Risatriptan

Pharmacological properties

risatriptan selectively binds to human receptors 5-ht1b and 5-ht1d with high affinity and has little or no effect on 5-ht2, 5-ht3; adrenergic α1, α2 or β; dopaminergic d1, d2; histamine h1; muscarinic or benzodiazepine receptors.

The therapeutic activity of risatriptan for migraine headache can be explained by its agonistic effect on 5-HT receptors_1B and 5-HT_1D extracerebral intracranial blood vessels, which are thought to expand during an attack, and trigeminal sensory nerves that innervate them. 5-HT receptor activation_1B and 5-HT_1D can lead to a narrowing of the intracranial blood vessels that cause pain, and inhibition of the release of the neuropeptide, which leads to a decrease in the severity of inflammation of sensitive tissues and a decrease in the transmission of central trigeminal pain signal.

Pharmacokinetics Absorption. After oral administration, risatriptan is rapidly and completely absorbed. The oral bioavailability of tablets is approximately 40–45%, and C_maxin blood plasma is reached after 1-1.5 hours (Tmax). Oral administration of risatriptan during a high-fat breakfast does not affect the degree of absorption of risatriptan, but its absorption is delayed by approximately 1 hour.

Effect of food: Tmax is delayed by approximately 1 hour if the tablets are taken in a satiated state.

Distribution. Risatriptan minimally (14%) binds to plasma proteins. The distribution volume is approximately 140 liters in men and 110 liters in women.

Metabolism. The primary pathway of rhizatriptan metabolism is through the oxidative deamination of monoamine oxidase (MAO) of subtype A (MAO-A) to a metabolite of indolylacetic acid, which is not pharmacologically active. A small amount of N-monodesmethyl-risatriptan is formed, a metabolite whose activity is similar to that of the primary substance to 5-HT receptors_{1B / 1D}, but does not significantly affect the pharmacodynamic activity of risatriptan. The plasma concentration of N-monodesmethyl-risatriptan is approximately 14% of the concentration of the primary substance, the compound is excreted at the same rate. Other minor metabolites include N-oxide, 6-hydroxy compound, and 6-hydroxymetabolite sulfate conjugate. None of these minor metabolites show pharmacological activity.

After taking a dose above the 2.5-10 mg dose range, the area under the curve (AUC) increases almost proportionally. In men and women, the half-life of rhizatriptan in plasma is on average 2-3 hours. The clearance of rhizatriptan in plasma is on average about 1000-1500 ml / min in men and about 900-1100 ml / min in women; about 20-30% is renal clearance. After taking ¹⁴C-labeled risatriptan approximately 80% of the radioactivity excreted in the urine and about 10% - with feces. This suggests that metabolites are primarily excreted by the kidneys.

According to the presystemic metabolism of rhizatriptan, approximately 14% of the oral dose is excreted unchanged in the urine, while 51% is excreted as a metabolite of indolylacetic acid. No more than 1% is excreted in the urine as an active metabolite of N-monodesmethyl.

If rizatriptan is taken in maximum doses, daily accumulation of the drug in blood plasma does not occur.

Characteristics in different patients

Patients with a migraine attack: A migraine attack does not affect the pharmacokinetics of risatriptan.

Gender: In men, the AUC of risatriptan (10 mg orally) was approximately 25% less than in women, C_max - 11% less, and Tmax - approximately the same. This apparent pharmacokinetic difference is not clinically significant.

Elderly patients: plasma concentrations of risatriptan are similar to those of young patients.

Patients with impaired liver function (the severity of hepatic insufficiency according to Child - Pugh - 5-6 points): it is known that after oral administration in patients with hepatic insufficiency, the concentration of risatriptan in the blood plasma was similar to the concentration in men and young women who participated in research. Significant increase in AUC (by 50%) and C_max (25%) was observed in patients with moderate hepatic insufficiency (the severity of hepatic insufficiency according to Child - Pugh - 7 points). In patients with severity of hepatic insufficiency according to Child - Pugh 7 points (severe hepatic insufficiency), the pharmacokinetics were not studied.

