Relonova (Tablets) Instructions for Use

Marketing Authorization Holder

Novamedica, LLC (Russia)

Manufactured By

Novamedica Innotech, LLC (Russia)

Contact Information

Novamedica LLC (Russia)

ATC Code

N02CC04 (Rizatriptan)

Active Substance

Rizatriptan (Rec.INN registered by WHO)

Dosage Form

Relonova

Tablets 10 mg: 2 or 6 pcs.

Dosage Form, Packaging, and Composition

Tablets are round, biconvex, white or almost white in color.

Excipients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, magnesium stearate.

2 pcs. – blister packs (1) – cardboard boxes.
2 pcs. – blister packs (3) – cardboard boxes.

Clinical-Pharmacological Group

Serotonin 5-HT₁ receptor agonist. Agent with antimigraine activity

Pharmacotherapeutic Group

Analgesics; antimigraine preparations; selective agonists of serotonin 5-HT₁ receptors

Pharmacological Action

Mechanism of action

Rizatriptan selectively and with high affinity binds to human 5-HT1B and 5-HT1D receptors and has virtually no pharmacological activity on 5-HT2, 5-HT3; α₁-, and α₂– and β-adrenergic receptors; dopaminergic D₁-, D₂ receptors; histamine H₁ receptors; muscarinic receptors or benzodiazepine receptors.

Pharmacodynamic effects

The therapeutic efficacy of rizatriptan in the treatment of migraine headache may be explained by its agonistic action on 5-HT1B and 5-HT1D receptors on extracerebral intracranial vessels, which are thought to dilate during attacks, and on the sensory nerves of the trigeminal nerve that innervate them. Activation of 5-HT1B and 5-HT1D receptors may lead to constriction of pain-causing intracranial blood vessels and inhibition of neuropeptide release, thereby reducing inflammation in sensitive tissues and reducing central pain transmission via central trigeminal nerves.

Clinical efficacy and safety

Adults

The efficacy of rizatriptan in the treatment of acute migraine attacks was established in four multicenter, placebo-controlled studies involving more than 2000 patients receiving Rizatriptan at doses of 5 mg or 10 mg for 1 year. Headache relief occurred within 30 minutes after the first dose, and the efficacy rate (reduction of moderate or severe headache to mild pain or no pain) 2 hours after taking 10 mg of rizatriptan was 67-77%, after taking 5 mg of rizatriptan – 60-63% compared to 23-40% in the placebo group. Although patients who did not respond to rizatriptan did not receive a repeat dose of the drug to treat the same attack, there remains a possibility of a therapeutic effect in subsequent attacks. Rizatriptan also relieved migraine-associated discomfort, nausea, photophobia, and phonophobia.

Rizatriptan remains effective in treating menstrual migraine, i.e., migraine that occurs within 3 days before or after the start of menstruation.

The safety of Relonova was assessed in a bioequivalence clinical study. All adverse events were mild in severity, and the relationship with drug administration was assessed as possible.

Children (from 12 to 17 years)

The efficacy of rizatriptan in the form of orally disintegrating tablets was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study (n=570). The patient group was not sensitive to treatment with NSAIDs and paracetamol. Patients with an appropriate migraine first took placebo or Rizatriptan 30 minutes after the onset of an attack. After a 15-minute placebo administration, patients receiving placebo or Rizatriptan developed a migraine attack. Patients received a dose depending on their body weight: from 20 kg to <40 kg – 5 mg rizatriptan; ≥40 kg – 10 mg rizatriptan.

In this extended group study, a 9% difference between active treatment and placebo was observed for the primary efficacy endpoint of pain-free (reduction from moderate or severe pain to no pain) at 2 hours post-dose (31% for rizatriptan vs. 22% for placebo (p=0.025)). No significant differences for the secondary endpoint of pain relief (reduction from moderate or severe pain to mild or no pain) were observed.

Children (from 6 to 11 years)

The efficacy of rizatriptan in the form of orally disintegrating tablets was also evaluated in children aged 6 to 11 years in the same placebo-controlled clinical study (n=200). The proportion of patients with no pain at 2 hours did not differ statistically significantly between patients taking Rizatriptan and placebo (39.8% and 30.4%, p=0.269).

