Active ingredients: Rizatriptan
MAXALT 5 mg tablets
MAXALT 10 mg tablets
Maxalt package inserts are available for pack sizes: - MAXALT 5 mg tablets, MAXALT 10 mg tablets,
- MAXALT RPD 5 mg oral lyophilisate, MAXALT RPD 10 mg oral lyophilisate
Indications Why is Maxalt used? What is it for?
MAXALT belongs to a class of medicines called selective serotonin 5-HT1B / 1D receptor agonists.
MAXALT is used to treat the headache phase of the migraine attack in adults.
Treatment with MAXALT:
reduces swelling of the blood vessels around the brain. This swelling causes the pain of the headache of the migraine attack.
Contraindications When Maxalt should not be used
Do not take MAXALT if:
- you are allergic to rizatriptan benzoate or any of the other ingredients of this medicine
- have moderately severe or severe or mild high blood pressure that is not controlled by therapy
- have or have had heart problems including heart attack or chest pain (angina) or have had signs of heart disease
- have severe liver or kidney problems
- have had a stroke (ACV cerebrovascular accident) or mini-stroke (transient ischemic attack TIA)
- have problems with blockage of the arteries (peripheral vascular disease)
- you are taking monoamine oxidase (MAO) inhibitor drugs such as moclobemide, phenelzine, tranylcypromine, or pargyline (medicines for depression), or linezolid (an antibiotic), or if it has been less than two weeks since you stopped taking MAO inhibitors
- you are taking ergotamine-like medicines, such as ergotamine or dihydroergotamine for the treatment of migraine or methysergide for the prevention of migraine attacks
- you are taking other medicines of the same class such as sumatriptan, naratriptan, or zolmitriptan for the treatment of migraine (see below: Other medicines and MAXALT).
If you are unsure whether any of the above information applies to you, contact your doctor or pharmacist.
Precautions for use What you need to know before taking Maxalt
Before taking MAXALT, tell your doctor or pharmacist if:
- have any of the following risk factors for heart disease: high blood pressure, diabetes, if you smoke or are using nicotine substitutes, if you have heart disease in your family, if you are a man over 40, or if you are a postmenopausal woman
- suffer from kidney or liver problems
- have a particular problem affecting your heartbeat (bundle branch block)
- have or have had allergies
- your headache is associated with dizziness, difficulty walking, lack of coordination or weakness in the arms or legs
- use herbal preparations based on St. John's wort
- have had allergic reactions such as swelling of the face, lips, tongue and / or throat which may cause difficulty in breathing and / or swallowing (angioedema)
- are taking selective serotonin reuptake inhibitors (SSRIs) such as sertraline, escitalopram oxalate and fluoxetine or serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine for depression
- have had short-lived symptoms including chest pain and chest tightness.
Taking MAXALT too often can cause chronic headaches. In this case, contact your doctor as you may need to stop taking MAXALT.
Tell your doctor or pharmacist about your symptoms. Your doctor will decide if you have a migraine. You should only take MAXALT for migraine attacks. MAXALT must not be used to treat headaches which may be caused by other more serious diseases.
Tell your doctor if you are taking, have recently taken or intend to take any other medicines, even those obtained without a prescription, including herbal preparations and medicines you normally take for migraine. This is important because MAXALT can modify the way some medicines work Other medicines can also affect MAXALT.
Interactions Which drugs or foods can change the effect of Maxalt
Do not take MAXALT
- If you are already taking a 5-HT1B / 1D agonist (sometimes called 'triptans') such as sumatriptan, naratriptan or zolmitriptan.
- If you are taking a monoamine oxidase (MAO) inhibitor such as moclobemide, phenelzine, tranylcypromine, linezolid or pargiline or if you have stopped taking an MAO inhibitor for less than two weeks.
- If you use ergotamine-like medicines, such as ergotamine or dihydroergotamine to treat migraines.
- If you use methysergide to prevent migraine attacks.
The above medicines may increase the risk of side effects when taken with MAXALT.
You must wait at least 6 hours after taking MAXALT before taking ergotamine-like medicines such as ergotamine or dihydroergotamine or methysergide.
You must wait at least 24 hours after taking ergotamine-like medicines before taking MAXALT.
Ask your doctor about the instructions and the risks of taking MAXALT
- If you are taking propranolol (see section How to take MAXALT).
