MIGRENOS [Zolmitriptan] 5 mg Tablets
instructions
for the medical use of a medicinal product
MIGRENOS
Tradename
Migrenos, Мигренос
International non-proprietary
name or generic name
Zolmitriptan, Золмитриптан
Tablets.
Composition
Each film-coated tablet contains:
active substance: zolmitriptan USP 5 mg;
excipients: avicel-102, di-calcium phosphate,
corn starch, primogel, talc, magnesium stearate.
Pharmacotherapeutic
group
Analgesics; Antimigraine agents;
Selective serotonin 5-HT1 receptor agonists.
Code АТХ: N02CC03
Pharmacological properties
Pharmacodynamics
Zolmitriptan is a selective agonist of 5HT3/T
receptors, stimulation of which leads to vasoconstriction. It has high affinity
for recombinant human 5HT3/T receptors and moderate affinity for 5HT1d receptors.
Zolmitriptan has no affinity and does not exhibit significant pharmacological
activity in relation to 5HT4, 5HT3, 5HT4, adrenergic, histamine, muscarinic and
dopaminergic receptors. Administration of zolmitriptan to laboratory animals
led to vasoconstriction in the carotid artery basin. In addition, animal
studies indicate that zolmitriptan blocks central and peripheral trigeminal
nerve activity by inhibiting the release of calcitonin gene-related peptide,
vasoactive intestinal peptide, and substance P. In clinical studies, the effect
of zolmitriptan on headache and other migraine symptoms (such as nausea,
photophobia, phonophobia) was observed within 1 hour and increased over the
period from 2 to 4 hours after drug administration. Zolmitriptan is equally
effective against migraine with aura, migraine without aura, and
menstrual-associated migraine. Taking zolmitriptan during aura did not prevent
migraine headaches, so the drug should be taken after the onset of a pain
attack.
Pharmacokinetics
After oral administration, zolmitriptan is rapidly and
completely absorbed (at least 64%). Absorption of zolmitriptan is not affected
by food intake. The mean absolute bioavailability is approximately 40%. The
mean volume of distribution is 7.0 L/kg. Plasma protein binding is low
(approximately 25%). The active metabolite of zolmitriptan (N-desmethyl
metabolite) is also a serotonin 5HT3/T receptor agonist, 2-6 times more potent
than zolmitriptan. When administered to healthy volunteers as a single dose in
the range of 2.5 to 50 mg, zolmitriptan and its active metabolite have
dose-dependent area under the concentration-time curve (AUC) and maximum
concentration (Cmax). Cmax is achieved within 1.5 hours (75% of Cmax - within 1
hour), the maximum concentration of the drug in plasma is maintained for the
next 4-6 hours. No accumulation of the drug was observed with multiple doses.
Within 4 hours after oral administration of the drug during a migraine attack,
the concentration of zolmitriptan and its metabolites in the blood plasma was
lower than in the case of administration of the drug between attacks. This is
probably due to a slowdown in the absorption of zolmitriptan associated with a
slowdown in gastric emptying during a migraine attack. Zolmitriptan is eliminated
primarily by hepatic biotransformation with subsequent excretion of metabolites
in the urine. Three main metabolites have been identified: indoleacetic acid
(the main metabolite detected in plasma and urine), N-oxide and N-desmethyl
derivatives. The N-desmethyl metabolite is active, and the other two
metabolites do not exhibit pharmacological activity. The concentration of the
N-desmethyl metabolite in plasma is approximately 2 times less than the
concentration of zolmitriptan. Therefore, it can be assumed that this
metabolite contributes to the therapeutic effect of zolmitriptan. More than 60%
of zolmitriptan administered as a single oral dose is excreted in the urine
(mainly as the indoleacetic metabolite) and about 30% is eliminated in the
feces, mainly as unchanged drug. The mean total plasma clearance of
zolmitriptan is 31.5 ml/min/kg, of which one-sixth is due to renal clearance.
Renal clearance is greater than the glomerular filtration rate, suggesting
tubular secretion. The mean half-lives of zolmitriptan and the N-desmethyl
metabolite are 4.7 h and 5.7 h in healthy volunteers, 7.3 h and 7.5 h in
patients with moderate hepatic impairment, and 12 h and 7.8 h in patients with
severe hepatic impairment, respectively. Renal clearance of zolmitriptan and its
metabolites is 7-8 times lower in patients with moderate and severe renal
impairment compared to healthy individuals, although AUC of zolmitriptan and
the active metabolite increases slightly (by 16% and 35%, respectively) with an
increase in the half-life by 1 hour (up to 3-3.5 hours). The values of these pharmacokinetic parameters did not go beyond
the values observed in healthy volunteers. In patients with
impaired liver function, a slowdown in zolmitriptan metabolism was observed,
proportional to the severity of liver dysfunction. In patients with severe
liver dysfunction, compared to healthy volunteers, an increase in AUC by 226%,
Cmax by 47%, and half-life by up to 12 hours was shown. At the same time, a
decrease in the concentration of zolmitriptan metabolites, including the active
metabolite, was noted. Pharmacokinetic parameters in healthy elderly subjects
are similar to those in young healthy volunteers.
