Active ingredients: Zolmitriptan
Zomig 2.5 mg / dose and 5 mg / dose nasal spray, solution
Zomig package inserts are available for pack sizes:- Zomig 2.5 mg and 5 mg film-coated tablets
- Zomig 2.5 mg / dose and 5 mg / dose nasal spray, solution
- Zomig Rapimelt 2.5 mg and 5 mg orodispersible tablets
Indications Why is Zomig used? What is it for?
Zomig Nasal Spray contains zolmitriptan and belongs to a group of medicines called triptans.
Zomig Nasal Spray is used for the treatment of migraine headache and cluster headache.
- Headache symptoms can be caused by dilation of the blood vessels in the head. Zomig Nasal Spray is believed to reduce the dilation of these blood vessels. This helps to take away the headache and other common symptoms of an attack, such as: - Feeling sick (nausea or vomiting) and sensitivity to light and sound during a migraine attack. - Tearing and redness of the eye. (conjunctival hyperemia) and occlusion or runny nose on the same side as pain during the cluster headache attack.
- Zomig Nasal Spray only works when the headache attack has started. It does not prevent the onset of the attack.
Contraindications When Zomig should not be used
Do not use Zomig Nasal Spray:
- if you are allergic (hypersensitive) to zolmitriptan or any of the other ingredients of this medicine (see section 6: Further information)
- if you have high blood pressure
- if you have ever had heart problems, including heart attacks, angina (chest pain caused by exercise or exertion), Prinzmetal's angina (chest pain that appears at rest) or if you have experienced heart-related symptoms such as breathlessness or chest pressure
- if you have had a stroke or short-term stroke-like symptoms (transient ischemic attack or TIA)
- if you have severe kidney problems
- if you are taking other migraine medicines (eg ergotamine or ergot-type medicines such as dihydroergotamine and methysergide) or other triptans for migraine at the same time. See section: "Taking Zomig Nasal Spray with other medicines" for more information. If in doubt, consult your doctor or pharmacist.
Precautions for use What you need to know before taking Zomig
Before using Zomig Nasal Spray, tell your doctor if:
- you are at risk for ischemic heart disease (poor blood flow in the arteries of the heart). The risk is higher if you smoke, have high blood pressure, have high cholesterol levels, have diabetes, or if someone in your family has ischemic heart disease
- if you have been told that you have Wolff-Parkinson-White syndrome (a type of heartbeat abnormality)
- if you have ever had liver problems
- if you have headaches other than your usual migraine or cluster headache
- if you are taking a medicine to treat depression (see "Using Zomig Nasal Spray with other medicines" later in this section)
If you are hospitalized, please tell the medical staff that you are using Zomig Nasal Spray.
Zomig Nasal Spray is not recommended for children under the age of 12 or adults over the age of 65.
As with other migraine treatments, using too much Zomig Nasal Spray can cause daily headaches or may make migraine headaches worse. Talk to your doctor if you think this is the case. You may need to stop using Zomig. nasal spray to correct the problem.
Interactions Which drugs or foods can change the effect of Zomig
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including herbal medicines and medicines obtained without a prescription.
In particular, tell your doctor if you are taking any of the following medicines:
Medicines for migraine or cluster headache:
- If you take triptans other than Zomig Nasal Spray, allow 24 hours to elapse before using Zomig Nasal Spray.
- After taking Zomig Nasal Spray allow 24 hours to elapse before using other triptans other than Zomig Nasal Spray.
- If you take medicines containing ergotamine or medicines of the ergot type (such as dihydroergotamine or methysergide), allow 24 hours to pass before using Zomig Nasal Spray.
- After using Zomig Nasal Spray, allow 6 hours to elapse before taking ergotamine or ergot-type medicines.
Medicines for depression:
- moclobemide or fluvoxamine
- medicines called SSRIs (selective serotonin reuptake inhibitors)
- medicines called SNRIs (serotonin and norepinephrine reuptake inhibitors) such as venlafaxine, duloxetine.
Other Medicines:
- cimetidine (for digestive difficulties or stomach ulcer)
- a quinolone antibiotic (e.g. ciprofloxacin)
If you are taking herbal preparations containing St. John's wort (Hypericum perforatum), there is a greater chance of the side effects of Zomig Nasal Spray.
