2010/06/16

Zomig

Composition, structure and packing

Film-coated tablets are yellow, round, biconvex, labeled "Z" on one side. 1 tab. zolmitriptan 2.5 mg. Excipients: lactose anhydrous, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, polyethylene glycol, dye.

Clinico-pharmacological group: agonist 5-HT1-receptor.

The drug with protivomigrenoznoy activity.

Pharmacological action

Selective agonist 5NT1 receptor protivomigrenozny drug. It has a high affinity towards 5NT1B/1D-retseptoram and moderate affinity for 5HT1A-receptors. Zolmitriptan showed no significant pharmacological activity in relation to the 5HT2-, 5HT3-, 5HT4-, α1-, α2-, β1-adrenergic receptors, histamine H1-, H2-receptor-, muscarinic receptors, dopaminergic receptors type 1 and 2. Blood vessels and vessels of the dura mater are innervated by afferent fibers of the trigeminal nerve.

In animal experiments the introduction zolmitriptana is due to its properties agonist 5NT1B/1D-retseptorov vessels, vasoconstriction, associated with suppression of the release of the peptide, calcitonin gene-related, vasoactive intestinal peptide and substance P. The narrowing of blood vessels and inhibiting the release of neuropeptides, are presumed to be cause of improvement in migraine attacks, in particular, reduce the intensity of pain, not later than 1 hour after taking the drug and reduce nausea, vomiting, photophobia and fonofobii associated with migraine.

In addition to the peripheral action of zolmitriptan has effect on the nucleus of the brain stem involved in the mechanism of migraine, which explains the sustained effect of repeated use in the treatment of multiple migraine attacks in one patient. In migraine attacks there vasodilatation through activation of reflex excitation, supported orthodromic trigeminal nerve fibers and parasympathetic innervation of the cerebral vessels through the release of vasoactive intestinal peptide as a major effector neurotransmitter. Zolmitriptan blocks that reflex stimulation and release of vasoactive intestinal peptide.

Pharmacokinetics

Absorption

After oral zolmitriptan rapidly and well absorbed (at least 64%). 75% Cmax is achieved within 1 h, with concentrations in plasma stored in the next 4-6 hours Absorption zolmitriptana not depend on the meal. When receiving a single dose of zolmitriptan and its active metabolite are proportional to the dose of AUC and Cmax in the dose range from 2.5 to 50 mg. The average absolute bioavailability - approximately 40%. Repeated reception of cumulation of the drug were observed. The distribution of plasma protein binding is low (approximately 25%).

Metabolism

Metabolised in the liver with the formation of 3 major metabolites: indole-acetic acid (the major metabolite in plasma and urine), N-oxide and N-Desmet analogues. N-desmetilirovanny metabolite (183C91) is active, and two other metabolites are inactive. N-Desmet metabolite (183C91) has a 2-6 times greater activity 5HT1D-receptor agonist than zolmitriptan (according to experiments on animals). The concentration of N-Desmet metabolite (183C91) in plasma is approximately half the concentration of zolmitriptana, and, therefore, we can assume that this metabolite contributes to the therapeutic effect Zomiga.

Withdrawal

More than 60% of the drug, introduced in the form of single oral dose excreted in the urine (mainly in the form of indole-acetic acid metabolite) and about 30% is excreted in the faeces, mainly as unchanged. The average T1 / 2 zolmitriptana 4.7 h. T1 / 2 of its metabolites is approximately the same, which suggests removing as their education.

Pharmacokinetics in special clinical situations

In patients with renal failure of moderate and severe renal clearance zolmitriptana gravity and its metabolites in the 7-8 times lower compared to healthy volunteers, although the AUC zolmitriptana and active metabolite increases slightly (by 16% and 35% respectively), and T1 / 2 increased by 1 h (up to 3-3.5 h). In evaluating the pharmacokinetics zolmitriptana liver diseases of varying severity has been shown an increase in AUC by 94% and C max by 50% with moderate liver problems and, correspondingly, 226% and 47% for severe violations of liver function compared with healthy volunteers. The formation of metabolites (including active) in diseases of the liver is reduced.

For metabolite 183S91 value AUC and C max decreased by 33% and 44% in patients with moderate hepatic impairment and by 82% and 90% in patients with severe hepatic impairment. T1 / 2 zolmitriptana in patients with moderate hepatic impairment was 7.3 h in patients with severely impaired liver function - 12 hours T1 / 2 of metabolites, respectively, was 5.7 h, 7.5 h and 7.8 h was reported pharmacokinetic interaction with ergotamine.

