Ritaza 10
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE of the medicinal product Ritraza 5 (Ritraza5) Ritraza 10 (Ritraza10)
Composition:
Active substance: rizatriptan;
1 tablet contains rizatriptan benzoate equivalent to rizatriptan 5 mg or 10 mg;
Excipients: lactose monohydrate; microcrystalline cellulose; pregelatinized starch; iron oxide red (E 172); magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties:
for 5 mg dosage: uncoated tablets, capsule-shaped, pale pink in color, engraved with «CL 33» on one side and smooth on the other side;
for 10 mg dosage: uncoated tablets, capsule-shaped, pale pink in color, engraved with «CL 34» on one side and smooth on the other side.
Pharmacotherapeutic group. Medicinal products used in migraine. Selective serotonin 5-HT1 receptor agonists. Rizatriptan. ATC code N02C C04.
Pharmacological properties.
Pharmacodynamics.
Rizatriptan selectively binds with high affinity to human 5-HT1B and 5-HT1D receptors and has little or no effect or pharmacological activity on 5-HT2-, 5-HT3-, adrenergic α1-, α2-, or β-, dopaminergic D1-, D2-, histamine H1-, muscarinic, or benzodiazepine receptors.
The therapeutic efficacy of rizatriptan in the treatment of migraine headache may be explained by its agonist effect on 5-HT1B and 5-HT1D receptors located on extracerebral intracranial blood vessels, which are believed to dilate during an attack, and on trigeminal sensory nerves innervating them. Activation of 5-HT1B and 5-HT1D receptors may lead to constriction of pain-producing intracranial blood vessels and inhibition of neuropeptide release, resulting in reduced inflammation of sensitive tissues and decreased transmission of central trigeminal pain signals.
Pharmacokinetics.
Absorption
After oral administration, rizatriptan is rapidly and completely absorbed. The mean bioavailability of tablets following oral administration is approximately 40–45%, and the mean maximum plasma concentration (Cmax) is reached within approximately 1–1.5 hours (Tmax). Administration of rizatriptan with a high-fat breakfast did not affect the extent of absorption, but absorption was delayed by approximately 1 hour.
Effect of food: Tmax is delayed by approximately 1 hour when tablets are taken with food.
Distribution
Rizatriptan is minimally bound to plasma proteins (14%). The volume of distribution is approximately 140 L in males and 110 L in females.
Metabolism
The primary metabolic pathway of rizatriptan involves oxidative deamination by monoamine oxidase-A (MAO-A) to form indoleacetic acid metabolite, which is not pharmacologically active. A small amount of N-desmethyl-rizatriptan is formed, a metabolite whose activity on 5-HT1B/1D receptors is similar to that of the parent compound, but which does not significantly contribute to the pharmacodynamic activity of rizatriptan. The plasma concentration of N-desmethyl-rizatriptan is approximately 14% of the parent compound and is eliminated at a similar rate. Other minor metabolites include N-oxide, 6-hydroxy compound, and sulfate conjugate of the 6-hydroxy metabolite. None of these minor metabolites exhibit pharmacological activity.
Elimination
After oral administration of doses above the 2.5–10 mg range, the area under the curve (AUC) increases almost proportionally. In both males and females, the mean plasma half-life of rizatriptan is 2–3 hours. The plasma clearance of rizatriptan is approximately 1000–1500 mL/min in males and approximately 900–1100 mL/min in females; about 20–30% of this is renal clearance. After oral administration of 14C-labeled rizatriptan, approximately 80% of radioactivity is excreted in urine and about 10% of the dose is excreted in feces. This indicates that metabolites are primarily eliminated via the kidneys.
Due to presystemic metabolism, approximately 14% of the oral dose is excreted unchanged in urine, while 51% is excreted as the indoleacetic acid metabolite. No more than 1% is excreted in urine as the active N-desmethyl metabolite.
When rizatriptan is administered at maximum recommended doses, no daily accumulation of the drug in plasma occurs.
Population characteristics
Patients experiencing migraine attacks. Migraine attacks do not affect the pharmacokinetics of rizatriptan.
Gender. In males, AUC of rizatriptan (10 mg orally) was approximately 25% lower than in females, Cmax was 11% lower, while Tmax was approximately the same. This apparent pharmacokinetic difference has no clinical significance.
Elderly patients. Plasma concentrations of rizatriptan are similar to those in younger patients.