Using Zomig Nasal Spray with food and drink
You can use Zomig Nasal Spray with or without food. Food does not affect the action of Zomig Nasal Spray.
Warnings It is important to know that:
Pregnancy and breastfeeding
It is not known whether the use of Zomig Nasal Spray during pregnancy is harmful. Before using Zomig Nasal Spray, tell your doctor if you are pregnant or trying to get pregnant.
Do not breastfeed for 24 hours after using Zomig Nasal Spray.
Driving and using machines
During a headache attack, your reactions may be slower than usual. This should be borne in mind when driving or using tools or machines.
Zomig Nasal Spray is unlikely to affect your ability to drive or use tools or machines. However, it is best to wait to see what the effect of Zomig Nasal Spray is before undertaking these activities.
Dose, Method and Time of Administration How to use Zomig: Posology
Zomig Nasal Spray is available in a ready-to-use "spray unit". Each unit contains 2.5 mg or 5 mg of zolmitriptan. Each unit is for single use and delivers only one dose.
Always use Zomig Nasal Spray exactly as your doctor has told you. If in doubt, you should consult your doctor or pharmacist. Your doctor will decide on the right dose for you, depending on your disease.
Migraine headache
Adults and adolescents (over 12 years of age)
The usual dose is one spray (2.5 mg or 5 mg) into one nostril. It does not matter which nostril is used and you can use Zomig as soon as your migraine headache starts or once the attack is in progress. You can use another dose if the migraine is still present after two hours or if it comes back within 24 hours.
However, do not use more than two doses of the spray in a day. If you have been prescribed the 2.5 mg spray, the maximum daily dose is 5 mg. If you have been prescribed the 5 mg spray, the maximum daily dose is 10 mg.
Cluster headache
Adults
The usual dose is 5 mg or 10 mg in one nostril. You may have a blocked nostril on the same side as the headache. In these cases, use the unobstructed nostril contralateral to the side of the headache. Take Zomig as soon as the cluster headache attack begins. The maximum daily dose is 10 mg.
Therefore, do not take more than one 10 mg dose of Zomig Nasal Spray or two 5 mg doses of Zomig Nasal Spray in any 24 hour period.
If the nasal spray has not helped your migraine enough, tell your doctor. Your doctor may increase your dose or change your treatment.
How to use Zomig nasal spray
Read the instructions before using Zomig Nasal Spray.
Do not push the plunger before inserting the dispenser into the nostril or you will lose the dose.
- Blow your nose gently before use.
Remove the protective cap.
- Hold the nasal spray gently with your fingers and thumb. Do not push the plunger in yet!
- Close one nostril by pressing with a finger on the side of the nose, as shown in figure 3 (if you already have a blocked nostril as a symptom of your disease this may not be necessary).
Insert the nasal spray dispenser into the opposite non-occluded nostril without forcing.
Tilt your head back slightly and close your mouth.
Breathe in gently with your nose and at the same time press the plunger firmly with your thumb. The plunger may feel hard and a click can be heard.
Keep your head tilted back slightly. Pull the dispenser out of your nose.
Breathe quietly through your mouth for 5-10 seconds. It is possible that you feel liquid in your nose. This does not mean that the dose is being missed or that the spray has not worked. It is a normal sensation that disappears quickly.
Overdose What to do if you have taken too much Zomig
If you have used more Zomig Nasal Spray than prescribed by your doctor, contact your doctor immediately or go to the nearest hospital. Take the Zomig Nasal Spray with you.
Side Effects What are the side effects of Zomig
Like all medicines, Zomig Nasal Spray can cause side effects, although not everybody gets them. Some of the symptoms below could be part of the migraine attack itself.
Very common side effects (affecting more than 1 in 10 people):
- Changes in taste.
Common side effects (affecting more than 1 in 100 people):
- Abnormal sensation such as tingling in the fingers and toes or skin that is sensitive to the touch
- Sleepiness, dizziness or a sense of heat
- Headache
- Irregular heartbeat
- Nasal bleeding. Nasal irritation. Nosebleed and / or runny nose (rhinitis)
- Nausea. He retched
- Stomach ache
- Dry mouth
- Muscle weakness or muscle pain
- Weakness
- Heaviness, tightness, pain or a feeling of pressure in the throat, neck, arms and legs or chest
- Difficulty in swallowing.