- If you are taking SSRIs such as sertraline, escitalopram oxalate and fluoxetine or SNRIs such as venlafaxine and duloxetine for depression.
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those obtained without a prescription.
MAXALT with food and drink
MAXALT may take longer to take effect if taken after meals. Although it is best taken on an empty stomach, it can also be taken after eating.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
It is not known whether MAXALT can cause harm to the unborn baby when taken by a pregnant woman.
Breastfeeding should be avoided for 24 hours after taking the medicine.
Children and adolescents
The use of MAXALT tablets in children under 18 years of age is not recommended.
Use in patients over 65 years of age
No comprehensive studies have been conducted to verify the safety and efficacy of MAXALT in patients over 65 years of age.
Driving and using machines
You may feel sleepy or dizzy when taking MAXALT. If this happens, don't drive or use machines.
MAXALT contains lactose monohydrate
MAXALT 5 mg tablets
The 5 mg tablet contains 30.25 mg of lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
MAXALT 10 mg tablets
The 10 mg tablet contains 60.50 mg of lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Maxalt: Posology
MAXALT is used to treat migraine attacks. Take MAXALT as soon as possible after the onset of migraine headaches. Do not use it to prevent attacks.
Always take MAXALT exactly as your doctor has told you. If you are unsure, you should consult your doctor or pharmacist.
The usual dose is 10 mg.
If you are taking propranolol or have kidney or liver problems you should use the 5 mg strength of MAXALT. You must allow at least 2 hours after taking propranolol before taking MAXALT, up to a maximum of 2 doses over a 24 hour period.
MAXALT (rizatriptan benzoate) tablets should be taken by mouth and swallowed whole with liquid.
MAXALT is also available as a 5 or 10 mg oral lyophilisate that melts in the mouth. The oral lyophilisate can be used in circumstances where no liquids are available, or to avoid the nausea and vomiting that may accompany the ingestion of tablets with liquids.
If the migraine returns within 24 hours
In some patients the migraine symptoms may return within 24 hours. If the migraine returns, you can take an additional dose of MAXALT. You must wait at least 2 hours between the two doses.
If after 2 hours you still have a migraine
If you do not respond to the first dose of MAXALT during the attack, you should not take a second dose of MAXALT to treat the same attack. However, you are still likely to respond to MAXALT during the next attack.
Do not take more than two doses of MAXALT in any 24 hour period (for example, do not take more than two 10 mg or 5 mg oral lyophilisates or tablets in 24 hours). You should always wait at least 2 hours between the two doses.
If your symptoms get worse, ask your doctor for help.
Overdose What to do if you have taken too much Maxalt
If you take more MAXALT than you should
If you take more MAXALT than you should, tell your doctor or pharmacist straight away. Take the medicine box with you.
Signs of overdose include dizziness, sleepiness, vomiting, fainting and slow heart rate.
If you have any further questions on the use of this drug, ask your doctor or pharmacist.
Side Effects What are the side effects of Maxalt
Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may occur with this medicine.
In studies in adult subjects, the most commonly reported side effects were dizziness, sleepiness and tiredness.
Common (affects 1 to 10 users in 100)
- tingling (paraesthesia), headache, decreased sensitivity of the skin (hypoesthesia), decreased mental acuity, insomnia.
- fast or irregular heartbeat (palpitations).
- flushing (short-lived redness of the face).
- discomfort in the throat.
- feeling sick (nausea), dry mouth, vomiting, diarrhea, indigestion (dyspepsia).
- feeling of heaviness in some parts of the body, pain in the neck, stiffness.
- pain in the abdomen or chest.
Uncommon (affects 1 to 10 users in 1,000)
- bad taste in the mouth.
- loss of coordination of movements when walking (ataxia), dizziness (vertigo), blurred vision, tremor, fainting (syncope).
- confusion, nervousness.
- high blood pressure (hypertension), thirst, hot flashes, sweating.
- rash; itching and redness with hives (hives), swelling of the face, lips, tongue and / or throat which may cause difficulty in breathing and / or swallowing (angioedema), difficulty in breathing (dyspnoea).
- feeling of tightness in some parts of the body, muscle weakness.