Pharmacokinetics

Absorption

After oral administration, Rizatriptan is rapidly and completely absorbed. The mean oral bioavailability of the tablets is approximately 40-45%, and the mean C_max is 23.9 ng/ml and is achieved approximately 1-1.5 hours (T_max). The mean AUC is 76.5 ng×h/ml. Oral administration of rizatriptan tablets with a high-fat breakfast does not affect the extent of rizatriptan absorption, but the absorption of rizatriptan is delayed by approximately 1 hour.

Distribution

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

Metabolism

Rizatriptan is primarily converted to the pharmacologically inactive metabolite indoleacetic acid by oxidative deamination by monoamine oxidase A (MAO-A). N-monodesmethyl-Rizatriptan, a metabolite with activity similar to that of the parent compound at 5-HT1B/D1 receptors, is formed to a small extent but does not contribute significantly to the pharmacodynamic efficacy of rizatriptan. The plasma concentration of N-monodesmethyl-rizatriptan is about 14% of the parent compound concentration and is eliminated at a similar rate.

Other minor metabolites include the N-oxide and 6-hydroxy compound and the sulfate conjugate of the 6-hydroxy metabolite. None of these metabolites are pharmacologically active. After oral administration of ¹⁴C-labeled rizatriptan, Rizatriptan accounts for approximately 17% of the circulating radioactivity in plasma.

Elimination

After IV administration, AUC increases proportionally with dose in the dose range of 10-60 pg/kg in men and nearly proportionally in women. After oral administration, AUC increases nearly proportionally with dose in the range of 2.5-10 mg. The T_1/2 of rizatriptan from plasma in men and women is approximately 2-3 hours. The plasma clearance of rizatriptan averages about 1000-1500 ml/min in men and about 900-1100 ml/min in women; of which approximately 20-30% is renal clearance. After oral administration of a dose of ¹⁴C-labeled rizatriptan, approximately 80% of the radioactivity is excreted in the urine; approximately 10% of the dose is excreted in the feces. Accordingly, metabolites are mainly excreted by the kidneys. Due to the presystemic metabolism of rizatriptan, approximately 14% of the oral dose is excreted unchanged in the urine, while 51% is excreted as the indoleacetic acid metabolite. No more than 1% is excreted in the urine as the active metabolite N-monodesmethyl. No accumulation was observed when rizatriptan was used at maximum doses.

Linearity (non-linearity)

The pharmacokinetics are linear.

Pharmacokinetics in special patient groups

Renal impairment. In patients with renal impairment (CrCl 10-60 ml/min/1.73 m²), the AUC values of rizatriptan did not differ significantly from those in healthy individuals. In patients on hemodialysis (CrCl <10 ml/min/1.73 m²), the AUC value of rizatriptan was approximately 44% higher than in patients with normal renal function. The C_max of rizatriptan in plasma in patients with any degree of renal impairment was similar to that in healthy individuals.

Hepatic impairment. After oral administration in patients with hepatic impairment (severity of hepatic impairment on the Child-Pugh scale – 5-6 points) due to alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were comparable to its concentrations in young men and women participating in the study. In patients with moderate hepatic impairment (7 points on the Child-Pugh scale), a significant increase in AUC (by 50%) and C_max (by 25%) was observed. Pharmacokinetics have not been studied in patients with severe hepatic impairment (> 7 points on the Child-Pugh scale).

Elderly patients. Plasma concentrations of rizatriptan in elderly patients (age 65-77 years) were similar to concentrations in younger patients.

Gender. In men, the AUC of rizatriptan (10 mg orally) was approximately 25% lower than in women, C_max was 11% lower, and T_max was approximately the same. This pharmacokinetic difference is not clinically significant.

Children. A pharmacokinetic study of rizatriptan (in the form of orally disintegrating tablets) was conducted in children with migraine aged 6-17 years. The mean exposure after a single dose of 5 mg rizatriptan tablet for children weighing 20-39 kg or 10 mg rizatriptan tablet for children weighing > 40 kg was 15% lower and 17% higher, respectively, than the exposure of a single dose of 10 mg rizatriptan tablet for adults. The clinical significance of these differences is unclear.