Uncommon side effects (affecting less than 1 in 100 people):
- Very fast heartbeat
- Slightly higher blood pressure
- Increased amount of urine or the need to urinate
Rare side effects (affecting less than 1 in 1,000 people):
- Allergic / hypersensitivity reactions, including raised skin rash (hives) and swelling of the face, lips, mouth, tongue and throat. If you think Zomig Nasal Spray is causing an allergic reaction, stop using it and contact your doctor immediately.
Very rare side effects (affecting less than 1 in 10,000 people):
- Angina (chest pain, often caused by exercise), heart attacks or spasms of the blood vessels of the heart.If you notice chest pain or breathlessness after using Zomig Nasal Spray, contact your doctor and do not use any more Zomig Nasal Spray.
- Spasms of the blood vessels in the intestine, which can damage the intestines. You may notice stomach pain or bloody diarrhea. If this happens, contact your doctor and do not use any more Zomig Nasal Spray.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep out of the reach and sight of children.
- Do not use Zomig Nasal Spray after the expiry date which is stated on the carton. The expiry date refers to the last day of the month.
- Do not store above 25 ° C.
- Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Zomig Nasal Spray contains
The active ingredient is zolmitriptan. Zomig Nasal Spray contains 2.5 mg or 5 mg of zolmitriptan in each dose.
The other ingredients are: citric acid, disodium phosphate and purified water.
What Zomig Nasal Spray looks like and contents of the pack
- Zomig 2.5 mg / dose and 5 mg / dose nasal spray is a pre-assembled device.
- Zomig Nasal Spray 2.5 mg / dose is available in packs of 1, 2 or 6 disposable nasal sprays.
- Zomig Nasal Spray 5 mg / dose is available in packs of 1, 2, 6 or 18 single use nasal sprays.
- Each nasal spray unit is ready to use and delivers only one dose.
Not all pack sizes may be marketed.
Zomig may also be available as 2.5 mg and 5 mg film-coated tablets and 2.5 mg orodispersible tablets.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ZOMIG NASAL SPRAY, SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Zolmitriptan
Zomig 5 mg / dose nasal spray contains zolmitriptan 50 mg / ml, corresponding to 5 mg zolmitriptan per dose.
Zomig 2.5 mg / dose nasal spray contains 25 mg / ml zolmitriptan, corresponding to 2.5 mg zolmitriptan per dose.
The solution is buffered to pH 5.0.
The device is designed for a single single dose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Nasal spray, solution.
Clear, colorless to yellow liquid. Nasal spray device containing a single unit dose glass vial.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Zomig Nasal Spray is indicated for the acute treatment of migraine headache with or without aura and cluster headache.
04.2 Posology and method of administration
Treatment of migraine
Adults
The recommended dose of Zomig Nasal Spray to treat a migraine attack is 2.5 mg or 5 mg. If the patient has not achieved a satisfactory response with the 2.5 mg dose, doses of 5 mg may be considered for subsequent attacks.
It is recommended to take Zomig Nasal Spray as soon as possible after the onset of migraine headaches, however it is also effective when taken at a later stage.
Adolescents (over 12 years of age)
The recommended dose of Zomig Nasal Spray to treat a migraine attack is 2.5 mg or 5 mg. If the patient has not achieved a satisfactory response with the 2.5 mg dose, doses of 5 mg may be considered for subsequent attacks. In adolescents the 2.5 mg dose has not been studied (see section 5.1).
It is recommended to take Zomig Nasal Spray as soon as possible after the onset of migraine headaches, however it is also effective when taken at a later stage.
Zomig Nasal Spray is administered as a single dose directly into one nostril.
If migraine symptoms reappear within 24 hours of the initial response, a second dose may be taken. If a second dose is required, this should not be taken earlier than 2 hours after the initial dose. If the patient does not respond to the first dose. a second dose is unlikely to be of benefit during the same attack.
The total daily dose should not exceed 10 mg, therefore zolmitriptan should not be taken in more than 2 doses of 5 mg in any 24 hour period.
