4.1. Therapeutic indications

Acute treatment of the headache phase of migraine attacks, with or without aura in adults.

Rizatriptan should not be used prophylactically.

4.2. Posology and method of administration

Posology

Adults 18 years of age and older

The recommended dose is 10 mg.

Redosing: Doses should be separated by at least two hours; no more than two doses should be taken in any 24-hour period.

- for headache recurrence within 24 hours: If headache returns after relief of the initial attack, one further dose may be taken. The above dosing limits should be observed.

- after non-response: the effectiveness of a second dose for treatment of the same attack, when an initial dose is ineffective, has not been examined in controlled trials. 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 patients who do not respond to treatment of an attack are still likely to respond to treatment for subsequent attacks.

Some patients should receive the lower (5 mg) dose of Rizatriptan, in particular the following patient groups:

− patients on propranolol. Administration of rizatriptan should be separated by at least two hours from administration of propranolol. (See section 4.5)

− patients with mild or moderate renal insufficiency.

− patients with mild to moderate hepatic insufficiency.

Doses should be separated by at least two hours; no more than two doses should be taken in any 24 hour period.

Patients older than 65 years

The safety and effectiveness of rizatriptan in patients older than 65 years have not been systematically evaluated.

Paediatric patients

Children and Adolescents (under 18 years of age)

The safety and efficacy of rizatriptan in children and adolescents under 18 years of age has 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.

Method of administration

The tablets should be swallowed whole with liquid.

Effects of food: The absorption of rizatriptan is delayed by approximately 1 hour when administered together with food. Therefore, onset of effect may be delayed when rizatriptan is administered in the fed state. (See also 5.2 'Pharmacokinetic properties', Absorption).

4.3. Contraindications

Hypersensitivity to rizatriptan or to any of the excipients.

Concurrent administration of monoamine oxidase (MAO) inhibitors or use within two weeks of discontinuation of MAO inhibitor therapy. (See section 4.5)

Rizatriptan is contra-indicated in patients with severe hepatic or severe renal insufficiency.

Rizatriptan is contra-indicated in patients with a previous cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

Moderately severe or severe hypertension, or untreated mild hypertension.

Established coronary artery disease, including ischaemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischaemia), signs and symptoms of ischaemic heart disease, or Prinzmetal's angina.

Peripheral vascular disease.

Concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide), or other 5-HT1B/1D receptor agonists. (See section 4.5).

4.4. Special warnings and precautions for use

Rizatriptan should only be administered to patients in whom a clear diagnosis of migraine has been established. Rizatriptan should not be administered to patients with basilar or hemiplegic migraine.

Rizatriptan should not be used to treat 'atypical' headaches, i.e. those that might be associated with potentially serious medical conditions, (e.g. CVA, ruptured aneurysm) in which cerebrovascular vasoconstriction could be harmful.

Rizatriptan can be associated with transient symptoms including chest pain and tightness which may be intense and involve the throat (see section 4.8). Where such symptoms are thought to indicate ischaemic heart disease, no further dose should be taken and appropriate evaluation should be carried out.

As with other 5-HT1B/1D receptor agonists, rizatriptan should not be given, without prior evaluation, to patients in whom unrecognised cardiac disease is likely or to patients at risk for coronary artery disease (CAD) [e.g. patients with hypertension, diabetics, smokers or users of nicotine substitution therapy, men over 40 years of age, post- menopausal women, patients with bundle branch block, and those with strong family history for CAD]. Cardiac evaluations may not identify every patient who has cardiac disease and, in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease when 5-HT1 agonists have been administered. Those in whom CAD is established should not be given Rizatriptan. (See section 4.3)

5-HT1B/1D receptor agonists have been associated with coronary vasospasm. In rare cases, myocardial ischaemia or infarction have been reported with 5-HT1B/1D receptor agonists including Rizatriptan (see section 4.8)

Other 5-HT1B/1D agonists (e.g. sumatriptan) should not be used concomitantly with [To be completed nationally] (see section 4.5).