- changes in the rhythm or rate of the heartbeat (arrhythmia); abnormal electrocardiogram (a test that records the electrical activity of the heart), very fast heartbeat (tachycardia).
- face pain, muscle pain.
Rare (affects 1 to 10 users in 10,000)
- wheezing.
- allergic reaction (hypersensitivity); sudden life-threatening allergic reaction (anaphylaxis).
- stroke (this usually occurs in patients with risk factors for heart and blood vessel disease (high blood pressure, diabetes, smoking habit, use of nicotine substitutes, family history of heart disease or stroke, men over 40 years, postmenopausal women, particular heart beat problems (branch block)).
- slow heart rate (bradycardia).
Not known (frequency cannot be estimated from the available data):
- heart attack, spasm of the blood vessels of the heart (this usually occurs in patients with risk factors for heart and blood vessel disease (high blood pressure, diabetes, smoking habit, use of nicotine substitutes, family history of heart disease) heart or stroke, men over 40, postmenopausal women, particular heartbeat problems (branch block)).
- a syndrome called 'serotonin syndrome' which can cause side effects such as coma, unstable blood pressure, extremely high body temperature, lack of muscle coordination, agitation and hallucinations.
- severe peeling of the skin with or without fever (toxic epidermal necrolysis).
- convulsions / seizures.
- spasm of blood vessels in the extremities including cold sensations and decreased tactile sensitivity of the hands or feet.
- spasm of the blood vessels of the colon (large intestine), which can cause abdominal pain.
Tell your doctor immediately if you have symptoms of allergic reactions, serotonin syndrome, heart attack or stroke.
Also tell your doctor if you experience symptoms suggesting an allergic reaction (such as redness of the skin or itching) after taking MAXALT.
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: https://www.aifa.gov.it/content/segnalazioni-reazioni-avversei. By reporting side effects you can help provide more information about safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton / blister after "EXP". The expiry date refers to the last day of that month.
Do not store MAXALT above 30 ° C.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What MAXALT contains
MAXALT 5 mg tablets
The active substance of MAXALT is rizatriptan. One tablet contains 5 mg of rizatriptan as 7.265 mg of rizatriptan benzoate.
MAXALT 10 mg tablets
The active substance of MAXALT is rizatriptan. One tablet contains 10 mg of rizatriptan as 14.53 mg of rizatriptan benzoate.
The other ingredients of MAXALT are lactose monohydrate, microcrystalline cellulose (E460a), pregelatinised starch, red iron oxide (E172) and magnesium stearate (E572).
What MAXALT looks like and contents of the pack
MAXALT 5 mg tablets
The 5 mg tablets are pale pink, capsule shaped, debossed with MSD on one side and 266 on the other.
MAXALT 10 mg tablets
The 10 mg tablets are pale pink, capsule shaped, debossed with MAXALT on one side and MSD 267 on the other.
Pack sizes: packs with 3, 6 or 12 tablets
Not all pack sizes may be marketed.
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
MAXALT TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
MAXALT 5 mg
Each tablet contains 7.265 mg of rizatriptan benzoate (corresponding to 5 mg of rizatriptan).
Excipients: lactose monohydrate 30.25 mg in the 5 mg tablet.
MAXALT 10 mg
Each tablet contains 14.53 mg of rizatriptan benzoate (corresponding to 10 mg of rizatriptan).
Excipients: lactose monohydrate and 60.5 mg in the 10 mg tablet.
For a full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet
MAXALT 5 mg
The 5 mg tablets are pale pink, capsule shaped, debossed with MSD on one side and 266 on the other.
MAXALT 10 mg
The 10 mg tablets are pale pink, capsule shaped, debossed with MAXALT on one side and MSD 267 on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Acute treatment of the headache phase of migraine attacks with or without aura in adults.
04.2 Posology and method of administration
General
MAXALT must not be used for prophylaxis.
The oral tablets should be swallowed whole with liquids.
Effect of food: The absorption of rizatriptan is delayed by approximately 1 hour when administered with food. The onset of effect may therefore be delayed when rizatriptan is administered in the fed state (see also Pharmacokinetic properties, Absorption).
MAXALT is also available as a formulation in oral lyophilisates.
Adults aged 18 and over
The recommended dose is 10 mg.
Further doses: the doses must be administered at least 2 hours apart; no more than 2 doses should be taken in 24 hours.