For adult patients Zomig Nasal Spray is an alternative to the oral tablet formulation of Zomig and may be of particular benefit in patients suffering from nausea and vomiting during a migraine headache attack.
However, it should be noted that equal doses of Zomig tablets and Zomig nasal spray may not have identical efficacy (see section 5.1).
Treatment of cluster headache
Patients with cluster headaches may experience a nostril occlusion on the same side as the pain. In these cases it is recommended that Zomig Nasal Spray be administered in the nostril contralateral to the pain side.
The recommended dose of Zomig Nasal Spray to treat a cluster headache attack is 5 mg or 10 mg.
If the patient has not achieved a satisfactory response with the 5 mg dose, 10 mg doses may be effective for subsequent attacks.
It is recommended that you take Zomig Nasal Spray as soon as possible from the onset of cluster headaches.
The total daily dose should not exceed 10 mg, therefore zolmitriptan should not be taken in more than 1 dose of 10 mg or two doses of 5 mg in any 24 hour period.
Zomig Nasal Spray is not indicated for the prophylaxis of migraine or cluster headache.
Use in children (under 12 years of age)
The safety and efficacy of Zomig Nasal Spray in pediatric patients have not been evaluated. Therefore, the use of Zomig Nasal Spray in children is not recommended.
Use in patients over 65 years of age
The safety and efficacy of Zomig Nasal Spray in patients over the age of 65 have not been established. Therefore, the use of Zomig Nasal Spray in the elderly is not recommended.
Patients with hepatic insufficiency
The metabolism of zolmitriptan is reduced in patients with hepatic impairment (see section 5.2). For patients with moderate or severe hepatic impairment, a maximum dose of 5 mg in 24 hours is recommended. However, no dose adjustment is required for patients with mild hepatic impairment.
Patients with renal insufficiency
No dosage adjustment is required in patients with creatinine clearance greater than 15 ml / min. (see section 4.3 and section 5.2).
Recommended dosage in interactions (see section 4.5)
A maximum dose of 5 mg in 24 hours is recommended in patients taking MAO-A inhibitors.
A maximum dose of 5 mg zolmitriptan in 24 hours is recommended in patients taking cimetidine.
In patients taking specific inhibitors of CYP 1A2, such as fluvoxamine and quinolones (e.g. ciprofloxacin), a maximum dose of 5 mg of zolmitriptan in 24 hours is recommended.
04.3 Contraindications
Hypersensitivity to zolmitriptan or to any of the excipients.
Moderate and severe hypertension or mild uncontrolled hypertension.
This class of compounds (5HT1B / 1D receptor agonists) has been associated with coronary vasospasm, consequently, patients with ischemic heart disease were excluded from clinical trials. Therefore, Zomig Nasal Spray should not be given to patients who have had myocardial infarction or who have ischemic heart disease, coronary vasospasm (Prinzmetal's angina), peripheral vascular disease or to patients who have symptoms or signs indicative of ischemic heart disease. .
Concomitant administration of zolmitriptan with ergotamine, or ergotamine derivatives (including methysergide) and with other 5HT1B / 1D receptor agonists is contraindicated (see section 4.5).
Zolmitriptan should not be given to patients with a history of cerebrovascular accident (ACV) or transient ischemic attack (TIA).
Zolmitriptan is contraindicated in patients with creatinine clearance below 15 ml / min.
04.4 Special warnings and appropriate precautions for use
Zomig Nasal Spray should only be given when a clear diagnosis of migraine or cluster headache has been made. As with other acute headache therapies, caution should be exercised to rule out other potentially serious neurological conditions before treating patients previously undiagnosed as migraine or cluster headache sufferers and in patients presenting with atypical symptoms. Zolmitriptan is not indicated for use in hemiplegic, basilar or ophthalmoplegic migraine. Strokes and other cerebrovascular events have been reported in patients treated with 5HT1B / 1D receptor agonists. It should be noted that in these patients there is a greater risk of cerebrovascular events.
Zolmitriptan should not be given to patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias affecting other accessory pathways of cardiac conduction.