Indications for use
Relief of migraine attacks with or without aura.
Contraindications
• hypersensitivity to zolmitriptan or to any of the excipients;
• uncontrolled hypertension;
• ischemic heart disease, including history of myocardial infarction;
• coronary vasospasm/Prinzmetal's angina;
• Wolff-Parkinson-White syndrome or arrhythmias associated with other
accessory pathways;
• peripheral arterial disease;
• cerebrovascular accident (including stroke or transient ischemic
attack)
in history;
• severe renal failure (CC < 15 ml/min);
• concomitant use with other serotonin 5-HT1B/1D receptor agonists
(e.g. sumatriptan, naratriptan), ergotamine or its derivatives
(including methysergide), as well as within 24 hours after their
withdrawal;
• concomitant use with MAO-A inhibitors and within 14 days after their withdrawal;
• pregnancy;
• breastfeeding period;
• elderly age (over 65 years);
• childhood and adolescence under 18 years.
Method of administration and dosage
Orally, without chewing, with a
small amount of liquid.
The recommended dose of the drug to relieve
a migraine attack is 2.5 mg. It is recommended to take the drug as soon as
possible after the onset of a headache, but the drug is also effective when
taken later after the onset of an attack. If migraine symptoms recur within 24
hours, you can take a repeat dose of 2.5 mg. The repeat dose should not be
taken earlier than 2 hours after the first dose. If no clinical effect is
observed after taking the first dose, it is unlikely that repeated
administration of the drug during the same attack will be beneficial. If the
patient has not achieved a therapeutic effect after taking a dose of 2.5 mg,
the drug can be used at a dose of 5 mg to relieve subsequent migraine attacks.
Do not take more than 2 doses of the drug per day. The total dose of zolmitriptan
taken during the day should not exceed 10 mg.
The drug Migrenos is not indicated
for the prevention of migraines.
For patients with severe liver
dysfunction, the total daily dose of zolmitriptan should not exceed 5 mg.
For patients taking cimetidine or selective
CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin, and other quinolones), the
total daily dose of zolmitriptan should not exceed 5 mg.
Special instructions and precautions
Before using the drug, consult a
doctor.
Migraine can only be used in cases
of clearly diagnosed migraine or
cluster headache. Before prescribing
the drug, as with other drugs for relieving headaches, it is necessary to
exclude other possible serious neurological diseases in patients with
previously undiagnosed migraine or cluster headache, as well as in patients
with an established diagnosis of migraine in the presence of atypical symptoms.
Migraine is not indicated for the treatment of hemiplegic, basilar and
ophthalmoplegic migraine. In patients taking serotonin 5HT1B/1D receptor
agonists, cerebrovascular accidents, including strokes, have been observed.
Patients with migraine may be at risk of developing certain cerebrovascular
accidents. Migraine should not be used in patients with Wolff-Parkinson-White
syndrome or arrhythmias associated with other accessory impulse pathways. Very
rarely, coronary vasospasm, angina and myocardial infarction have been reported
with the use of this class of drugs (serotonin 5HT1B/1D receptor agonists).
Before prescribing the drug to patients with risk factors for coronary heart
disease (CHD) (eg, smoking, hypertension, hyperlipidemia, diabetes mellitus,
aggravated family history of CHD), it is recommended to conduct an examination
of the cardiovascular system, it is necessary to monitor blood pressure and
electrocardiogram. Particular attention should be paid to postmenopausal women
and men over 40 years of age in the presence of the above risk factors.
However, not all patients can be diagnosed with cardiovascular disease during
examination, and in very rare cases, serious cardiovascular complications can
develop in patients with no history of cardiovascular disease. As with other
serotonin 5HT1B/1D receptor agonists, sensations of heaviness, pressure, or
tightness in the precordial region have been reported with zolmitriptan. If
chest pain or symptoms suggestive of coronary artery disease occur,
zolmitriptan should be discontinued until appropriate medical evaluation has
been performed. As with other serotonin 5HT1B/1D receptor agonists, transient
increases in blood pressure have been reported in patients with or without a
history of hypertension (very rarely, these increases in blood pressure have
been clinically significant). The recommended dose of zolmitriptan should not
be exceeded. Adverse effects may be more frequent with concomitant use of
triptans and herbal preparations containing St. John's wort (Hypericum
perforatum). Serotonin syndrome has been reported with concomitant use of
triptans and SSRIs or SNRIs. Serotonin syndrome may include the following signs
and symptoms: mental status changes, autonomic and neuromuscular symptoms.