Zolmitriptana pharmacokinetics in healthy elderly people is similar to the pharmacokinetics in healthy young people. Simultaneous injection zolmitriptana with ergotamine / caffeine is well tolerated and does not lead to an increase in the frequency of adverse reactions or changes in blood pressure compared with the introduction of only zolmitriptana. Selegiline (an inhibitor of MAO type B) and fluoxetine (selective serotonin reuptake inhibitor) did not influence the pharmacokinetic parameters zolmitriptana.

Statement
relief of migraine with aura or without aura.

Dosage regimen

The recommended dose for relief of migraine attack - 2.5 mg. If symptoms persist or recur within 24 hours may be needed to re-dose Zomiga. In this re-dose should not be taken within 2 hours after the first dose. If, after Zomiga a dose of 2.5 mg of the therapeutic effect is not reached, for relief of subsequent migraine attacks can use the drug at a dose of 5 mg. Clinically significant effect occurs within 1 h after administration Zomiga. The effectiveness of the drug did not depend on how long after the attack, was adopted by the tablet, but it is recommended to take Zomig as soon as possible since the beginning of migraine headaches. In the event of repeated migraine attacks total dose Zomiga adopted within 24 hours should not exceed 10 mg.

Patients with mild and moderate hepatic impairment dose adjustment is required in cases of severe violations of liver function recommended maximum dose taken during 24 h, 5 mg. Patients with impaired renal function does not require correction dosing regimen Zomiga.

Side effect

In describing the side effects we used the following criteria for frequency of occurrence: often - ≥ 1% but <10% rarely - ≥ 0.01%, but <0.1%, very rarely - <0.01%.
From the side of the central nervous system and peripheral nervous system: frequent - Sensory symptoms, asthenia, dizziness, feeling of heaviness and stiffness in the limbs, tightness in the throat, neck and chest area (not accompanied by ischemic ECG changes), paresthesia, drowsiness, feeling of warmth; rarely - a headache.
On the part of the digestive system: frequent - nausea, dry mouth, very rare - abdominal pain, hemorrhagic diarrhea, ischemic colitis, infarction of the spleen, bowel ischemia or infarction.
On the part of the musculoskeletal system: often - myalgia, muscular weakness.
Since the cardiovascular system: rarely - tachycardia, palpitations, very rarely - angina, coronary spasm, myocardial infarction, transient hypertension (very rarely associated with significant symptoms).
From the urinary system: very rarely - polyuria, frequent urination.

Allergic reactions: seldom - anaphylactic reaction, angioedema, urticaria. Zomig is usually well tolerated. Adverse reactions are expressed mild or moderate, were transient and resolved spontaneously without treatment. Possible adverse reactions usually occur within 4 h after taking the drug and did not become more frequent with the reception of repeated doses.

Contraindications
uncontrolled arterial hypertension;
CHD
angiospastic angina (Prinzmetal angina);
ischemic attacks or transient ischemic attack in history;
joint application with ergotamine or its derivatives or other agonists 5NT1B/1D-serotoninovyh receptors;
WPW syndrome or arrhythmias associated with other additional ways of impulse conduction - increased sensitivity to the drug's components.

With care prescribers in elderly patients (safety and efficacy of Zomiga in patients older than 65 years have not been studied).

Pregnancy and lactation

Clinical trials of the drug during pregnancy has not been. Application Zomiga during pregnancy is possible only in cases where the intended benefits to the mother exceeds potential risk to the fetus.

In experimental studies on laboratory animals teratogenic action zolmitriptana not revealed. Precautions should decide on the possibility of appointing Zomiga during lactation (breastfeeding). In experimental studies found that zolmitriptan is excreted in the milk of lactating animals. Data on the allocation zolmitriptana with breast milk in humans there.

Application for violations of liver function

Patients with mild and moderate hepatic impairment dose adjustment is required in cases of severe violations of liver function recommended maximum dose taken during 24 h, 5 mg.

Application for violations of renal function

Patients with impaired renal function does not require correction dosing regimen Zomiga.

Cautions

Zomig is not intended for prevention of migraine. Zomig has a pronounced effect in migraine with aura and without aura and migraine associated with menstruation. The effectiveness of the drug did not affect the sex and age of the patient, duration of attack, the presence of nausea before taking the drug and the use of conventional drugs for the prevention of migraine. The drug should only be used for diagnosis.

Before using the product should exclude other potentially serious neurological conditions. There is currently no data on the use Zomiga with hemiplegic or basilar migraine. Patients with migraine may be at increased risk of cerebrovascular events.