In very rare cases, as with other 5HT1B / 1D receptor agonists, coronary vasospasm, angina pectoris and myocardial infarction have been reported. Prior to initiating treatment with zolmitriptan, a prior cardiovascular evaluation should be performed in patients with risk factors for ischemic heart disease (such as smoking, hypertension, hyperlipidaemia, diabetes mellitus, family history) (see section 4.3). Particular attention should be paid to postmenopausal women and men over 40 years of age with these risk factors.
However, through such assessments, it is not always possible to identify all patients with heart disease, and in very rare cases, patients without any underlying cardiovascular disease have developed serious cardiac events.
As with other 5HT1B / 1D receptor agonists, heaviness, tightness or precordial tension have been described following administration of zolmitriptan (see section 4.8).
If chest pain or other symptoms suggestive of ischemic heart disease appear, no further doses of zolmitriptan should be taken until appropriate medical evaluation has been made.
As with other 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 associated with significant clinical events.
The recommended dose of zolmitriptan should not be exceeded.
Undesirable effects may be more common during concomitant use of triptans and herbal preparations containing St. John's wort (Hypericum perforatum).
Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) has been reported following concomitant treatment with triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). These reactions can be severe. If concomitant treatment with zolmitriptan and an SSRI or SNRI is clinically justified, it is suggested that the patient be kept under adequate observation, particularly at the start of treatment, in case of dose increases or the addition of another serotonergic drug (see paragraph 4.5).
Prolonged use of any pain reliever for headache treatment can worsen the situation. If this situation occurs or is suspected, the doctor should be consulted and treatment discontinued. The diagnosis of drug abuse headache should be suspected in patients who have frequent or daily headache despite (or due to) regular use of headache medication.
04.5 Interactions with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Data from healthy subjects suggest that there are no significant clinical interactions between zolmitriptan and ergotamine. However, the increased risk of coronary vasospasm is a theoretical possibility and concomitant administration is contraindicated. It is recommended to wait at least 24 hours after the use of ergotamine-containing preparations before administering zolmitriptan. Conversely, it is advised to wait at least six hours after administration of zolmitriptan before administering an ergotamine-containing product (see section 4.3).
Pharmacokinetic interactions (effects of zolmitriptan on the pharmacokinetic parameters of other medicinal products)
Following administration of moclobemide, a specific MAO-A inhibitor, there was a slight increase (26%) in the AUC of zolmitriptan and a 3-fold increase in the AUC of the active metabolite. Therefore, in patients treated with a MAO-A inhibitor, a maximum intake of 5 mg of zolmitriptan in 24 hours is recommended. Medicinal products should not be taken at the same time if doses of moclobemide higher than 150 mg are used. bid.
After administration of cimetidine, a general inhibitor of cytochrome P450, the half-life and AUC of zolmitriptan were increased by 44% and 48%, respectively. Furthermore, the half-life and AUC of its active N-desmethyl metabolite (183C91) are doubled.
Therefore, in patients taking cimetidine, a 24-hour dose of zolmitriptan not exceeding 5 mg is recommended.
Treatment with specific inhibitors of CYP 1A2 may increase plasma levels of zolmitriptan and decrease concentrations of the active metabolite. The clinical significance of this effect is unknown. Therefore, with substances of this type, such as fluvoxamine and quinolones (eg ciprofloxacin), it is recommended to reduce the dosage.
Selegiline (a MAO-B inhibitor) and fluoxetine (an SSRI) did not cause any pharmacokinetic interactions with zolmitriptan. However, there have been reports of patients with symptoms consistent with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin reuptake inhibitors and norepinephrine (SNRI) and triptans (see section 4.4).
As with other 5HT1B / 1D agonists, zolmitriptan may delay the absorption of other medicinal products.
Concomitant administration of other 5HT1B / 1D agonists within 24 hours following treatment with zolmitriptan should be avoided. Similarly, administration of zolmitriptan within 24 hours of using other 5HT1B / 1D agonists should be avoided.
Pharmacokinetic interactions (effects of other medicinal products on the pharmacokinetic parameters of zolmitriptan)
Interaction studies have been conducted with caffeine, ergotamine, dihydroergotamine, paracetamol, metoclopramide, pizotifen, fluoxetine, rifampicin and propranolol without clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolites being observed.