Patients with hepatic impairment (Child-Pugh score 5–6). Following oral administration, plasma concentrations of rizatriptan in patients with hepatic impairment were similar to those observed in healthy young males and females in clinical studies. A significant increase in AUC (by 50%) and Cmax (by 25%) was observed in patients with moderate hepatic impairment (Child-Pugh score 7). Pharmacokinetics in patients with Child-Pugh score > 7 (severe hepatic impairment) have not been studied.
Patients with renal impairment. In patients with renal impairment (creatinine clearance 10–60 mL/min/1.73 m²), AUC of rizatriptan did not differ significantly from that in healthy volunteers. In patients undergoing hemodialysis (creatinine clearance < 10 mL/min/1.73 m²), AUC of rizatriptan was approximately 44% higher than in patients with normal renal function. Cmax of rizatriptan in plasma in patients with any degree of renal impairment was similar to that in healthy volunteers.
Clinical characteristics.
Indications.
Acute treatment of the headache phase of migraine attacks, with or without aura, in adults.
Contraindications.
Hypersensitivity to rizatriptan or to any of the excipients of the medicinal product.
Concomitant use with monoamine oxidase inhibitors (MAO inhibitors) or within two weeks of discontinuation of MAO inhibitor therapy.
Severe hepatic or severe renal impairment.
History of cerebrovascular accident or transient ischemic attack.
Moderate or severe arterial hypertension, as well as untreated mild arterial hypertension.
Established coronary artery disease, including ischemic heart disease (angina, history of myocardial infarction, or documented silent ischemia), signs and symptoms of ischemic heart disease, or Prinzmetal's angina.
Peripheral vascular disease.
Concomitant use of rizatriptan with ergotamine, ergot alkaloid derivatives (including methysergide), or other 5-HT1B/1D receptor agonists.
Interaction with other medicinal products and other types of interactions.
Ergotamine, ergot alkaloid derivatives (including methysergide), other 5-HT1B/1D receptor agonists.
Due to an additive effect, concomitant administration of rizatriptan with ergotamine, ergot alkaloid derivatives (including methysergide) or other 5-HT1B/1D receptor agonists (e.g., sumatriptan, zolmitriptan, naratriptan) increases the risk of coronary artery vasoconstriction and hypertensive effects. Such combinations are contraindicated (see section "Contraindications").
MAO inhibitors.
Rizatriptan is primarily metabolized by monoamine oxidase subtype A (MAO-A). Plasma concentrations of rizatriptan and its active N-monodesmethyl metabolite increase when co-administered with a selective, reversible MAO-A inhibitor. A similar or greater effect is expected with non-selective, reversible MAO inhibitors (e.g., linezolid). Due to the risk of coronary spasm and arterial hypertension, rizatriptan is contraindicated in patients taking MAO inhibitors (see section "Contraindications").
Beta-blockers.
Plasma concentrations of rizatriptan may increase when co-administered with propranolol. This increase is most likely due to interaction in the primary metabolism of both drugs, as MAO-A plays a role in the metabolism of both rizatriptan and propranolol. This interaction results in an average increase in AUC and Cmax by 70–80%. Patients taking propranolol should receive rizatriptan at a dose of 5 mg (see section "Dosage and administration").
The medicinal products nadolol and metoprolol do not alter rizatriptan plasma concentrations.
Selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors and serotonin syndrome.
Cases have been reported in patients presenting symptoms suggestive of serotonin syndrome (including altered mental status, autonomic nervous system dysfunction, and neuromuscular disturbances) following concomitant use of serotonin reuptake inhibitors/norepinephrine-serotonin reuptake inhibitors and triptans (see section "Special precautions for use").
In vitro studies show that rizatriptan inhibits cytochrome P450 2D6 (CYP2D6). Clinical data on such interactions are lacking. Potential interactions should be considered when prescribing rizatriptan to patients taking CYP2D6 substrates.
Special precautions.
Rizatriptan should be prescribed only to patients who have been clearly diagnosed with migraine. Rizatriptan should not be prescribed to patients with basilar or hemiplegic migraine.
Rizatriptan should not be used to treat atypical headache, i.e., headache that may be associated with potentially serious conditions (e.g., stroke, ruptured aneurysm), in which cerebral vasoconstriction could be hazardous.
Administration of rizatriptan may be associated with transient symptoms, including chest pain and chest tightness, which may be intense and radiate to the throat. If such symptoms raise suspicion of ischemic heart disease, the drug should be discontinued and appropriate evaluation initiated.