Preclinical safety data

In preclinical pharmacological safety studies, traditional multiple-dose toxicity studies, genotoxicity, mutagenicity, carcinogenic potential, and reproductive toxicity studies, no toxic effects of the drug at therapeutic doses used in humans were identified. Preclinical studies revealed no teratogenic effects in mice, rats, or rabbits.

Indications

• For the emergency treatment of the headache phase of migraine attacks (with or without aura) in adults over 18 years of age.

ICD codes

Dosage Regimen

Relonova should not be used for prophylactic purposes.

Orally. The tablets should be taken whole, without chewing, with water.

When taken with food, the absorption of rizatriptan is delayed by approximately 1 hour. Therefore, if rizatriptan is taken after a meal, the effect may be delayed (see also the “Pharmacokinetics” section).

The recommended single dose is 1 tablet (10 mg)

Subsequent doses: Consecutive doses may be taken at intervals of at least 2 hours; no more than 2 doses should be taken within 24 hours.

• In case of recurrent headache within 24 hours: if headache recurs after initial relief of symptoms, another dose may be taken, taking into account the limitations described above;
• In case of no effect: if the first dose has no effect, the efficacy of a second dose for treating the same attack has not been studied in controlled clinical trials. Thus, if the patient does not respond to the first dose, a second dose should not be taken for the same attack in this case.

Clinical studies show that patients who do not respond to treatment for one attack are more likely to respond to treatment for another attack.

Doses should be taken at intervals of at least 2 hours; no more than 2 doses should be taken in a 24-hour period. The maximum daily dose is 20 mg (2 tablets).

Special patient groups

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

The use of Relonova in patients with renal impairment is contraindicated.

The use of Relonova in patients with hepatic impairment is contraindicated.

Relonova is contraindicated in children under 18 years of age. The safety and efficacy of Relonova in children under 18 years of age have not been established to date.

Adverse Reactions

The most common adverse reactions occurring during treatment include dizziness, drowsiness, and weakness/fatigue.

Adverse reactions are grouped by system and organ according to the MedDRA dictionary and using WHO classification: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (>1/10000), frequency unknown (frequency cannot be determined from available data).

Immune system disorders rare – hypersensitivity reactions, anaphylaxis/anaphylactoid reaction.

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

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

Eye disorders uncommon – blurred vision.

Cardiac disorders common – palpitations; uncommon – arrhythmia, ECG abnormalities, tachycardia; rare – cerebrovascular accident (reports indicate that most of these adverse reactions occurred in patients with risk factors for coronary artery disease), bradycardia; frequency unknown – myocardial ischemia or infarction (reports indicate that most of these adverse reactions occurred in patients with risk factors for coronary artery disease).

Vascular disorders uncommon – arterial hypertension, flushing; 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; uncommon – thirst; unknown – ischemic colitis.

Skin and subcutaneous tissue disorders common – redness; uncommon – itching, urticaria, angioedema (facial edema, tongue edema, pharyngeal edema), rash, hyperhidrosis; unknown – toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders common – pain and discomfort, neck pain, stiffness; uncommon – chest discomfort, muscle weakness, facial pain, myalgia.

General disorders and administration site conditions common – weakness/fatigue, abdominal pain, chest pain.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to rizatriptan or any of the excipients included in the drug;
• Moderate or severe arterial hypertension or mild hypertension not undergoing treatment;
• Established coronary artery disease, including coronary artery disease (angina pectoris, history of myocardial infarction or established silent ischemia), objective and subjective symptoms of coronary artery disease or Prinzmetal’s angina;
• History of acute cerebrovascular accident (stroke) or transient ischemic attack (TIA);
• Peripheral arterial disease;
• Hepatic impairment;
• Renal impairment;
• Hemiplegic or basilar migraine;
• Concomitant use of MAO inhibitors or use within 2 weeks after discontinuation of MAO inhibitor treatment;
• Concomitant use of rizatriptan and ergotamine, ergot alkaloid derivatives (including methysergide) or other 5-HT1B/1D receptor agonists within the previous 24 hours;
• Concomitant use of rizatriptan and propranolol (see section “Drug Interactions”).