It is advised to wait at least six hours following use of rizatriptan before administering ergotamine-type medications, (e.g. ergotamine, dihydro-ergotamine or methysergide). At least 24 hours should elapse after the administration of an ergotamine-containing preparation before rizatriptan is given. Although additive vasospastic effects were not observed in a clinical pharmacology study in which 16 healthy males received oral rizatriptan and parenteral ergotamine, such additive effects are theoretically possible, (see section 4.3)

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 noradrenaline reuptake inhibitors (SNRIs). These reactions can be severe. If concomitant treatment with rizatriptan and an SSRI or SNRI is clinically warranted, appropriate observation of the patient is advised, particularly during treatment initiation, with dose increases, or with addition of another serotonergic medication (see section 4.5).

Undesirable effects may be more common during concomitant use of triptans (5- HT1B/1D agonists) and herbal preparations containing St John's wort (Hypericum perforatum).

Angioedema (e.g. facial oedema, tongue swelling and pharyngeal oedema) may occur in patients treated with triptans, among which rizatriptan. If angioedema of the tongue or pharynx occurs, the patient should be placed under medical supervision until symptoms have resolved. Treatment should promptly be discontinued and replaced by an agent belonging to another class of drugs.

The potential for interaction should be considered when rizatriptan is administered to patients taking CYP 2D6 substrates (see section 4.5)

Medication overuse headache (MOH)

Prolonged use of any painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of MOH should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Rizatriptan contains aspartame (E951) as a source of phenylalanine. May be harmful for people with phenylketonuria.

4.5. Interaction with other medicinal products and other forms of interaction

Ergotamine, ergot derivatives (including methysergide), other 5 HT 1B/1D receptor agonists: Due to an additive effect, the concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide), or other 5 HT 1B/1D receptor agonists (e.g. sumatriptan, zolmitriptan, naratriptan) increase the risk of coronary artery vasoconstriction and hypertensive effects. This combination is contraindicated (see section 4.3).

Monoamine oxidase inhibitors: Rizatriptan is principally metabolised via monoamine oxidase, 'A' subtype (MAO-A). Plasma concentrations of rizatriptan and its active N- monodesmethyl metabolite were increased by concomitant administration of a selective, reversible MAO-A inhibitor. Similar or greater effects are expected with non-selective, reversible (e.g. linezolid) and irreversible MAO inhibitors. Due to a risk of coronary artery vasoconstriction and hypertensive episodes, administration of Rizatriptan to patients taking inhibitors of MAO is contraindicated. (See section 4.3)

Beta-blockers: Plasma concentrations of rizatriptan may be increased by concomitant administration of propranolol. This increase is most probably due to first-pass metabolic interaction between the two drugs, since MAO-A plays a role in the metabolism of both rizatriptan and propranolol. This interaction leads to a mean increase in AUC and Cmax of 70-80%. In patients receiving propranolol, the 5 mg dose of Rizatriptan should be used. (See section 4.2)

In a drug-interaction study, nadolol and metoprolol did not alter plasma concentrations of rizatriptan.

Selective Serotonin Reuptake Inhibitors (SSRIs) /Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) and Serotonin Syndrome: There have been reports describing patients with symptoms compatible with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs) and triptans (see section 4.4).

In vitro studies indicate that rizatriptan inhibits cytochrome P450 2D6 (CYP 2D6). Clinical interaction data are not available. The potential for interaction should be considered when rizatriptan is administered to patients taking CYP 2D6 substrates.

4.6. Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative toxicity following first trimester exposure. Animal studies do not indicate reproductive toxicity (see section 5.3).

There is limited data in relation to use of rizatriptan in the second and third trimester of pregnancy. Use of rizatriptan may be considered during pregnancy, if clinically necessary

Breast-feeding

Rizatriptan is excreted in low concentration in human milk with an average relative infant dose less than < 1% (less than 6% in worst case scenario based on Cmax in breast milk).

Caution should be exercised when administering rizatriptan to women who are breast- feeding. Infant exposure may be minimised by avoiding breast-feeding for 12 hours after administration of rizatriptan.

Fertility

Effects on human fertility have not been investigated. Animal studies only revealed minimal effects on fertility at plasma concentrations far in excess of human therapeutic concentrations (more than 500-fold).