The absorption and pharmacokinetic parameters of Zomig Nasal Spray are not affected by the previous administration of xylometazoline, a sympathomimetic vasoconstrictor.
The interaction studies discussed in the previous sections were conducted in adults, however there is no indication of a different interaction profile in adolescents.
04.6 Pregnancy and lactation
Pregnancy
The safety of this drug for use in pregnancy has not been established in women. Evaluation of experimental studies in animals does not indicate direct teratogenic effects. However, some results from embryotoxicity studies suggest impairment of embryonic viability. Administration of zolmitriptan should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.
Feeding time
Studies in lactating animals have shown that zolmitriptan passes into milk.There are no data on the passage of zolmitriptan into human breast milk. Therefore, caution should be exercised when intending to administer zolmitriptan to breastfeeding women. Infant exposure should be minimized by avoiding breastfeeding for 24 hours after treatment.
04.7 Effects on ability to drive and use machines
In a small group of healthy individuals, no significant reduction in psychomotor performance, assessed by testing, was found with doses up to 20 mg of zolmitriptan. Caution is advised in patients who are required to drive or operate machinery as somnolence and other symptoms may occur during a migraine attack.
04.8 Undesirable effects
Possible side effects are generally transient, tend to occur within four hours of administration, repeated administration does not increase the frequency and resolve spontaneously without further treatment.
The following definitions refer to the incidence of undesirable effects:
Very common (≥1 / 10); common (≥1 / 100,
Within each frequency group undesirable effects are presented in descending order of severity.
The following side effects have been reported following administration of zolmitriptan:
The incidence of local adverse events was dose related.
Some symptoms may be part of the migraine attack itself.
The frequency, type and severity of side effects are similar in both adults and adolescents.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Administration of 50 mg zolmitriptan, as a single oral dose, to volunteers frequently resulted in sedation.
The elimination half-life of zolmitriptan is between 2.5 and 3 hours (see section 5.2) and therefore, in the event of overdose with Zomig Nasal Spray, patient monitoring should be performed for at least 15 hours or as long as signs or symptoms persist. .
There is no specific antidote for zolmitriptan. In case of severe intoxication, intensive care procedures are recommended with the establishment and maintenance of a patent airway, support of adequate oxygenation and ventilation, monitoring and support of cardiovascular function.
The effect of hemodialysis and peritoneal dialysis on the serum concentration of zolmitriptan is unknown.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective serotonin (5HT1) agonists.
ATC code: N02CC03.
Zolmitriptan has been shown to be a selective agonist of 5HT1B / 1D receptors that mediate vascular contraction. Zolmitriptan has a high affinity for human recombinant receptors, 5HT1B and 5HT1D, and a modest affinity for 5HT1A receptors. Zolmitriptan has no significant affinity or pharmacological activity against other 5HT receptor subtypes (5HT2, 5HT3, 5HT4) or against adrenergic, histamine, muscarinic or dopaminergic receptors.
In animal models, administration of zolmitriptan causes vasoconstriction in the carotid arterial circulation. Furthermore, experimental studies conducted in animals suggest that zolmitriptan inhibits the activity of the trigeminal nerve both centrally and peripherally, with inhibition of the release of neuropeptides, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP ) and Substance P.
In clinical trials the proportion of patients with side effects increased with increasing dose (see section 4.8).
Acute treatment of migraine headache
In a clinical study evaluating more than 1300 migraine patients and where Zomig Nasal Spray was used to treat up to 3 migraine headache attacks, the 2.5 mg dose reduced the intensity 2 hours after administration. severe / moderate to mild / absent headache in 59% of attacks, leading to pain relief in 26% of attacks. With the 5 mg dose the corresponding results were 70% and 36%, respectively, while with placebo the results were 31% and 8%, respectively. A statistically significant initial effect was observed following administration of both doses after 15 minutes (in 8% and 11% of attacks treated with Zomig Nasal Spray, respectively. 2.5 mg and 5 mg, compared to 5% found with placebo). Due to the different pharmacokinetic profiles between the oral and nasal formulations, efficacy in patients treated with 2.5 mg nasal spray may not be sufficient for t late detection compared to the efficacy of the 2.5 mg tablet formulation.