Use in Pregnancy and Lactation

Pregnancy

The safety of rizatriptan in human pregnancy has not been established. Animal studies have shown no harmful effects on embryonic or intrauterine development or the course of pregnancy, childbirth, and postnatal development at doses exceeding therapeutically equivalent doses.

Since reproduction and development studies in animals do not always predict the response in humans, Relonova should be used during pregnancy only if absolutely necessary.

Breastfeeding

Studies in rats have shown that Rizatriptan is excreted in breast milk in large quantities. A temporary, very slight decrease in the body weight of the offspring before weaning was observed only if the systemic exposure to the mother was significantly higher than the maximum human exposure. There are no data from human studies. Therefore, caution should be exercised when prescribing rizatriptan to nursing women. Exposure to newborns should be minimal if breastfeeding is avoided for 24 hours after taking the tablet.

Fertility

Animal reproduction studies have shown minimal effects on reproductive function at plasma concentrations much higher than therapeutic concentrations in humans (more than 500 times).

Use in Hepatic Impairment

The use of Relonova in patients with hepatic impairment is contraindicated

Use in Renal Impairment

The use of Relonova in patients with renal impairment is contraindicated.

Pediatric Use

Relonova is contraindicated in children under 18 years of age. The safety and efficacy of the drug in this category of patients have not been established to date.

Geriatric Use

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

Special Precautions

The drug Relonova should be prescribed exclusively to patients who have been diagnosed with migraine. Relonova should not be prescribed to patients with basilar or hemiplegic migraine.

Cerebrovascular Disorders

Relonova should not be used to treat atypical headache, i.e., those cases where the headache may be associated with a potentially serious condition (such as stroke, ruptured aneurysm) in which cerebral vasoconstriction may be dangerous.

Coronary Artery Disease, Myocardial Infarction, and Prinzmetal’s Angina

The use of rizatriptan may be associated with transient symptoms, including chest pain and shortness of breath, which can be intense and involve the throat. If symptoms suggestive of coronary artery disease are suspected, an additional dose should not be taken, and appropriate examinations should be performed.

As with other selective 5-HT1B/1D receptor agonists, Rizatriptan should not be prescribed without prior evaluation to patients who are likely to have unrecognized heart disease, or to patients at risk of coronary artery disease (for example, patients with arterial hypertension, diabetes, smokers or individuals using nicotine replacement therapy, men over 40 years of age, postmenopausal women, patients with bundle branch block, and patients with a serious family history of coronary artery disease). Cardiac examinations may not detect existing heart conditions; in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease following the administration of 5-HT1 agonists. Patients with established coronary artery disease should not take Relonova.

Selective 5-HT1B/1D receptor agonists are associated with coronary vasospasm. In rare cases, myocardial ischemia or infarction has been reported with the use of selective 5-HT1B/1D receptor agonists.

Other 5-HT1B/1D agonists (for example, sumatriptan) should not be used concurrently with Relonova.

After taking rizatriptan, it is recommended to wait at least 6 hours before starting ergotamine derivatives (such as ergotamine, dihydroergotamine, or methysergide). At least 24 hours should elapse after taking an ergotamine medication before using rizatriptan. Although no additional vasospastic effects were observed in a clinical pharmacology study in which 16 healthy men received oral Rizatriptan and parenteral ergotamine, such additive effects are theoretically possible.

Serotonin Syndrome

Serotonin syndrome (including changes in mental status, autonomic instability, and neuromuscular abnormalities) has been reported with concomitant treatment with triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). These reactions can have serious consequences. If concomitant treatment with rizatriptan and an SSRI or SNRI is clinically warranted, appropriate patient monitoring is recommended. This is especially important at the start of treatment, when increasing the dose, or when adding another serotonergic medication.