Patients receiving agonists 5NT1B/1D-serotoninovyh receptors were observed hemorrhagic stroke, subarachnoid stroke, ischemic stroke and other ischemic attacks. Very rarely in the application of this class of drugs (agonists 5NT1B/1D-serotoninovyh receptors) have been reported spasms of the coronary vessels, angina or the development of myocardial infarction.

Patients with high risk of developing heart disease before the drug is recommended to conduct a survey of the cardiovascular system. In very rare cases, serious cardiovascular complications may develop in patients who had no indications of cardio-vascular system in history.

In applying Zomiga (and other serotonin agonists 5NT1B/1D-retseptorov) reported abnormal sensations in the heart. If you have chest pain or symptoms of coronary heart disease should stop taking zolmitriptana until their medical examination. Zomig can cause slight transient increase in BP (and other serotonin agonists 5NT1B/1D-retseptorov) regardless of the presence of arterial hypertension in history, very rarely is the increase in BP was clinically manifested.

In applying Zomiga (and other serotonin agonists 5NT1B/1D-retseptorov) rarely observed anaphylactic / anaphylactoid reactions. Excessive use of protivomigrenoznyh drugs may increase the incidence of headache, which potentially require discontinuation of treatment.

Use in Pediatrics

Safety and effectiveness Zomiga in children and adolescents under the age of 18 is not installed.

Effects on ability to drive vehicles and management mechanisms

There were no significant deterioration in the performance of psychomotor tests while taking Zomiga a dose of 20 mg. It is unlikely that the use of the drug will lead to a deterioration in the patient's ability to engage in potentially dangerous activities, but the patient should be warned of the possibility of drowsiness.

Overdose

Symptoms: When single dose Zomiga a dose of 50 mg is usually marked sedative effect.

Treatment: control of the state of patients should continue for at least 15 h (T1 / 2 zolmitriptana - 2.5-3 h), or stored until the symptoms of overdose. No specific antidote. When expressed intoxication recommended actions intensive therapy, including mechanical ventilation, as well as monitoring and maintaining the function of the cardiovascular system. It is unknown what effect on the concentration in serum zolmitriptana have hemodialysis and peritoneal dialysis.

Drug Interactions

There is no evidence that collateral taking medication for migraine prophylaxis (beta-blockers, dihydroergotamine, pizotifen) has had any effect on the efficacy or unwanted effects Zomiga.

Pharmacokinetic parameters and tolerability Zomiga not changed in the combined use of paracetamol, metoclopramide and ergotamine. During studies in healthy volunteers showed no clinically significant interaction between Zomigom and ergotamine, but increases the risk of coronary vasospasm is theoretically possible.

In this connection, we recommend that the interval (minimum 24 h) between the lifting ergotaminosoderzhaschih drugs and appointment Zomiga. After the abolition Zomiga should appoint ergotaminosoderzhaschie drugs no earlier than 6 pm Concurrent intake of other agonists 5NT1B/1D-serotoninovyh receptors within 12 h after administration Zomiga should be deleted. After the introduction of Moclobemide (MAO inhibitors type A) showed a slight increase (26%) AUC and a threefold increase zolmitriptana AUC of its active metabolite. Therefore, the maximum recommended dose Zomiga adopted within 24 hours, for patients receiving both MAO inhibitors type A, should not exceed 5 mg. After receiving cimetidine (an inhibitor of cytochrome P450 enzymes) showed an increase in T1 / 2 zolmitriptana by 44% and increased AUC by 48%. T1 / 2 and AUC of active N-demethylated metabolite is doubled, and therefore for the patients taking cimetidine, the recommended maximum dose of the drug Zomig, adopted within 24 h, is 5 mg.

Based on the general profile of interaction zolmitriptana, we can not exclude the possibility of its interaction with inhibitors of isoenzyme CYP1A2. Consequently, the joint application of drugs of this type (fluvoxamine and antibiotics hinolonovogo series) is recommended to reduce the total dose Zomiga adopted within 24 hours, up to 5 mg.

After the introduction of rifampicin was reported clinically significant changes in pharmacokinetics zolmitriptana or its active metabolite. In a joint application is possible interaction with drugs hypericum (Hypericum perforatum), which may increase the risk of adverse effects (as in the application of other agonists 5NT1B/1D-serotoninovyh receptors).

Terms and Conditions of storage

List B. The drug should be stored out of reach of small children at a temperature below 30 ° C. Do not apply after the expiry date stated on the packaging or blister. Shelf life - 2 years.