- If the headache returns within 24 hours: If the headache recurs after resolution of the initial attack, an additional dose may be taken. Observe the above dosage limits.
- In case of no effect: the efficacy of a second dose for treating the same attack when an initial dose is ineffective has not been examined in controlled studies. Therefore, if a patient does not respond to the first dose, a second dose should not be taken for the same attack. .
Clinical studies have shown that if a patient does not respond to treatment for one attack, they are still likely to respond to treatment for subsequent attacks.
Some patients should receive the lower dose (5 mg) of MAXALT especially the following patient groups:
• patients being treated with propranolol. Rizatriptan should be administered at least 2 hours after the administration of propranolol. (See section 4.5.)
• patients with mild or moderate renal insufficiency
• patients with mild to moderate hepatic insufficiency.
The doses must be separated by intervals of at least 2 hours; no more than 2 doses can be taken within 24 hours.
Pediatric patients
Children and Adolescents (under 18 years of age)
The safety and efficacy of MAXALT in children and adolescents under the age of 18 have not yet been established.
Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.
Patients over 65 years of age
The safety and efficacy of rizatriptan in patients over 65 years of age have not been systematically evaluated.
04.3 Contraindications
Hypersensitivity to rizatriptan or to any of the excipients.
Co-administration of monoamine oxidase (MAO) inhibitors or use within 2 weeks of discontinuing MAO inhibitor therapy. (See section 4.5.)
MAXALT is contraindicated in patients with severe hepatic or renal insufficiency.
MAXALT is contraindicated in patients with a history of cerebrovascular accident (ACV) or transient ischemic attack (TIA).
Moderately severe or severe hypertension, or mild untreated hypertension.
Established coronary artery disease, including ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), signs and symptoms of ischemic heart disease, or Prinzmetal's angina.
Peripheral vascular disease.
Simultaneous use of rizatriptan and ergotamine, ergot derivatives (including methysergide) or other 5-HT1B / 1D receptor agonists. (See section 4.5.)
04.4 Special warnings and appropriate precautions for use
MAXALT should only be given to patients in whom a clear diagnosis of migraine has been made. MAXALT must not be given to patients with hemiplegic or basilar migraine.
MAXALT should not be used to treat 'atypical' headaches, for example those which may be associated with potentially serious medical conditions (such as ACV, ruptured aneurysm) in which cerebrovascular vasoconstriction can be dangerous.
Rizatriptan may be associated with transient symptoms including chest pain and tightness which may be intense and affect the throat (see section 4.8). If these symptoms are thought to indicate ischemic heart disease, they should not be taken
further doses and appropriate clinical evaluation should be made.
As with other 5-HT1B / 1D receptor agonists, rizatriptan should not be administered, without prior evaluation, to patients in whom undiagnosed heart disease is likely or to patients at risk for coronary heart disease (CAD) [eg, patients with hypertension, diabetes mellitus, smokers or those using nicotine replacement therapy, men over 40 years of age, postmenopausal women, patients with branch block and those with a significant family history of CAD]. Cardiac assessments may not identify all patients with heart disease and, in very rare cases, serious cardiac events have occurred in patients without underlying heart disease following administration of 5-HT1 agonists. Patients with established CAD should not be treated with MAXALT. (See section 4.3.)
5-HT1B / 1D receptor agonists have been associated with coronary vasospasm. In rare cases, myocardial ischaemia or infarction has been reported with the use of 5-HT1B / 1D receptor agonists, including MAXALT (see section 4.8).
Other 5-HT1B / 1D agonists (e.g., sumatriptan) should not be used concomitantly with MAXALT. (See section 4.5.)
It is desirable to wait at least 6 hours after using rizatriptan before administering ergotamine-like drugs (eg, ergotamine, dihydroergotamine or methysergide). At least 24 hours should elapse after administration of an ergotamine-containing preparation before rizatriptan is administered. no additional vasospastic effects were observed in a clinical pharmacology study in 16 healthy male subjects treated with oral rizatriptan and parenteral ergotamine, these are theoretically possible (See section 4.3.)
Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormality) has been reported following concomitant treatment with triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). These reactions can be severe. If concomitant treatment with rizatriptan and an SSRI or SNRI is clinically warranted, it is advised that the patient be kept under appropriate observation, particularly during the initial phase of treatment, in case of dose escalation, or in case of another serotonergic drug added to therapy. (See section 4.5.)
