Rizatriptan Orifarm

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

[Product name] 10 mg orodispersible tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains 14.53 mg rizatriptan benzoate corresponding to 10 mg rizatriptan.

Excipient with known effect:

Each orodispersible tablet contains 2.90 mg aspartame.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Orodispersible tablet.

White, round, biconvex tablets with a score line on one side and a diameter of 10.0 mm.

The score line is not intended for breaking the tablet

4. Clinical particulars

4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

[Product name] should not be used prophylactially.

Adults of 18 years 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 the 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 a lower dose of 5 mg 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.

The doses should be separated by at least two hours and no more than two doses should be taken in any 24-hour period. [Product name] cannot be divided into equal doses, and is therefore not suitable for treatment of patients that require a dose of 5 mg.

Paediatric population

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 section 5.1 and 5.2, but no recommendation on a posology can be made.

Patients older than 65 years

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

Method of administration

The orodispersible tablet needs not be taken with liquid. The orodispersible tablets should be placed on the tongue, where it will dissolve and be swallowed with the saliva. The orodispersible tablet can be used in situations in which liquid is not available, or to avoid the nausea and vomiting that may accompany the ingestion of tablets with liquid.

4.3 Contraindications

[Product name] is contraindicated in patients with the following conditions:

Hypersensitivity to the active substance or any of the excipients listed in section 6.1.
Concurrent administration of monoamine oxidase (MAO) inhibitors or use within two weeks of discontinuation of MAO inhibitor therapy (see section 4.5).
Severe hepatic or severe renal insufficiency.
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-HT_1B/1D receptor agonists (see section 4.5).

4.4 Special warnings and precautions for use

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

[Product name] 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-HT_1B/1Dreceptor agonists, rizatriptan should not be given, without prior evaluation, to patients in whom unrecognized 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-HT₁agonists have been administered. Those in whom CAD is established should not be given [Product name]. (See section 4.3)

5-HT_1B/1Dreceptor agonists have been associated with coronary vasospasm. In rare cases, myocardial ischaemia or infarction have been reported with 5-HT_1B/1Dreceptor agonists including rizatriptan (see section 4.8)

Other 5-HT_1B/1Dagonists, (e.g. sumatriptan) should not be used concomitantly with rizatriptan. (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-HT_1B/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.

Phenylketonuric patients should be informed that phenylalanine may be harmful. [Product name] orodispersible tabletscontain aspartame (which contains phenylalanine). Each 10 mg orodispersible tabletcontains 2.90 mg aspartame.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Ergotamine, ergot derivatives (including methysergide), other 5 HT _1B/1Dreceptor agonists

Due to an additive effect, the concomitant use of rizatriptan and ergotamine, ergot derivatives (including methysergide), or other 5 HT _1B/1Dreceptor 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 C_maxof 70-80%. In patients receiving propranolol, a lower dose of 5 mg 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 vitrostudies 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

The safety of rizatriptan for the use in human pregnancy has not been established. Animal studies do not indicate harmful effects at dose levels that exceed therapeutic dose levels with respect to the development of the embryo or foetus, or the course of gestation, parturition and post-natal development.

Because animal reproductive and developmental studies are not always predictive of human response, [Product name] should be used during pregnancy only if clearly needed.

Breast-feeding

Studies in rats indicated that very high milk transfer of rizatriptan occurred. Transient, very slight decreases in pre-weaning pup body weights were observed only when the mother's systemic exposure was well in excess of the maximum exposure level for humans. No data exist in humans.

Therefore, caution should be exercised when administering rizatriptan to women who are breast-feeding. Infant exposure should be minimised by avoiding breast-feeding for 24 hours after treatment.

4.7 Effects on ability to drive and use machines

Migraine or treatment with [Product name] 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 [Product name].

4.8 Undesirable effects

Rizatriptan (as tablet and oral lyophilisate formulation) was evaluated in over 3,600 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 with the frequencies:

Very common (≥ 1/10)
Common (≥ 1/100 to <1/10)
Uncommon (≥ 1/1,000 to <1/100)
Rare (≥ 1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data).

Immune system disorders:

Uncommon Hypersensitivity reaction

Rare Anaphylaxis/anaphylactoid reaction.

Psychiatric disorders:

Uncommon Disorientation, insomnia, nervousness.

Nervous system disorders:

Common: Dizziness, somnolence, paresthesia, headache, hypaesthesia, decreased mental acuity, tremor.

Uncommon: Ataxia, vertigo.

Rare: Syncope, dysgeusia/bad taste, serotonin syndrome.

Not known: Seizure.

Eye disorders:

Uncommon: Blurred vision.

