MIGRENOS [Zolmitriptan] 2 mg/dose Nasal spray
instructions for the medical use of the medicinal
product
MIGRENOS
Tradename: Migrenos, Мигренос
International non-proprietary name
or generic name: zolmitriptan, золмитриптан
Dosage form: dosed
nasal spray.
Composition per dose/spray:
active
substance: zolmitriptan 2,5 mg,
excipients: citric acid monohydrate, disodium
hydrogen phosphate, benzalkonium chloride, distilled water.
Pharmacotherapeutic
group: Analgesics; antimigraine
drugs; selective serotonin 5-HT1 receptor agonists.
ATX
code: N02CC03
Pharmacological properties
Pharmacodynamics
Zolmitriptan
is a selective agonist of 5-HT1B/1D receptors, the stimulation of which leads
to vasoconstriction. It has high affinity for recombinant human 5-HT1B/1D
receptors and moderate affinity for 5HT1A receptors. Zolmitriptan has no
affinity and does not exhibit significant pharmacological activity towards
5HT2, 5HT3, 5HT4, adrenergic, histamine, muscarinic and dopaminergic receptors.
Administration
of zolmitriptan to laboratory animals led to vasoconstriction in the carotid
artery. In addition, results from studies in laboratory animals 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 after 1 hour
and increased from 2 to 4 hours after taking the drug.
Zolmitriptan
is equally effective against migraine with aura, migraine without aura, and
migraine associated with menstruation. Taking zolmitriptan during an aura did
not prevent migraine headache pain, so the drug should be taken after the onset
of a pain attack.
Pharmacokinetics
When administered
intranasally, zolmitriptan is rapidly absorbed, with blood concentrations
reaching the limit of quantitation within 5 minutes. Part of the zolmitriptan
dose is rapidly absorbed directly through the nasopharyngeal mucosa. Individual
pharmacokinetic profiles are characterized by one or two peaks in plasma
concentrations in the range of 0.5-5 hours after intranasal administration. The
median Tmax is about 2 hours. 15 minutes after intranasal administration in
healthy volunteers, the concentration of zolmitriptan on average reached 40% of
Cmax.
For the active metabolite
N-desmethylzolmitriptan (183C91), the median Tmax was slightly higher (about 3
hours after the 2.5 mg dose and about 5 hours after the 5 mg dose). Therapeutic
concentrations of zolmitriptan and its active metabolite 183C91 are maintained
until 6 hours after administration (6 hours after administration, the
concentration is 40% of the Cmax for zolmitriptan and 60% of the Cmax for
183C91). According to the comparative AUC assessment, the average relative
bioavailability of intranasally administered zolmitriptan 2.5 mg is 102%
compared with oral administration of zolmitriptan 2.5 mg tablet. With repeated
use, cumulation of the drug is not observed.
The pharmacokinetic parameters
of zolmitriptan and its active metabolite after use in the form of a nasal
spray and in tablet form are comparable.
Zolmitriptan is eliminated
primarily through hepatic biotransformation followed by excretion of
metabolites in the urine. More than 60% of zolmitriptan administered as a
single oral dose is excreted in the urine (primarily as an indoleacetic
metabolite) and about 30% is excreted through the intestines, predominantly
unchanged.
The average total plasma
clearance of zolmitriptan is 25.9 ml/min/kg, 1/6 of which is renal clearance.
Renal clearance is greater than the glomerular filtration rate, suggesting
tubular secretion.
The average T1/2 of
zolmitriptan and N-desmethylated metabolite is about 3 hours.
Indications for use
• relief of migraine attacks with and without aura;
• relief of acute cluster headaches in adults.
Contraindications
•
hypersensitivity to zolmitriptan or to any of the excipients;
•
uncontrolled arterial hypertension;
• old age
(over 65 years);
• IHD,
incl. history of myocardial infarction;
•
coronary vasospasm/Prinzmetal's angina;
•
Wolff-Parkinson-White syndrome or arrhythmias associated with other additional
impulse pathways;
•
peripheral arterial diseases;
• a
history of cerebrovascular accident (including stroke or transient ischemic
attack);
• severe
renal failure (creatinine clearance < 15 ml/min);
•
simultaneous use with other agonists of serotonin 5-HT1B/1D receptors (for
example, sumatriptan, naratriptan), ergotamine or its derivatives (including
methysergide), as well as within 24 hours after their withdrawal;
•
simultaneous use with MAO-A inhibitors and within 14 days after their
discontinuation;
•
pregnancy;
•
breastfeeding period;
•
children and adolescents under 18 years of age.
Method of
administration and dosage
Migranos is not indicated for
the prevention of migraine or cluster headaches.