Undesirable effects may occur more frequently with concomitant use of triptans (5-HT1B / 1D agonists) and herbal preparations containing St. John's wort (Hypericum perforatum).
Angioedema (e.g. face edema, tongue swelling and pharyngeal edema) may occur in patients treated with triptans, including rizatriptan. In case of angioedema of the tongue or pharynx the patient should be placed under medical observation until the symptoms are resolved. Treatment should be stopped immediately and replaced with a drug of a different class.
The amount of lactose monohydrate in each tablet is as follows: 30.25 mg in the 5 mg tablets and 60.50 mg in the 10 mg tablets. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicine.
When rizatriptan is administered to patients receiving CYP 2D6 substrates, the potential for interaction should be considered (see section 4.5).
Medication overuse headache
Prolonged use of any pain reliever for headache can make it worse. If this occurs or is suspected, medical advice should be obtained and treatment discontinued. The diagnosis of medication overuse headache should be suspected in patients with headaches frequent or daily despite (or because of) regular use of headache medications.
04.5 Interactions with other medicinal products and other forms of interaction
Ergotamine, ergot derivatives (including methysergide), other 5-HT1B / 1D receptor agonists : due to an additive effect, concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide), or other 5-HT1B / 1D receptor agonists (eg, sumatriptan, zolmitriptan, naratriptan) increases the risk of coronary arterial vasoconstriction and hypertensive effects. This association is contraindicated (See section 4.3.).
Monoamine oxidase inhibitors: rizatriptan is mainly metabolised via monoamine oxidase type A (MAO-A). Plasma concentrations of rizatriptan and its active N-monodesmethyl metabolite were increased by concomitant administration of a selective and reversible MAO-A inhibitor. Similar or greater effects are expected with non-selective, reversible (e.g. linezolid) and irreversible MAO inhibitors. Due to the risk of coronary arterial vasoconstriction and hypertensive episodes, administration of MAXALT to patients taking MAO inhibitors is contraindicated. (See section 4.3.)
Beta blockers: plasma concentrations of rizatriptan may be increased by concomitant administration of propranolol. This increase is mostly due to the first pass metabolism interaction between the two drugs, as MAO-A plays a role in the metabolism of both rizatriptan and propranolol. This interaction leads to an average increase in AUC and Cmax. 70-80%. In patients receiving propranolol, the 5 mg dose of MAXALT should be used. (See section 4.2.)
In a drug interaction study, nadolol and metoprolol did not alter the plasma concentrations of rizatriptan.
Selective Serotonin Reuptake Inhibitors (SSRIs) / Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and Serotonin Syndrome: There have been reports of patients with symptoms consistent with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) after the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRI) and triptans (see section 4.4).
Education in vitro indicate that rizatriptan in vitro inhibits cytochrome P450 2D6 (CYP 2D6). No clinical interaction data are available. When rizatriptan is administered to patients taking CYP 2D6 substrates, the potential interaction should be considered.
04.6 Pregnancy and lactation
Fertility
Effects on human fertility have not been investigated. Animal studies have shown only minimal effects on fertility at plasma concentrations far in excess of the therapeutic concentration in humans (more than 500 times).
Use in pregnancy
The safety of use of rizatriptan during human pregnancy has not been established. Animal studies at higher than therapeutic dose levels do not indicate harmful effects on the development of the embryo or fetus, or on the course of gestation, of the fetus. childbirth and postnatal development.
Since reproductive and developmental studies in animals are not always predictive of response in humans, MAXALT should only be used during pregnancy when clearly needed.
Use while breastfeeding
Studies in rats indicated that there was a very high passage of rizatriptan into milk. Transient and very little reductions in pre-weaning pup body weights were observed only when maternal systemic exposure far exceeded the maximum human exposure levels. There are no data in man.
Therefore, caution should be exercised when administering rizatriptan to breastfeeding women. Infant exposure should be minimized by avoiding breastfeeding for 24 hours following treatment.
04.7 Effects on ability to drive and use machines
Migraine or treatment with MAXALT may cause somnolence in some patients. Dizziness has also been reported in some patients receiving MAXALT. Patients should therefore evaluate their ability to perform complex activities during migraine attacks and after administration of MAXALT. .