Like other 5-HT1B/1D receptor agonists, rizatriptan should not be prescribed without prior cardiovascular evaluation in patients with probable heart disease or those at risk of coronary artery disease (e.g., patients with arterial hypertension, diabetes mellitus, smokers or those using nicotine replacement therapy; men aged 40 years or older, postmenopausal women, patients with interventricular conduction defects, or those with a family history of serious coronary artery disease). Cardiovascular evaluation may not detect all patients with heart disease; in very rare cases, serious cardiac complications have been reported with 5-HT1 receptor agonists in patients without known cardiovascular disease. Rizatriptan is contraindicated in patients with diagnosed coronary atherosclerosis (see section "Contraindications").
5-HT1B/1D receptor agonists have been associated with coronary spasm. In some cases, myocardial ischemia or infarction has been reported during treatment with 5-HT1B/1D receptor agonists.
Other 5-HT1B/1D receptor agonists (e.g., sumatriptan) should not be administered concomitantly with rizatriptan.
It is recommended to wait at least 6 hours after rizatriptan administration before taking ergotamine-containing agents (e.g., ergotamine, dihydroergotamine, or methysergide). Before administering rizatriptan, it is necessary to ensure that at least 24 hours have elapsed since the last dose of any ergotamine-containing medication.
Cases of serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) have been reported following concomitant use of triptans and SSRIs or serotonin-norepinephrine reuptake inhibitors. These reactions may be serious. If concomitant use of rizatriptan with SSRIs or serotonin-norepinephrine reuptake inhibitors is clinically indicated, appropriate monitoring of the patient is recommended, particularly at the beginning of treatment, during dose escalation, or when adding another serotonergic agent.
Adverse effects occur more frequently when triptans (5-HT1B/1D agonists), including rizatriptan, are used concomitantly with herbal preparations containing St. John's wort (Hypericum perforatum).
Angioedema (e.g., facial, tongue, and laryngeal swelling) may occur in patients receiving triptans, including rizatriptan. If angioedema of the tongue or pharynx develops, the patient should remain under medical supervision until symptoms resolve. Triptan therapy should be discontinued immediately and replaced with a medication from a different drug class.
When prescribing rizatriptan to patients taking CYP2D6 substrates, potential drug interactions should be considered.
Medication-overuse headache
Prolonged use of any analgesic for headache may lead to worsening of headache. If this occurs (or is suspected), medical advice should be sought and treatment discontinued. Medication-overuse headache should be suspected in patients who experience frequent or daily headaches despite regular use of headache medications.
Excipients
Since the medicinal product contains lactose, it is not recommended for patients with diagnosed intolerance to certain sugars. Consult a physician before taking this medicinal product.
Use during pregnancy or breastfeeding.
Pregnancy. A moderate amount of data from pregnant women (from 300 to 1000 pregnancies) indicates no evidence of teratogenic toxicity following exposure during the first trimester. Animal studies do not indicate reproductive toxicity.
Data on the use of rizatriptan during the second and third trimesters of pregnancy are limited. Rizatriptan may be considered during pregnancy if clinically necessary.
Breastfeeding. Rizatriptan passes into breast milk at low concentrations, with a mean relative infant dose of < 1% (up to 6% in the worst-case scenario based on Cmax in breast milk). Rizatriptan should be used with caution in breastfeeding women. Infant exposure should be minimized by avoiding breastfeeding for 12 hours after drug administration.
Fertility. The effect on human fertility has not been studied. In animal studies, minimal effects on fertility were observed at plasma concentrations more than 500 times higher than therapeutic concentrations in humans.
Ability to affect reaction speed when driving or operating machinery.
Migraine or treatment with rizatriptan benzoate may cause drowsiness and dizziness; therefore, patients should assess their ability to perform complex tasks during migraine attacks and after taking the medication.
Administration and Dosage
Adults
Dosage information in adult patients
Administer orally. Do not use rizatriptan benzoate for prophylactic purposes.
Tablets should be swallowed whole with liquid.
Effect of food: when taken with food, absorption of rizatriptan is delayed by approximately 1 hour. Therefore, the onset of action of the drug may be delayed if taken in a fed state (see also section "Pharmacological properties").
The recommended dose is 10 mg.
Repeat dosing: the next dose may be taken no sooner than 2 hours after the previous one; no more than two doses should be taken within a 24-hour period.
- In case of recurrent headache within the following 24 hours: if headache returns after initial relief, another dose may be taken. The dosage limits stated above must be observed.
- In case of lack of effect: the efficacy of a second dose for treating the same attack when the initial dose is ineffective has not been studied in controlled trials. Therefore, if no therapeutic effect occurs after the first dose, a second dose should not be taken for the same attack.