Zomig, in conventional tablet formulation, is equally effective in migraine with or without aura and in migraine associated with the menstrual cycle. Zolmitriptan conventional tablets, when taken during the aura, have not been shown to prevent migraine headache and therefore Zomig Nasal Spray should be taken during the headache phase of migraine.
Adolescents with migraine headache
A multicentre, double-blind, randomized, placebo-controlled, 2-way crossover study was conducted to evaluate the efficacy of zolmitriptan nasal spray 5 mg in the treatment of acute migraine attacks. The study included a placebo treatment in single blind for two attacks in 171 assessed adolescents aged 12-17 years. The results of the primary endpoints for one-hour response (defined as an improvement in migraine intensity from severe-moderate to mild- absent, and two-hour response, were 58.1% vs. 43.3% (p = 0.013) and 51.4% vs. 33.1% (p = 0.003), respectively, for zolmitriptan vs. placebo, respectively. In addition, 27.7% and 39.2% of zolmitriptan-treated patients were pain-free after one and two hours, respectively, compared with 10.2% and 18.9% of placebo-treated patients (p
Acute treatment of cluster headache
Two controlled clinical trials of comparable design had a combined total of 121 patients, each treated with up to 3 cluster headache attacks. From a combined analysis of these two studies, the reduction in headache from very severe / severe / moderate to mild / none was statistically significant in 48.3% of patients treated with Zomig 5 mg Nasal Spray 30 minutes after dosing versus 29.5% of patients treated with placebo. Complete pain relief occurred in 34.8% of treated patients versus 19.3% of placebo patients. Corresponding results for the 10 mg dose were 63.1% headache response and 44.0% complete pain relief .
05.2 Pharmacokinetic properties
Following intranasal administration, a fraction of the dose appears to be absorbed directly into the nasopharynx. The individual pharmacokinetic profile of zolmitriptan, after nasal spray administration, typically shows two peaks at 0.5 and 5 hours after administration. The mean Tmax is approximately 2 hours. Following administration of zolmitriptan nasal spray to healthy volunteers, an average of 40% of Cmax is reached 15 minutes after administration.
Zolmitriptan is metabolised by CYP1A2 to the active metabolite, N-demethylzolmitriptan (183C91). The active metabolite is further metabolised via MAO-A. The mean Tmax of 183C91 is slightly later (approximately 3 hours with the 2.5 mg dose and approximately 5 hours with the 5 mg dose). Plasma concentrations of zolmitriptan and 183C91 are maintained for up to 6 hours, with a 6-hour mean concentration of approximately 40% of C for zolmitriptan and 60% of C for 183C91. The elimination of zolmitriptan and the active metabolite 183C91 appear similar after oral and intranasal administration; the mean elimination half-life (t½) is approximately 3 hours for both zolmitriptan and 183C91. The comparison between the AUC found after administration of 2.5 mg intranasally (22.4 ng. Hr / ml) and the AUC found after administration of 2.5 mg orally (22.0 ng. Hr / ml) demonstrates that the bioavailability of intranasal zolmitriptan is 102% of that found with oral administration.
In humans, after oral administration, zolmitriptan is rapidly and well absorbed (at least 64%). The mean absolute bioavailability of the parent compound is approximately 40%. There is an active metabolite, N-demethylated, also with 5HT1B / 1D agonist activity, which was 2 to 6 times more potent than zolmitriptan in animal models.
Absorption of zolmitriptan is unaffected by the presence of food. There were no signs of accumulation after repeated oral administration of zolmitriptan.
The plasma concentration of zolmitriptan and its metabolites is lower in the first 4 hours after oral administration of the drug during migraine than in the migraine-free periods, indicating a delay in absorption in accordance with the reduction in rate. gastric emptying observed during the migraine attack.
Zolmitriptan is eliminated predominantly by hepatic metabolism followed by renal excretion of metabolites. There are three major metabolites: indole acetic acid (the major metabolite in plasma and urine) and N-oxidized and N-demethylated analogues. The N-desmethyl metabolite is pharmacologically active, while the other two are devoid of activity. Plasma concentrations of the N-desmethyl metabolite are approximately half those of the parent product, and therefore it can be expected to contribute to the therapeutic effect. More than 60% of a single oral dose is excreted in the urine, mainly in the form of the indole acetic acid metabolite and approximately 30% is excreted in the faeces, mainly as unchanged product.