Patients with impaired renal function: it is known that in patients with renal failure (creatinine clearance - 10-60 ml / min / 1.73 m²) AUC of risatriptan did not differ significantly from that in healthy patients. In patients on hemodialysis (creatinine clearance 10 ml / min / 1.73 m²), The AUC of risatriptan was approximately 44% greater than in individuals with normal renal function. C_max Plasma risatriptan in patients with any degree of renal failure was the same as in healthy patients.

Indications

Emergency treatment of the headache phase with migraine attacks, with or without aura.

Application

Apply inside. do not use rhizoptan for preventive purposes.

The tablets should be swallowed whole, washed down with liquid.

The absorption time is delayed by approximately 1 hour if the drug is taken in a state of satiety.

The recommended dose is 10 mg.

Repeated intake: the next dose can be taken no earlier than 2 hours; within a 24-hour period, you can take no more than two doses.

With repeated headache within 24 hours, if after relieving the initial attack, the headache returns, you can take another dose. The above dosing rates must be observed.

In the absence of effect: the effectiveness of a repeated dose for the treatment of the same attack, when the first dose did not produce an effect, was not tested during studies of risatriptan. Thus, if after taking the first dose the patient does not have a therapeutic effect, the second dose cannot be taken to treat the same attack.

Risatriptan studies have shown that even in the absence of a therapeutic effect during one attack, there is a likelihood of a therapeutic effect in the following attacks.

Some patients should be given a low dose of Risotriptan (5 mg), especially to these groups:

• patients taking propranolol. Rizatriptan should be taken no earlier than 2 hours after taking propranolol;
• patients with mild to moderate renal failure;
• patients with mild to moderate liver failure.

Between taking two doses, the period of time should be at least 2 hours; within a 24-hour period, you can take no more than two doses.

Patients over the age of 65. The efficacy and safety of taking risatriptan in patients over the age of 65 have not been systematically studied.

Contraindications

Hypersensitivity to risatriptan or any excipient. concomitant use with MAO inhibitors or use within 2 weeks from the termination of treatment with mao inhibitors. severe hepatic or severe renal failure. history of cerebrovascular accident or transient ischemic attack. moderate or severe ag, as well as untreated light ag. established coronary artery disease, including coronary artery disease (angina pectoris, a history of myocardial infarction or fixed asymptomatic ischemia), signs and symptoms of coronary artery disease or angina pectoris. peripheral blood vessel diseases. the simultaneous use of risatriptan and ergotamine, ergot alkaloids derivatives (including methysergide) or other 5-ht1b / 1d receptor agonists.

Side effects

The most common side effects are dizziness, drowsiness, and weakness / fatigue. the frequency of adverse reactions is defined as follows: very often (10%); often (1-10%); infrequently (0.1–1%); single (0.01–0.1%); rarely (0.01%); the frequency is unknown (impossible to estimate from the available data).

From the side of the immune system: single - allergic reactions, anaphylactic shock / anaphylactoid reactions.

From the psyche: often - insomnia; infrequently - disorientation, irritability.

From the nervous system: often - dizziness, drowsiness, paresthesia, headache, hypesthesia, decreased mental activity; infrequently - ataxia, tremor, vertigo, dysgeusia / unpleasant aftertaste, fainting; frequency unknown - convulsions, serotonin syndrome.

From the side of the organ of vision: infrequently - blurred vision.

From the cardiovascular system: often - palpitations, hot flashes; infrequently - arrhythmia, tachycardia, changes in the ECG, hypertension; single - cerebrovascular accident (according to reports, most of these adverse reactions occurred in patients with risk factors for developing coronary artery disease), bradycardia; the frequency is unknown - ischemia or myocardial infarction (according to reports, most of these adverse reactions occurred in patients with risk factors for coronary artery disease), peripheral vascular ischemia.

From the respiratory system, chest and mediastinal organs: often - discomfort in the throat; infrequently - shortness of breath; single - wheezing.

From the digestive system: often - nausea, dry mouth, vomiting, diarrhea, dyspepsia; infrequently - a feeling of thirst; frequency unknown - ischemic colitis.