04.8 Undesirable effects
MAXALT (both tablet and oral lyophilisate) has been evaluated in 8,630 adult patients for up to one year in controlled clinical trials. The most common side effects evaluated in clinical trials were dizziness, somnolence and asthenia / fatigue. The following undesirable effects have been evaluated in clinical trials and / or reported in post-marketing experience:
[Very common (≥ 1/10); Common (≥1 / 100,
Disorders of the immune system :
Rare: hypersensitivity reaction, anaphylaxis / anaphylactoid reaction.
Psychiatric disorders :
Uncommon: disorientation, insomnia, nervousness.
Nervous system disorders :
common: dizziness, somnolence, paraesthesia, headache, hypoesthesia, decreased mental acuity, tremor.
Uncommon: ataxia, dizziness, dysgeusia / altered taste.
Rare: syncope.
Not known: seizures, serotonin syndrome.
Eye disorders :
Uncommon: blurred vision.
Cardiac pathologies :
common: palpitations, tachycardia.
Uncommon: arrhythmia, ECG abnormalities.
Rare: cerebrovascular accident (most of these adverse reactions have been reported in patients with risk factors predicting coronary heart disease), bradycardia.
Not known: myocardial ischaemia or infarction (most of these adverse reactions have been reported in patients with predictive risk factors for coronary heart disease).
Vascular pathologies :
common: hot flashes.
Uncommon: hypertension.
Not known: peripheral vascular ischemia.
Respiratory, thoracic and mediastinal disorders :
common: pharyngeal disorders, dyspnoea.
Rare: wheezing.
Gastrointestinal disorders :
common: nausea, dry mouth, vomiting, diarrhea.
Uncommon: thirst, dyspepsia.
Not known: ischemic colitis.
Skin and subcutaneous tissue disorders :
common: redness, sweating.
Uncommon: pruritus, urticaria, angioedema (eg face edema, tongue swelling, pharyngeal edema) (for angioedema, see also section 4.4), rash.
Not known: toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders :
common: local heaviness
Uncommon: neck pain, local stiffness, stiffness, muscle weakness, facial pain, myalgia.
General disorders and administration site conditions :
common: asthenia / fatigue, abdominal or chest pain.
04.9 Overdose
Rizatriptan 40 mg (given either as a single dose or as two doses with a 2 hour interval) was generally well tolerated in more than 300 adult patients; dizziness and somnolence were the most common drug-related side effects.
In a clinical pharmacology study, where 12 adult subjects received rizatriptan at total cumulative doses of 80 mg (administered over 4 hours), two subjects reported syncope and / or bradycardia. One subject, a 29-year-old female, developed vomiting, bradycardia and dizziness 3 hours after receiving a total of 80 mg of rizatriptan (administered over 2 hours). Third degree AV block, responsive to atropine, was observed 1 hour after the onset of other symptoms.The second subject, a 25-year-old man, experienced transient dizziness, syncope, incontinence, and a 5-second systolic pause (recorded by ECG) immediately following painful venipuncture. Venipuncture was performed 2 hours after the subject received a total of 80 mg of rizatriptan (administered over 4 hours).
In addition, based on the pharmacology of rizatriptan, hypertension or other more serious cardiovascular symptoms may occur after an overdose. If an overdose of MAXALT is suspected, gastrointestinal detoxification (e.g. gastric lavage followed by activated charcoal) should be considered. Clinical and electrocardiographic monitoring should last at least 12 hours, even in the absence of clinical symptoms.
The effects of hemodialysis or peritoneal dialysis on serum concentrations of rizatriptan are unknown.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Mechanism of action: selective serotonin agonists (5-HT1B / 1D).
Pharmacotherapeutic group: anti-migraine preparations, selective serotonin agonists (5-HT1 ), ATC code: N02C C04
Rizatriptan selectively binds with high affinity to human 5-HT1B and 5-HT1D receptors and has little or no effect or pharmacological activity at the level of 5-HT2, 5-HT3 receptors, at the level of a1, a2- or b-adrenergic receptors , D1, D2, dopaminergic, H1histamines, muscarinics or benzodiazepines.
