/1D receptor agonists, Rizatriptan should not be prescribed without prior examination to patients with a likelihood of unrecognized/undiagnosed heart disease, or to patients at risk of coronary artery disease (CAD) (e.g., patients with hypertension, patients with diabetes mellitus, smokers or patients on nicotine replacement therapy, men over 40 years of age, postmenopausal women, patients with bundle branch block, and patients with a family history of CAD). Cardiac examinations may not always detect every patient with cardiovascular disease, and in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease when 5-HT₁ agonists were administered.

Those with established CAD should not be prescribed Kaporiza^® (see section “Contraindications”).

Administration of 5-HT_1B/1D receptor agonists is associated with coronary vasospasm. In rare cases, myocardial ischemia or infarction has been reported with the use of 5-HT_1B/1D receptor agonists, including Rizatriptan (see section “Adverse Reactions”).

Other 5-HT_1B/1D agonists (e.g., sumatriptan) should not be used concurrently with rizatriptan (see section “Drug Interactions”).

It is recommended to wait at least 6 hours after taking rizatriptan before taking ergotamine-type medications (e.g., ergotamine, dihydroergotamine, or methysergide). At least 24 hours should elapse after taking a medication containing ergotamine before using rizatriptan. Although a clinical pharmacology study involving 16 healthy men who received Rizatriptan orally and ergotamine parenterally did not observe vasospastic effects, such effects are theoretically possible (see section “Contraindications”).

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular abnormalities) has been reported following concomitant treatment with triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). These reactions can be serious. If concomitant treatment with rizatriptan and an SSRI or SNRI is clinically warranted, appropriate patient monitoring is recommended, especially at treatment initiation, during dose increases, or when adding another serotonergic drug (see section “Drug Interactions”).

Adverse effects may be more frequent with the concomitant use of triptans (5-HT_1B/1D agonists) and herbal preparations containing St. John’s wort (Hypericum perforatum).

Angioedema (e.g., facial edema, tongue edema, and laryngeal edema) may occur in patients taking triptans, including Rizatriptan. If angioedema of the tongue or larynx occurs, the patient should be placed under medical supervision until symptoms resolve. Treatment should be discontinued immediately and replaced with a drug from a different class.

The possibility of interaction should be considered when prescribing rizatriptan to patients taking CYP 2D6 substrates (see section “Drug Interactions”).

Medication-overuse headache (MOH)

Prolonged use of any headache pain reliever can worsen headaches. If such a situation occurs or is suspected, medical attention should be sought and treatment discontinued. MOH should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medication.

Excipients

Phenylketonuria. Patients with phenylketonuria should be informed that the product contains aspartame (a source of phenylalanine). Each Kaporiza^® 10 mg orally disintegrating tablet contains 2 mg of aspartame.

Kaporiza^® 10 mg orally disintegrating tablets contain 91.62 mg of mannitol (E 421), which may have a mild laxative effect.

Effect on ability to drive and use machines

Kaporiza^® has a minor/slight influence on the ability to drive and use machines.

Since adverse reactions such as drowsiness and dizziness may develop when taking rizatriptan, caution should be exercised when driving vehicles and operating machinery.

Overdose

Symptoms

Rizatriptan 40 mg (administered as a single dose or two doses with a 2-hour interval between administrations) was well tolerated by more than 300 adult patients: dizziness and drowsiness were the most frequent drug-related adverse effects. Overdose may lead to hypertension or other more serious cardiovascular symptoms.

Treatment

In patients suspected of rizatriptan overdose, gastrointestinal decontamination (e.g., gastric lavage followed by activated charcoal) should be considered. Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if no clinical symptoms are observed. The effect of hemodialysis or peritoneal dialysis on serum rizatriptan concentrations is unknown.

Drug Interactions

Ergotamine, ergot derivatives (including methysergide), other 5-HT_1B/1D receptor agonists

Due to an additive effect, concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide), or other 5-HT_1B/1D receptor agonists (e.g., sumatriptan, zolmitriptan, naratriptan) increases the risk of coronary artery vasoconstriction and hypertension. This combination is contraindicated (see section “Contraindications”).

MAO inhibitors

Rizatriptan is metabolized primarily by monoamine oxidase subtype A (MAO-A). Plasma concentrations of rizatriptan and its active N-monodesmethyl metabolite were increased with the concomitant use of a selective reversible MAO-A inhibitor. Similar or stronger effects are expected with non-selective, reversible (e.g., linezolid) and irreversible MAO inhibitors. Due to the risk of coronary artery vasoconstriction and hypertensive episodes, prescribing rizatriptan to patients taking MAO inhibitors is contraindicated (see section “Contraindications”).

Beta-blockers

The plasma concentration of rizatriptan may increase with the concomitant use of propranolol. This increase is most likely due to a first-pass metabolic interaction between the two drugs, as MAO-A plays a role in the metabolism of both rizatriptan and propranolol. This interaction results in a mean increase in AUC and C_max of 70-80%. Patients receiving propranolol should use Rizatriptan at a dose of 5 mg. At least 2 hours should elapse between taking rizatriptan and taking propranolol (see section “Dosage and Administration”).

In a drug interaction study, nadolol and metoprolol did not affect rizatriptan plasma concentrations.

Selective serotonin reuptake inhibitors (SSRIs) / serotonin and norepinephrine reuptake inhibitors (SNRIs) and serotonin syndrome

There have been reports describing patients with symptoms resembling serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular abnormalities) following the use of SSRIs or SNRIs and triptans (see section “Special Warnings and Precautions”).

In vitro studies indicate that Rizatriptan inhibits cytochrome P450 2D6 (CYP2D6). Clinical interaction data are lacking. The possibility of interaction should be considered when prescribing rizatriptan to patients taking CYP2D6 substrates.

Storage Conditions

The drug should be stored out of the reach of children at a temperature above 25°C (77°F).

Shelf Life

Shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.