On the part of the skin and subcutaneous tissues: often - redness; infrequently - itching, urticaria, angioedema (for example, swelling of the face, tongue and swelling of the pharynx), rash, increased sweating; frequency unknown - toxic epidermal necrolysis.

On the part of skeletal muscles and connective tissue: often - a feeling of heaviness; infrequently - neck pain, stiffness, stiffness, muscle weakness, pain in the face, myalgia.

General disorders: often - asthenia / fatigue, pain in the abdomen or chest.

special instructions

Risoptan can not be used for prevention.

The effect of food: while taking with food, the absorption of risatriptan is delayed by about 1 hour. Therefore, the onset of the drug may be delayed if taken in a state of satiety (see PHARMACOLOGICAL PROPERTIES).

Rizoptan should be prescribed only to those patients who have an accurate diagnosis of migraine. Rizoptan should not be prescribed to patients with basilar or hemiplegic migraine.

Risoptan should not be used to treat an atypical headache, that is, one that may be associated with potentially serious diseases (for example, a stroke, burst aneurysm), in which narrowing of the cerebrovascular vessels can be dangerous.

Risatriptan may be associated with transient symptoms, including chest pain and a feeling of tightness in the chest, which can become intense and cover the throat. If such symptoms cause a suspicion of coronary heart disease, the drug should be discontinued and a proper examination carried out.

Like other 5-HT receptor agonists_{1B / 1D}Rizatriptan should not be prescribed without preliminary examination to patients who are likely to have heart disease and people at risk of developing coronary artery disease (for example, patients with hypertension, diabetes mellitus, smokers or those who are taking nicotine replacement therapy, men over 40 years old, postmenopausal women, patients with interventricular blockade, and those with a family history of serious cases of coronary artery disease).A cardiological examination may not reveal all patients with heart disease, and in very rare cases when taking 5-HT receptor agonists₁ serious heart complications were observed in patients without existing cardiovascular disease. In patients with diagnosed coronary atherosclerosis, risatriptan should not be prescribed (see CONTRAINDICATIONS).

5-HT receptor agonists_{1B / 1D} associated with coronary spasm. In some cases, when using 5-HT receptor agonists_{1B / 1D} reported the development of ischemia or myocardial infarction.

Other 5-HT receptor agonists_{1B / 1D} (e.g. sumatriptan) should not be given concurrently with risatriptan.

It is recommended that you wait at least 6 hours after taking rizatriptan before taking ergotamine-type drugs (such as ergotamine, dihydroergotamine, or metisergide). Before taking rizatriptan, you must make sure that after the last dose of drugs containing ergotamine, less than 24 hours have passed.

Following the simultaneous use of triptans and selective serotonin reuptake inhibitors or norepinephrine and serotonin reuptake inhibitors, serotonin syndrome has been reported (including altered mental status, autonomic nervous system disorder, and neuromuscular disorders). These reactions can be serious. If the simultaneous use of rizatriptan and selective serotonin reuptake inhibitors or norepinephrine and serotonin reuptake inhibitors is consistent with the clinical indications, it is recommended that the patients health status be monitored appropriately, especially at the beginning of treatment, during an increase in doses or when another serotonergic agent is added.

Side effects often occur with the simultaneous use of triptans (5-HT agonists_{1B / 1D}) and herbal preparations containing St. Johns wort (Hypericum perforatum).

In patients taking triptans, which include risatriptan, Quinckes edema (for example, swelling of the face, tongue, and larynx) may occur. If angioedema of the tongue or pharynx occurs, the patient should be monitored until the symptoms disappear. Triptan treatment should be stopped immediately and replaced with a drug belonging to another class of drugs.

The drug contains lactose, so patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose and galactose malabsorption syndrome should not take it.

When administering rizatriptan to patients using CYP 2D6 substrates, their potential interaction should be considered.

Headache caused by excessive use of the drug. Prolonged use of any headache pain medication can aggravate headache. If such a situation arises (or there is suspicion of it), it is necessary to consult a doctor and stop treatment. Headache caused by excessive use of the drug can be suspected in patients who often or daily have a headache, despite taking regular headache medications.

Use during pregnancy and lactation. Reproductive function. The effect on the human body has not been studied. Animal studies are known to show minimal effect on reproductive function at plasma concentrations that far exceeded therapeutic concentrations for humans (more than 500 times).