It is used intranasally. It is
possible to use the drug both on an empty stomach and after meals.
Migraine
The recommended dose for the
treatment of a migraine attack is 2.5 mg or 5 mg. For those patients who do not
respond satisfactorily to 2.5 mg, a dose of 5 mg may be effective for
subsequent attacks. It is advisable that Migranos be taken as early as possible
after the onset of a migraine headache, but the drug is also effective if taken
at a later stage.
Injections of the drug (one or
more doses) can be performed in any nostril.
Cluster headache
The recommended dose for
treating an attack of cluster headache is 5 mg or 10 mg. For those patients who
do not respond satisfactorily to 5 mg, a dose of 10 mg may be effective for
subsequent attacks. The total daily dose should not exceed 10 mg, therefore, no
more than 4 doses of 2.5 mg zolmitriptan or 2 doses of 5 mg zolmitriptan should
be taken in any 24-hour period.
Patients with an attack of
cluster headache may experience nasal congestion on the side where the pain is
located. In such cases, it is recommended to inject the drug into the nasal
passage located on the opposite side (contralateral).
Special patient groups
The metabolism of zolmitriptan
is reduced in patients with impaired liver function. For patients with moderate or severe hepatic impairment,
the maximum daily dose should not exceed 5 mg of zolmitriptan. However, no dose
adjustment is required in patients with
mild hepatic impairment.
In patients with
CC above 15 ml/min, no dose adjustment is required. The drug is
contraindicated in patients with severe
renal failure.
For patients taking MAO-A inhibitors, the maximum daily dose
is 5 mg.
For patients taking cimetidine, the maximum daily dose is 5
mg.
For patients taking CYP1A2 inhibitor drugs such as
fluvoxamine and quinolones (eg, ciprofloxacin), the maximum daily dose is 5 mg.
You should not take a double
dose to make up for a missed dose.
Method of administration
Before using Migranos, you
should clear your nostrils (blow your nose gently). Before using the drug for
the first time, press the spray dispenser several times, directing the spray
into the air until a uniform cloud of spray is formed. If more than 4 weeks
have passed since the last use of the drug, the first spray should be made into
the air to prevent the use of an incomplete dose. Between uses, the bottle with
the drug should be stored with the cap tightly closed.
When using, the bottle should
be held with the sprayer facing up.
Tilt your head slightly
forward, insert the spray into the nostril, slightly tilting the tip of the
spray away from the center of the nose, and make 1 press.
If necessary, repeat the same
with the other nostril.
Side effect
Adverse reactions when using
zolmitriptan, as a rule, occur within 4 hours after taking the drug, are
transient in nature and resolve spontaneously without treatment. The frequency
of adverse reactions does not increase with repeated doses.
From the immune system: hypersensitivity
reactions, incl. urticaria, angioedema and anaphylactic reactions.
From the nervous system: dysgeusia,
sensory disturbances, dizziness, headache, hyperesthesia, paresthesia,
drowsiness, sensation of heat or cold, vertigo.
From the cardiovascular system: palpitations,
tachycardia, myocardial infarction, angina pectoris, coronary vasospasm, slight
increase in blood pressure, transient increases in blood pressure.
From the respiratory system, chest and mediastinal
organs: nosebleeds, discomfort in the nasal passages, non-infectious rhinitis
(rhinorrhea).
From the digestive system: abdominal
pain, nausea, vomiting, dry mouth, dyspepsia, dysphagia, ischemia or infarction
(for example, intestinal ischemia or infarction, splenic infarction), symptoms
of which may include bloody diarrhea or abdominal pain.
From the musculoskeletal system: muscle
weakness, myalgia.
From the urinary system: polyuria,
frequent urination, imperative urge to urinate.
Other: asthenia, inertia,
shortness of breath, pain, tension or tightness in the throat, neck, chest or
limbs, increased sweating.
If any of the side effects indicated in the
instructions get worse, 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, concomitant
use of zolmitriptan and ergotamine is contraindicated. It is recommended to
take zolmitriptan no earlier than 24 hours after taking ergotamine and its
derivatives; in turn, it is recommended to take ergotamine-containing drugs no
earlier than 6 hours after taking zolmitriptan.
MAO-A inhibitors increase the systemic exposure of
zolmitriptan, therefore the administration of Migrenos to patients receiving
MAO-A inhibitors is contraindicated.
After taking cimetidine, a cytochrome P450 inhibitor,
there was an increase in T1/2 and AUC of zolmitriptan and its active
N-desmethylated metabolite (183C91). Therefore, for patients taking Migrenos
simultaneously with cimetidine, the maximum daily dose of Migrenos should be no
more than 5 mg.