Cardiac disorders:

Common: Palpitation, tachycardia.

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

Not known: Arrhythmia, bradycardia.

Vascular disorders:

Common: Hot flushes/flashes.

Uncommon: Hypertension.

Not known: Peripheral vascular ischaemia.

Respiratory, thoracic and mediastinal disorders:

Common: Pharyngeal discomfort, dyspnoea.

Rare: Wheezing.

Gastrointestinal disorders:

Common: Nausea, dry mouth, vomiting, diarrhoea.

Uncommon: Thirst, dyspepsia.

Not known: Ischemic colitis

Skin and subcutaneous tissue disorders:

Common: Flushing, sweating, rash.

Uncommon: Pruritus, urticarial, angioedema (e.g. facial edema,

tongue swelling, pharyngeal edema) (for angioedema see also section 4.4).

Rare: Toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders:

Common: Regional heaviness.

Uncommon: Neck pain, regional tightness, stiffness, muscle weakness.

Rare: Facial pain.

Not known: Myalgia.

General disorders and administration site conditions:

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

Investigations:

Not known: ECG abnormalities.

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 via the national reporting system listed in Appendix V.

4.9 Overdose

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

In a clinical pharmacology study in which 12 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective serotonin (5HT_1B/1D) agonists. ATC-code: N02C C04

Mechanism of action:

Rizatriptan binds selectively with high affinity to human 5-HT_1Band 5-HT_1D receptors and has little or no effect or pharmacological activity at 5-HT₂, 5-HT₃; adrenergic alpha₁, alpha₂ or beta; D₁, D₂, dopaminergic, histaminic H₁; muscarinic; or benzodiazepine receptors.

The therapeutic activity of rizatriptan in treating migraine headache may be attributed to its agonist effects at 5-HT_1Band 5-HT_1D receptors on the extracerebral intracranial blood vessels that are thought to become dilated during an attack and on the trigeminal sensory nerves that innervate them. Activation of these 5-HT_1Band 5-HT_1Dreceptors may result in constriction of pain-producing intracranial blood vessels and inhibition of neuropeptide release that leads to decreased inflammation in sensitive tissues and reduced central trigeminal pain signal transmission.

Pharmacodynamic effects

Adults

Theefficacyofrizatriptanorallyophilisatesintheacutetreatmentofmigraineattackswasestablishedintwo multicentre,randomised,placebo-controlledtrialsthatweresimilarindesigntothetrialsofrizatriptan tablets.Inonestudy(n=311),bytwohourspost-dosing,reliefratesinpatientstreatedwithrizatriptanoral lyophilisateswereapproximately66%forrizatriptan5mgand10mg,comparedto47%intheplacebo group.Inalargerstudy(n=547),bytwohourspost-dosing,reliefrateswere59%inpatientstreatedwith rizatriptanorallyophilisates5mg,and74%after10mg,comparedto28%intheplacebogroup.Rizatriptan orallyophilisatesalsorelievedthedisability,nausea,photophobia,andphonophobiawhichaccompaniedthe migraineepisodes.Asignificanteffectonpainreliefwasobservedasearlyas30minutespost-dosinginone ofthetwoclinicaltrialsforthe10mgdose(seesection5.2).

Basedonstudieswiththeoraltablet,rizatriptanremainseffectiveintreatingmenstrualmigraine,i.e. migrainethatoccurswithin3daysbeforeoraftertheonsetofmenses.

Adolescents (12-17 years of age)

The efficacy of rizatriptan oral lyophilisates in paediatric patients (12 to 17 years of age) was evaluated in a multicenter, randomized, double‑blind, placebo‑controlled, parallel group study (n=570). The patient population was required to be historically non‑responsive to NSAIDs and acetaminophen therapy. Patients with a qualifying migraine headache initially administered placebo or rizatriptan within 30 minutes of onset. Following the 15 minute placebo run-in, subjects who did not respond to placebo then treated a single migraine attack with placebo or rizatriptan. Using a weight‑based dosing strategy, patients 20 kg to <40 kg received 5 mg rizatriptan and patients ≥40 kg received 10 mg rizatriptan.

In this enriched population study, a difference of 9% between active treatment and placebo was observed for the primary efficacy endpoint of pain freedom (reduction from moderate or severe pain to no pain) 2 hours after treatment (31% under rizatriptan vs. 22% for placebo (p=0.025)). No significant difference for the secondary endpoint of pain relief (reduction from moderate or severe pain to mild or no pain) was found.