Clinical studies with rizatriptan have shown that even if no therapeutic effect occurs during one attack, there remains a possibility of achieving a therapeutic effect during subsequent attacks.
Some patients may require a lower dose of rizatriptan (5 mg), particularly the following patient groups:
- patients taking propranolol (rizatriptan should be taken no sooner than 2 hours after propranolol);
- patients with mild to moderate renal impairment;
- patients with mild to moderate hepatic impairment.
The interval between two doses should be at least 2 hours; no more than 2 doses should be taken within a 24-hour period.
Elderly patients
The efficacy and safety of rizatriptan in patients aged 65 years and older have not been systematically studied.
Children
The efficacy and safety of rizatriptan benzoate in children (under 18 years of age) have not been established.
Overdose
Rizatriptan 40 mg (administered as a single dose or two doses with a 2-hour interval between doses) was generally well tolerated; the most common adverse effects observed were dizziness and somnolence.
In a clinical pharmacology study in which 12 adult subjects received a total cumulative dose of 80 mg rizatriptan (over 4 hours), two subjects experienced loss of consciousness and/or bradycardia. In one subject, a 29-year-old female, vomiting, bradycardia, and dizziness were observed 3 hours after a total intake of 80 mg rizatriptan (administered over 2 hours). Following these symptoms, third-degree atrioventricular block occurred, which was responsive to atropine. In the second subject, a 25-year-old male, transient dizziness, loss of consciousness, urinary incontinence, and a five-second systolic pause (on ECG monitoring) occurred immediately after a painful venipuncture. The venipuncture was performed 2 hours after the subject had received a total cumulative dose of 80 mg rizatriptan (administered over 4 hours).
After overdose, hypertension or other more serious cardiovascular symptoms may occur. Patients suspected of rizatriptan overdose should undergo gastrointestinal decontamination (e.g., gastric lavage followed by activated charcoal). Afterwards, clinical and electrocardiographic monitoring should be performed for at least 12 hours, even in the absence of clinical symptoms.
The effect of hemodialysis and peritoneal dialysis on rizatriptan plasma concentration is unknown.
Adverse Reactions
Rizatriptan was evaluated in 8,630 adult patients over 1 year in controlled clinical studies. The most commonly reported adverse reactions in clinical trials were dizziness, somnolence, and asthenia/fatigue. The following adverse effects were observed in clinical studies and/or reported in post-marketing experience: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (≤1/10,000), frequency not known (cannot be estimated from available data).
Immune system disorders:
Rare – allergic reactions, anaphylaxis/anaphylactoid reaction.
Psychiatric disorders:
Common – insomnia; uncommon – confusion, irritability.
Nervous system disorders:
Common – dizziness, somnolence, paraesthesia, headache, hypoesthesia, decreased mental sharpness; uncommon – ataxia, tremor, vertigo, dysgeusia/unpleasant taste, syncope; frequency not known – seizures, serotonin syndrome.
Eye disorders:
Uncommon – blurred vision.
Cardiac disorders:
Common – palpitations; uncommon – arrhythmia, tachycardia, ECG changes; rare – cerebrovascular events (according to reports, most of these adverse reactions occurred in patients with risk factors for coronary artery disease), bradycardia; frequency not known – myocardial ischemia or infarction (according to reports, most of these adverse reactions occurred in patients with risk factors for coronary artery disease).
Vascular disorders:
Uncommon – arterial hypertension, flushing; frequency not known – peripheral ischemia.
Respiratory, thoracic and mediastinal disorders:
Common – throat discomfort; uncommon – dyspnea; rare – wheezing.
Gastrointestinal disorders:
Common – nausea, dry mouth, vomiting, diarrhea, dyspepsia; uncommon – thirst; frequency not known – ischemic colitis.
Skin and subcutaneous tissue disorders:
Common – erythema; uncommon – pruritus, urticaria, angioneurotic edema (e.g., facial, tongue, and throat swelling), rash, increased sweating; frequency not known – toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders:
Common – heaviness, stiffness, neck pain; uncommon – rigidity, muscle weakness, facial pain, myalgia.
General disorders and administration site conditions:
Common – asthenia/fatigue, abdominal or chest pain.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of reach and sight of children.
Packaging.
3 tablets in a blister pack, 1 or 3 blisters per cardboard package.
Prescription status. Prescription only.
Manufacturer. Macleods Pharmaceuticals Limited.
Manufacturer's address and location of operations.
Village Thieda, P.O. Lodhymaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.