Based on the general interaction profile of
zolmitriptan, the possibility of its interaction with inhibitors of the
cytochrome P450 isoenzyme CYP1A2 cannot be excluded. Therefore, for patients
taking selective inhibitors of the CYP1A2 isoenzyme (for example, fluvoxamine,
ciprofloxacin and other quinolones), the total dose of zolmitriptan taken
within 24 hours should not exceed 5 mg.
Cases of serotonin syndrome (including changes in
mental status, autonomic and neuromuscular disorders) have been described with
the simultaneous use of triptans and SSRIs or SSRIs.
When taking zolmitriptan concomitantly with St. John's
wort (Hypericum perforatum) preparations, an interaction is possible, which may
increase the risk of side effects.
Like other serotonin 5-HT1B/1D receptor agonists,
zolmitriptan may delay the absorption of other drugs.
Special instructions and precautions
The drug
Migranos can only be used in cases of clearly diagnosed migraine or cluster
headache. Before prescribing the drug, as well as other drugs for the relief of
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. Migranos is not indicated for the treatment of hemiplegic,
basilar or ophthalmoplegic migraine. Cerebrovascular accidents, including
strokes, have been reported in patients taking serotonin 5HT1B/1D receptor
agonists. Patients with migraine may be at risk of developing certain
cerebrovascular disorders.
Zolmitriptan
should not be used in patients with Wolff-Parkinson-White syndrome or
arrhythmias associated with other accessory pathways.
Very
rarely, when using this class of drugs (serotonin 5HT1B/1D receptor agonists),
coronary vasospasm, angina pectoris and myocardial infarction were observed.
Before
prescribing zolmitriptan to patients with risk factors for coronary heart
disease (CHD) (for example, smoking, hypertension, hyperlipidemia, diabetes
mellitus, family history of CAD), it is recommended to conduct a cardiovascular
examination, monitor blood pressure and electrocardiogram. Particular attention
should be paid to postmenopausal women and men over 40 years of age if these
risk factors are present. However, not all patients will be diagnosed with
cardiovascular disease, and in very rare cases, serious cardiovascular
complications may develop in patients without a history of cardiovascular
disease.
As with
other serotonin 5HT1B/1D receptor agonists, sensations of heaviness, pressure,
or tightness in the cardiac region have been reported with zolmitriptan. If
chest pain or symptoms of coronary artery disease occur, you should stop taking
zolmitriptan until appropriate medical evaluation is performed.
As with
other serotonin 5HT1B/1D receptor agonists, transient increases in blood
pressure were observed in patients regardless of a history of hypertension
(very rarely such increases in blood pressure were clinically significant). Do
not exceed recommended doses of zolmitriptan.
Side
effects may be more frequent when taking triptans and herbal preparations
containing St. John's wort (Hypericum perforatum) at the same time.
The
development of serotonin syndrome has been observed with the combined use of
triptans and SSRIs or SSRIs. Serotonin syndrome may include the following signs
and symptoms: mental status changes, autonomic symptoms, and neuromuscular
symptoms. Careful monitoring of patients is recommended when concomitantly
prescribed Zolmitriptan-SZ and an SSRI or SSRI, especially when starting
therapy, increasing the dose, or adding another drug that affects serotonin
metabolism to therapy (see section “Interaction with other drugs”).
Excessive
use of antimigraine drugs may lead to an increase in the frequency of
headaches, potentially requiring discontinuation of treatment. If a patient
experiences frequent or daily headache despite regular use of medications to
treat the condition, the patient should be aware of the possibility of
developing headaches from overuse of headache medications.
Influence on the ability to drive
vehicles and machinery
Patients whose activities
require a high speed of psychomotor reactions (for example, driving a vehicle
or operating machinery) are advised to exercise caution due to the possible
development of drowsiness and other migraine symptoms.
Overdose
Symptoms: nausea,
dry mouth, dizziness, drowsiness, feeling of warmth, asthenia, feeling of heaviness
and tightness in the throat, neck, limbs and chest, transient increase in blood
pressure, myalgia, muscle weakness, paresthesia.
Treatment: there
is no specific antidote. In case of severe intoxication, intensive care
measures are recommended, including restoration and maintenance of airway
patency, ensuring adequate oxygenation and ventilation of the lungs, as well as
monitoring and supporting the function of the cardiovascular system.
Release form
A dark glass bottle with a nasal spray dispenser
and a safety cap made of polymer materials. 15 doses of 2.5 mg per vial. One bottle along with instructions for use in a
cardboard box.
Storage conditions
Store in a dry place at a temperature not exceeding
25°C.
Keep out of the reach of children!
Shelf life
3 years. Do not use after the expiration date stated
on the packaging.
Vacation conditions
By prescription.