Concomitant use of triptans (5-HT1B/1D agonists) and herbal preparations containing St. John’s wort (Hypericum perforatum) may increase the incidence of side effects.

Allergic Reactions

Angioedema (e.g., swelling of the face or pharynx, or swelling of the tongue) may occur in patients taking triptans, including Rizatriptan. If angioedema of the tongue or pharynx occurs, the patient should be placed under medical supervision until the symptoms resolve. The medication should be discontinued immediately and replaced with a different type of drug.

When prescribing Rizatriptan to patients using CYP2D6 substrates, their potential interaction should be considered (see the “Drug Interactions” section).

Medication Overuse Headache

Prolonged use of any painkiller for headaches can worsen these headaches. If such a situation occurs or is suspected, a doctor should be consulted and treatment should be discontinued. Patients who experience frequent or daily headaches despite regular use of headache medication should consider a diagnosis of medication overuse headache.

Lactose

Patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Effect on Ability to Drive and Operate Machinery

Relonova has a significant effect on the ability to drive vehicles and operate machinery. Dizziness has been reported in some patients taking Rizatriptan. Therefore, during migraine attacks and after taking Relonova, patients should assess their ability to perform complex tasks and refrain from driving vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

Symptoms Rizatriptan 40 mg (as a single dose or in two doses 2 hours apart) was shown to be well tolerated in more than 300 adult patients; the most common drug-related adverse effects were dizziness and drowsiness.

In a clinical pharmacology study in which 12 adult subjects received Rizatriptan in a total cumulative dose of 80 mg (administered over 4 hours), two subjects experienced syncope and/or bradycardia. A 29-year-old woman developed vomiting with bradycardia and dizziness, which began 3 hours after receiving a total dose of 80 mg of rizatriptan (administered over 2 hours). One hour after the onset of other symptoms, third-degree AV block was observed, which responded to atropine. A second individual, a 25-year-old man, experienced transient dizziness, syncope, urinary incontinence, and a 5-second systolic pause (on ECG monitor) immediately after a painful venipuncture. The venipuncture was performed 2 hours after the subject had received a total of 80 mg of rizatriptan (administered over 4 hours).

Furthermore, based on the pharmacology of rizatriptan, hypertension or other more serious cardiovascular symptoms may occur following an overdose.

Treatment Patients suspected of rizatriptan overdose should undergo gastrointestinal decontamination (e.g., induction of vomiting, gastric lavage followed by administration of activated charcoal).

The effect of hemodialysis and peritoneal dialysis on serum concentrations of rizatriptan is unknown.

Given the possibility of hypertension and other more serious cardiovascular events in case of overdose, monitoring of the general clinical condition and ECG for at least 12 hours after overdose is indicated, even in the absence of patient complaints.

Drug Interactions

Ergotamine, Ergotamine Derivatives (including methysergide) and Other Selective 5-HT1B/1D Receptor Agonists Due to an additive effect, concomitant use of rizatriptan and ergotamine, ergotamine derivatives (including methysergide) or other selective 5-HT1B/1D receptor agonists (such as sumatriptan, zolmitriptan, naratriptan) increases the risk of coronary artery vasoconstriction and hypertensive effects. This combination is contraindicated (see the “Contraindications” section).

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

Beta-blockers The plasma concentration of rizatriptan may increase with the concomitant use of propranolol. The increase in concentration is 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 taking propranolol should not take Rizatriptan (see the “Dosage Regimen” section).

In a drug interaction study, nadolol and metoprolol did not affect the plasma concentration of rizatriptan.

SSRIs/SNRIs and Serotonin Syndrome Cases of patients with symptoms consistent with serotonin syndrome (including changes in mental status, autonomic instability, and neuromuscular abnormalities) have been reported after taking SSRIs or SNRIs and triptans (see the “Special Precautions” section).

According to in vitro studies, Rizatriptan inhibits the CYP2D6 isoenzyme. There are no data on clinical interaction. When prescribing Rizatriptan to patients taking CYP2D6 substrates, their potential interaction should be considered.

Storage Conditions

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

Shelf Life

Shelf life is 2 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.