The plasma concentrations and pharmacokinetic parameters of zolmitriptan and the three major metabolites found with the nasal spray and conventional tablet formulations are similar.
Following intravenous administration, the mean total plasma clearance is approximately 10 ml / min / kg, of which one quarter is renal clearance. Renal clearance is higher than glomerular filtration rate, suggesting the presence of renal tubular secretion. The volume of distribution after intravenous administration is 2.4 l / kg. The binding of zolmitriptan and the N-desmethyl metabolite to plasma proteins is approximately 25%. The mean elimination half-life of zolmitriptan is 2.5 to 3 hours. The half-life of its metabolites is similar, suggesting that their elimination is a process limited by the rate of formation.
The renal clearance of zolmitriptan and all its metabolites is reduced (7-8 times compared to healthy volunteers) in patients with moderate or severe renal impairment, although the AUCs of the parent compound and its active metabolite are only moderately higher. (respectively, 16% and 35%), with an increase of one "hour, or up to 3 and 3.5 hours, in the half-life. These values are within the range of those seen in healthy volunteers.
A study conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zolmitriptan showed that AUC and Cmax were increased by 94% and 50% respectively in patients with moderate hepatic impairment and by 226% and 47% respectively in patients with severe hepatic impairment compared to healthy volunteers. Exposure to metabolites, including the active metabolite, was decreased. For the active metabolite 183C91, AUC and Cmax were reduced by 33% and 44% in patients with moderate hepatic impairment, and by 82% and 90% in patients with severe hepatic impairment, respectively.
The pharmacokinetic profile of zolmitriptan in healthy elderly subjects was similar to that seen in young healthy volunteers. Pharmacokinetic results are similar in both adolescents and adults.
The exposure of zolmitriptan is similar or slightly reduced in adolescents when compared to adults. Correspondingly, the exposure of the active metabolite is somewhat increased. The differences are likely to be of no clinical relevance.
05.3 Preclinical safety data
Preclinical effects in single and repeated dose toxicity studies were observed only at exposures significantly in excess of the maximum human exposure.
Based on the results of genetic toxicity studies in vivo and in vitro, genotoxic effects of zolmitriptan are not expected under normal conditions of clinical use.
No clinically relevant tumors were observed in carcinogenicity studies in rats and mice.
Like other 5HT1B / 1D receptor agonists, zolmitriptan binds to melanin.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Anhydrous citric acid
Disodium phosphate (dihydrate or dodecahydrate)
Purified water.
06.2 Incompatibility
Not applicable.
06.3 Period of validity
Zomig 2.5 mg / dose nasal spray, solution: 2 years.
Zomig 5 mg / dose nasal spray, solution: 30 months.
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Ph. Eur. Type I glass vials with chlorobutyl rubber stoppers and spray device.
Zomig 5 mg / dose nasal spray, solution: The unit dose per spray device contains 0.1 ml of solution.
Packs of: 1, 2, 6 or 18 single dose nasal sprays.
Zomig 2.5 mg / dose nasal spray, solution: The unit dose per spray device contains 0.1 ml of solution.
Packs of: 1, 2 or 6 nasal sprays of one unit dose.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
AstraZeneca S.p.A.
Volta Palace
Via F. Sforza, 20080
Basiglio (MI)
08.0 MARKETING AUTHORIZATION NUMBER
Zomig 5 mg / dose nasal spray, solution:
Pack of 1 single-dose nasal spray: AIC 033345253
Pack of 2 single-dose nasal sprays: AIC 033345265
Pack of 6 single-dose nasal sprays: AIC 033345277
Pack of 18 single-dose nasal sprays: AIC 033345289
Zomig 2.5 mg / dose nasal spray, solution:
Pack of 1 single-dose nasal spray: AIC 033345226
Pack of 2 single-dose nasal sprays: AIC 033345238
Pack of 6 single-dose nasal sprays: AIC 033345240
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 12.04.2010
Date of the last renewal:
10.0 DATE OF REVISION OF THE TEXT
June 2015