4.7. Effects on ability to drive and use machines

Rizatriptan has no or negligible influence on the ability to drive and use machines. Migraine or treatment with Rizatriptan may cause somnolence in some patients.

Dizziness has also been reported in some patients receiving Rizatriptan. Patients should, therefore, evaluate their ability to perform complex tasks during migraine attacks and after administration of Rizatriptan.

4.8. Undesirable effects

Rizatriptan formulations (tablets and oral lyophilisates) have been evaluated in 8630 patients for up to one year in controlled clinical studies. The most common side effects evaluated in clinical studies were dizziness, somnolence, and asthenia/fatigue. The following side effects have been evaluated in clinical studies and/or reported in post-marketing experience:

(Very common [ ≥ 1/10]; Common [ ≥ 1/100 to <1/10]; Uncommon: [ ≥ 1/1000 to <1/100]; Rare [ ≥ 1/10,000 to <1/1,000]; Very rare [ ≤ 1/10000], not known [cannot be estimated from the available data]).

Immune system disorders:

Rare: hypersensitivity reaction, anaphylaxis/anaphylactoid reaction.

Pyschiatric disorders:

Common: insomnia

Uncommon: disorientation, nervousness.

Nervous system disorders:

Common: dizziness, somnolence, paraesthesia, headache, hypoaesthesia, decreased mental activity.

Uncommon: ataxia, vertigo, dysgeusia/bad taste, syncope.

Not known: seizure, serotonin syndrome

Eye disorders:

Uncommon: blurred vision.

Cardiac disorders:

Common: palpitation.

Uncommon: arrhythmia, ECG abnormalities, tachycardia.

Rare: cerebrovascular accident. Most of these adverse reactions have been reported in patients with risk factors predictive of coronary artery disease, bradycardia

Not known: myocardial ischaemia or infarction (most of these adverse reactions have been reported in patients with risk factors predictive of coronary artery disease)

Vascular disorders:

Uncommon: hypertension, hot flushes/flashes.

Not known: peripheral vascular ischaemia.

Respiratory, thoracic and mediastinal disorders:

Common: pharyngeal discomfort.

Uncommon: dyspnoea

Rare: wheezing.

Gastro-intestinal disorders:

Common: nausea, dry mouth, vomiting, diarrhea, dyspepsia.

Uncommon: thirst.

Not known: ischemic colitis

Skin and subcutaneous tissue disorders:

Common: flushing.

Uncommon: pruritus, urticaria, angioedema (e.g. facial oedema, tongue swelling, pharyngeal oedema) (for angioedema see also section 4.4), rash, sweating

Not known: toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders:

Common: regional heaviness, neck pain, stiffness.

Uncommon: regional tightness, muscle weakness, facial pain, myalgia

General disorders and administration site conditions:

Common: asthenia/fatigue, pain in abdomen or chest.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions directly via the Yellow Card Scheme at www.mhra.gov.co.uk/yellowcard.

4.9. Overdose

Rizatriptan 40 mg (administered as either a single dose or as two doses with a two- hour interdose interval) was generally well tolerated in over 300 adult patients; dizziness and somnolence were the most common drug-related adverse effects.

In a clinical pharmacology study in which 12 adult subjects received rizatriptan, at total cumulative doses of 80 mg (given within four hours), two subjects experienced syncope and/or bradycardia. One subject, a female aged 29 years, developed vomiting, bradycardia, and dizziness beginning three hours after receiving a total of 80 mg rizatriptan (administered over two hours). A third-degree AV block, responsive to atropine, was observed an hour after the onset of the other symptoms. The second subject, a 25 year-old male, experienced transient dizziness, syncope, incontinence, and a five-second systolic pause (on ECG monitor) immediately after a painful venipuncture. The venipuncture occurred two hours after the subject had received a total of 80 mg rizatriptan (administered over four hours).

In addition, based on the pharmacology of rizatriptan, hypertension or other more serious cardiovascular symptoms could occur after overdosage. Gastro-intestinal decontamination, (e.g. gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with Rizatriptan. Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed.

The effects of haemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.