The therapeutic activity of rizatriptan in the treatment of migraine headache can be attributed to its agonist effect at the 5-HT1B and 5-HT1D receptors of extracerebral intracranial blood vessels that are thought to dilate during an attack and on the sensory nerves of the trigeminal that cause them. The activation of these 5-HT1B and 5-HT1D receptors can cause the constriction of the intracranial blood vessels that generate pain and the inhibition of neuropeptide release which leads to reduced inflammation of the sensory tissues and a reduced central transmission of the trigeminal pain signal .
Pharmacodynamic effects
Adults
The efficacy of MAXALT tablets in the acute treatment of migraine attacks was demonstrated in four multicentre, placebo-controlled studies, which included more than 2,000 patients who received MAXALT at doses of 5 or 10 mg for up to one year. headache relief occurred as early as 30 minutes after dose and response rates (e.g., reduction of moderate or severe to mild or no headache pain) 2 hours after treatment was 67-77% with 10 mg tablets , 60-63% with the 5 mg tablets and 23-40% with placebo. Although patients who did not respond to initial treatment with MAXALT did not receive further doses for the same attack, it was still likely that they would respond to treatment for a longer time. subsequent attack MAXALT reduced functional disability and attenuated the nausea, photophobia, phonophobia associated with migraine attacks.
MAXALT confirms its efficacy in the treatment of menstrual migraine, that is, migraine that occurs within three days before or after the start of the menstrual cycle.
Teenagers (12-17 years of age)
The efficacy of oral lyophilisates MAXALT in pediatric patients (12-17 years of age) was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel group study (n = 570). patient population was anamnestically unresponsive to NSAID and acetaminophen therapy. Patients with qualifying migraine-type headache were initially treated with placebo or rizatriptan within 30 minutes after onset. After 15 minutes of placebo run-in, subjects who failed to respond to placebo then treated a single migraine attack with placebo or rizatriptan. Using a weight-based dosing strategy, patients weighing 20 kg to
In this enriched study population, a difference of 9% was observed between active treatment and placebo for the primary efficacy endpoint of pain freedom (reduction from moderate or severe pain to no pain) 2 hours after treatment ( 31% with rizatriptan versus 22% with placebo (p = 0.025)). No significant difference was found for the secondary endpoint of pain relief (reduction from moderate or severe pain to mild or no pain).
Children (6-11 years of age)
The efficacy of oral lyophilisates MAXALT was also evaluated in pediatric patients 6 to 11 years of age in the same placebo-controlled acute clinical study (n = 200). The percentage of patients who achieved pain freedom 2 hours after treatment was not statistically significantly different in patients who received oral MAXALT 5 and 10 mg lyophilisates compared to those who received placebo (39.8% vs 30.4%, p = 0.269).
The European Medicines Agency has waived the obligation to submit the results of studies with MAXALT tablets in all subsets of the pediatric population for the treatment of migraine. See section 4.2 for information on pediatric use.
05.2 Pharmacokinetic properties
Absorption
Rizatriptan is rapidly and completely absorbed following oral administration. The mean oral bioavailability of the tablet is approximately 40-45% and mean maximum plasma concentrations (Cmax) are reached in approximately 1-1.5 hours (Tmax). Oral administration of a tablet with a high fat breakfast had no effect on the extent of absorption of rizatriptan, but absorption was delayed by approximately 1 hour.
Effects of food: The effects of food on the absorption of rizatriptan oral lyophilisate have not been studied. For rizatriptan tablets, Tmax is delayed by approximately 1 hour after administration in a fed state. Further delay in absorption of rizatriptan may occur when oral lyophilisate it is given after meals. (See section 4.2.)
Distribution
Rizatriptan is minimally bound (14%) to plasma proteins. The volume of distribution is approximately 140 liters in males and 110 liters in females.
Biotransformation
The primary pathway of rizatriptan metabolism is oxidative deamination by monoamine oxidase-A (MAO-A) to the indolacetic acid metabolite, which is pharmacologically inactive. To a lesser extent, N-monodesmethyl-rizatriptan is formed, a metabolite with activity similar to that of the parent compound at the 5-HT1B / 1D receptor level, but which does not significantly contribute to the pharmacodynamic activity of rizatriptan. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of the parent compound and it is eliminated in similar amounts. Other minor metabolites include the N-oxide, the 6-hydroxylated compound, and the sulfate-conjugated form of the 6-hydroxylated metabolite. None of these minor metabolites are pharmacologically active. After oral administration of 14C-labeled rizatriptan, rizatriptan is responsible for approximately 17% of the circulating plasma radioactivity.