Use during pregnancy. The safety of rizatriptan for pregnant women has not been established. It is known that animal studies that took into account the development of the embryo / fetus or the course of pregnancy, childbirth and postpartum development did not show harmful effects at a dose exceeding the therapeutic dosage levels for humans.

Since studies of the reproductive function and intrauterine development of animals do not always predict the response of the human body, Risoptan during pregnancy should be prescribed only in case of emergency.

Use during lactation. In animal studies, risatriptan was excreted in large quantities with milk. A transient, barely noticeable decrease in body weight of the offspring that feeds on mother’s milk was observed only when the systemic effect on the mother’s body far exceeded the maximum level of exposure for humans. No data are available for people.

Therefore, lactation should be given to rizatriptan with caution. The effect on the infant should be minimized by refusing breast-feeding within 24 hours after taking the drug.

Children (under the age of 18). The effectiveness and safety of Rizoptan in children under the age of 18 have not been established.

The ability to influence the reaction rate when driving vehicles or other mechanisms. In some patients, migraine or taking Risoptan can cause drowsiness. Dizziness has also been reported in some patients taking rizatriptan. Therefore, during migraine attacks and after taking Rizoptan, patients should evaluate their ability to perform complex tasks.

Interactions

Ergotamine, ergot alkaloids derivatives (including methysergide), other 5-ht1b / 1d receptor agonists: due to the additive effect, the simultaneous use of risatriptan and ergotamine, ergot alkaloids derivatives (including metisergide) or other 5-htb1 receptor agonists (e.g. sumatriptan, zolmitriptan, naratriptan) increases the risk of vasoconstriction of the coronary artery and hypertensive effect. such a combination is contraindicated (see contraindications).

MAO Inhibitors: Risatriptan is mainly metabolized by MAO-A. The plasma concentration of risatriptan and its active N-monodesmethyl metabolite is increased by the simultaneous use of a selective inverse MAO-A inhibitor. With the use of non-selective reverse acting MAO inhibitors (e.g. linezolid), a similar or more pronounced effect is expected. Due to the risk of coronary spasm and hypertension, the administration of risatriptan to patients taking MAO inhibitors is contraindicated (see CONTRAINDICATIONS).

Β-adrenergic receptor blockers: the concentration of risatriptan in blood plasma may increase due to the simultaneous administration of propranolol. This is most likely due to the interaction of the primary metabolism of the two drugs, since MAO-A plays a role in the metabolism of both risatriptan and propranolol. This interaction leads to an average increase in AUC and C_max up to 70–80%. Patients taking propranolol are recommended to use Rizoptan in a dose of 5 mg (see APPLICATION).

Medicines nadolol and metaprolol do not change the concentration of risatriptan in the blood plasma.

Selective Serotonin Reuptake Inhibitors / Norepinephrine and Serotonin Reuptake Inhibitors and Serotonin Syndrome: Patients with symptoms similar to serotonin syndrome (including altered mental status, autonomic nervous system disorder and neuromuscular disorders) that have been reported after the use of reverse inhibitors have been reported serotonin uptake / norepinephrine, serotonin and tryptane reuptake inhibitors (see SPECIAL INSTRUCTIONS).

In vitro studies show that risatriptan inhibits cytochrome P450 2D6 (CYP 2D6). There is no clinical data on their interaction. When administering risatriptan to patients taking CYP 2D6 substrates, their potential interaction should be considered.

Overdose

Risatriptan 40 mg (which was taken in one or two doses with a 2-hour interval between doses) is usually well tolerated; frequent side effects when taking the drug were dizziness and drowsiness.

After an overdose, hypertension or other more serious cardiovascular symptoms may occur. Patients who are suspected of having an overdose of risatriptan should have a cleaned digestive tract (for example, gastric lavage followed by the use of activated charcoal). After this, clinical and ECG monitoring should be performed for at least 12 hours, even if no clinical symptoms are observed.

The effect of hemodialysis and peritoneal dialysis on the concentration of rizatriptan in plasma is unknown.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° C.

ACIN-PIM-122016-005