Close monitoring of patients is recommended when concomitantly prescribing
Migraine and SSRIs or SNRIs, especially during the initiation of therapy, dose
increases or addition of another drug that affects serotonin metabolism.
Excessive use of antimigraine drugs may lead to an increase in headache
frequency, potentially requiring discontinuation of treatment. If a patient
experiences frequent or daily headaches despite regular use of medications for
this condition, the possibility of developing headaches with excessive use of
medications for headache therapy should be kept in mind.
Effect on ability to drive vehicles and use machines
Caution is recommended in patients
whose activities require high speed of psychomotor reactions (e.g., driving a
vehicle or operating machinery) due to the possible development of drowsiness
and other migraine symptoms.
Side effect
From the central nervous system: sensory
disturbances, dizziness, hyperesthesia, paresthesia, drowsiness, a feeling of
"warmth" or "coldness", vertigo.
From the cardiovascular system: palpitations,
tachycardia, slight increase in blood pressure, transient increase in blood
pressure, myocardial infarction, angina pectoris, coronary angiospasm.
From the digestive system: abdominal
pain, nausea, vomiting, dry mouth, dyspepsia, dysphagia, ischemia or infarction
(for example, ischemia or infarction of the intestine, infarction of the
spleen), the symptoms of which may be diarrhea with an admixture of blood and
abdominal pain.
Musculoskeletal system: muscle
weakness, myalgia.
Urinary system: polyuria,
frequent urination, imperative urge to urinate.
Immune system: hypersensitivity
reactions, including urticaria, angioedema and anaphylactic reactions.
General disorders: asthenia,
lethargy, shortness of breath, pain or tightness in the throat, neck, chest or
limbs, increased sweating. Some of the symptoms listed may be symptoms of
migraine.
If any of the side effects listed in the instructions
worsen, or you notice any other side effects not listed in the instructions,
tell your doctor.
Interaction with other medicinal products
Due to the risk of coronary artery
spasm, the simultaneous use of zolmitriptan and ergotamine is contraindicated.
It is recommended to take zolmitriptan no earlier than 24 hours after taking
ergotamine and its derivatives, while it is recommended to take ergotamine-containing
drugs no earlier than 6 hours after taking zolmitriptan. MAO-A inhibitors
increase the systemic effect of zolmitriptan, therefore, the use of Migraenos
in patients receiving MAO-A inhibitors is contraindicated. After taking
cimetidine, an inhibitor of cytochrome P450, an increase in T1 / 2 and AUC of
zolmitriptan and its active N-desmethyl metabolite (183C91) was noted.
Therefore, for patients taking Migraenos simultaneously with cimetidine, the
maximum daily dose of Migraenos should not exceed 5 mg. Based on the overall
interaction profile of zolmitriptan, the possibility of its interaction with
inhibitors of the cytochrome P450 CYP1A2 isoenzyme cannot be excluded.
Therefore, for patients taking selective inhibitors of the CYP1A2 isoenzyme
(e.g. fluvoxamine, ciprofloxacin and other quinolones), the total dose of
zolmitriptan taken within 24 hours should not exceed 5 mg. Cases of serotonin
syndrome (including mental status changes, autonomic and neuromuscular
disorders) have been reported with concomitant use of triptans and SSRIs or
SNRIs. When zolmitriptan is taken concomitantly with St. John's wort (Hypericum
perforatum), an interaction is possible, which may increase the risk of adverse
effects. Like other serotonin 5-HT1B/1D receptor agonists, zolmitriptan may
delay the absorption of other drugs.
Symptoms: Sedation was commonly
observed in healthy volunteers following a single oral dose of 50 mg
zolmitriptan. Zolmitriptan has an elimination half-life of 2.5 to 3 hours; therefore,
in case of overdose, the patient should be observed for at least 15 hours or as
long as symptoms of overdose persist. Treatment: There is no specific
antidote for zolmitriptan. In cases of severe intoxication, intensive care
measures are recommended, including establishment and maintenance of a patent
airway, provision of adequate oxygenation and ventilation, and monitoring and
support of cardiovascular function. The effect of haemodialysis and peritoneal
dialysis on serum zolmitriptan concentrations has not been established.
Storage conditions
Store in a dry, dark place at a
temperature below 30°C.
Keep out of reach of children.
Shelf life
2 years. Do not use after the
expiration date stated on the package.
Vacation conditions
Dispensed by prescription.
Release form
3 tablets in an aluminum foil blister. 1 blister together with instructions for use in a cardboard box.