Elimination
After intravenous administration, the AUC increases proportionally in men and almost proportionally in women with the dose in the rangedosage 10-60 mcg / kg. Following oral administration, AUC increases almost proportionally with dose in a range dosage of 2.5-10 mg. The plasma half-life of rizatriptan in men and women averages 2-3 hours clearance plasma concentration of rizatriptan averages about 1000-1500 ml / min in men and about 900-1100 ml / min in women; about 20-30% of this is given by clearance renal. Following an oral dose of 14C-labeled rizatriptan, approximately 80% of the radioactivity is excreted in the urine and approximately 10% of the dose is excreted in the faeces. This demonstrates that the metabolites are excreted primarily via the kidney.
According to its first pass metabolism, approximately 14% of an oral dose is excreted in the urine as unchanged rizatriptan while 51% is excreted as the indolacetic acid metabolite. No more than 1% is excreted in the urine as the active N-monodesmethyl metabolite.
If rizatriptan is administered according to the maximum dosage regimen, there is no day-to-day plasma accumulation of the drug.
Characteristics of patients
Patients with a migraine attack: A migraine attack does not interfere with the pharmacokinetics of rizatriptan.
Sex: In men compared with women, the AUC of rizatriptan (10 mg administered orally) was approximately 25% lower, C 11% lower, and T was reached at approximately the same time. This apparent pharmacokinetic difference was not of clinical relevance.
Senior citizens: The plasma concentrations of rizatriptan observed in elderly subjects (aged 65 to 77 years) were similar to those observed in young adults.
Pediatric patients: A pharmacokinetic study of rizatriptan (oral lyophilisate formulation) was conducted in pediatric migraine patients 6 to 17 years of age. The mean exposures following administration of a single 5 mg dose of oral lyophilized rizatriptan to pediatric patients weighing 20-39 kg or 10 mg oral lyophilized rizatriptan to pediatric patients weighing ≥40 kg were 15% lower, respectively. and 17% higher than the exposure observed after administration of a single 10 mg dose of oral lyophilized rizatriptan to adult patients. The clinical relevance of these differences is unclear.
Hepatic impairment (Child-Pugh score 5-6): After oral administration in patients with liver damage caused by mild alcoholic liver cirrhosis, plasma concentrations of rizatriptan were similar to those observed in young subjects of both sexes. A significant increase in AUC (50%) and Cmax (25%) was observed in patients with moderate hepatic impairment (Child-Pugh score 7). Pharmacokinetics have not been studied in patients with Child-Pugh score> 7 (severe liver damage).
Renal impairment: In patients with impaired renal function (clearance creatinine 10-60 mL / min / 1.73m2), the AUC of rizatriptan was not significantly different from that observed in healthy subjects. In hemodialysis patients (clearance 2) The AUC of rizatriptan was approximately 44% higher than that observed in patients with normal renal function. The maximum plasma concentration of rizatriptan in patients with any degree of renal impairment was similar to that in healthy subjects.
05.3 Preclinical safety data
Non-clinical data indicate no risk to humans based on conventional studies of repeated dose toxicity, genotoxicity, potential carcinogenicity, reproductive and developmental toxicity, pharmacological safety, as well as pharmacokinetics and metabolism.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate, microcrystalline cellulose (E460a), pregelatinised starch, red iron oxide (E172), magnesium stearate (E572).
06.2 Incompatibility
Not applicable.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Aluminum blisters, packs of 2, 3, 6, 12 or 18 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
MSD Italia S.r.l.
Via Vitorchiano, 151 - 00189 Rome
08.0 MARKETING AUTHORIZATION NUMBER
3 tablets 5 mg n. 034115016 / M
6 tablets 5 mg n. 034115028 / M
12 tablets 5 mg n. 034115030 / M
3 tablets 10 mg No. 034115042 / M
6 tablets 10 mg n. 034115055 / M
12 tablets 10 mg n. 034115067 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: May 1999
Date of last renewal: April 2008
10.0 DATE OF REVISION OF THE TEXT
June 2013