Children (6-11 years of age)

The efficacy of rizatriptan oral lyophilisates was also evaluated in paediatric patients 6 to 11 years of age in the same acute placebo‑controlled clinical trial (n=200). The percentage of patients achieving pain freedom 2 hours after treatment was not statistically significantly different in patients who received rizatriptan oral lyophilisates 5 and 10 mg, compared with those who received placebo (39.8% vs. 30.4%, p=0.269).

Rizatriptanorodispersibletabletsenablesmigrainepatientstotreattheirmigraineattackswithouthavingto swallowliquids.Thismayallowpatientstoadministertheirmedicationearlier,forexample,whenliquids arenotavailable,andtoavoidpossibleworseningofGIsymptomsbyswallowingliquids

5.2 Pharmacokinetic properties

Absorption

Rizatriptan is rapidly and completely absorbed following oral administration.

Themeanoralbioavailabilityoftheorodispersibletabletisapproximately40-45%,andmeanpeakplasma concentrations(C_m_a_x)arereachedinapproximately1.58hours(T_m_ax).Thetimetomaximumplasma concentrationfollowingadministrationofrizatriptanastheorodispersibletabletformulationisdelayedby 30-60minutesrelativetothetablet.

Effect of food

The effect of food on the absorption of rizatriptan from the orodispersible tablet has not been studied. For the rizatriptan tablets, T_maxis delayed by approximately 1 hour when the tablets are administered in the fed state. A further delay in the absorption of rizatriptan may occur when the orodispersible tablet is administered after meals.

Distribution

Rizatriptan is minimally bound (14%) to plasma proteins. The volume of distribution is approximately 140 liters in male subjects, and 110 liters in female subjects.

Biotransformation

The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not pharmacologically active. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT_1B/1Dreceptors, is formed to a minor degree, but does not contribute significantly to the pharmacodynamic activity of rizatriptan. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites include the N-oxide, the 6-hydroxy compound, and the sulphate conjugate of the 6-hydroxy metabolite. None of these minor metabolites are pharmacologically active. Following oral administration of ¹⁴C-labelled rizatriptan, rizatriptan accounts for about 17% of circulating plasma radioactivity.

Elimination

Following intravenous administration, AUC in men increases proportionally and in women near-proportionally with the dose over a dose range of 10-60 µg/kg. Following oral administration, AUC increases near-proportionally with the dose over a dose range of 2.5-10 mg. The plasma half-life of rizatriptan in males and females averages 2-3 hours. The plasma clearance of rizatriptan averages about 1000-1500 ml/min in males and about 900-1100 ml/min in females; about 20-30% of this is renal clearance. Following an oral dose of ¹⁴C-labelled rizatriptan, about 80% of the radioactivity is excreted in urine, and about 10% of the dose is excreted in faeces. This shows that the metabolites are excreted primarily via the kidneys.

Consistent with its first pass metabolism, approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite. No more than 1% is excreted in urine as the active N-monodesmethyl metabolite.

If rizatriptan is administered according to the maximum dosage regimen, no drug accumulation in the plasma occurs from day to day.

Characteristics in patients

The following data are based on studies with the oral tablet formulation.

Patients with a migraine attack

A migraine attack does not affect the pharmacokinetics of rizatriptan.

Gender

The AUC of rizatriptan (10 mg orally) was about 25% lower in males as compared to females, C_maxwas 11% lower, and T_maxoccurred at approximately the same time. This apparent pharmacokinetic difference was of no clinical significance.

Elderly

The plasma concentrations of rizatriptan observed in elderly subjects (age range 65 to 77 years) after tablet administration were similar to those observed in young adults.

Paediatric:

A pharmacokinetics study of rizatriptan (as the oral lyophilisates formulation) was conducted in paediatric migraineurs 6 to 17 years of age. The mean exposures following a single dose administration of 5 mg rizatriptan oral lyophilisates to paediatric patients weighing 20‑39 kg or 10 mg rizatriptan oral lyophilisates to paediatric patients weighing ≥40 kg were respectively 15% lower and 17% higher compared to the exposure observed following singledose administration of 10 mg rizatriptan oral lyophilisates to adults. The clinical relevance of these differences is unclear.

Hepatic impairment (Child-Pugh's score 5-6)

Following oral tablet administration in patients with hepatic impairment caused by mild alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar to those seen in young male and female subjects. A significant increase in AUC (50%) and C_max(25%) was observed in patients with moderate hepatic impairment (Child Pugh's score 7). Pharmacokinetics were not studied in patients with Child Pugh's score >7 (severe hepatic impairment).

Renal impairment

In patients with renal impairment (creatinine clearance 10-60 ml/min/1.73 m²), the AUC of rizatriptan after tablet administration was not significantly different from that in healthy subjects. In haemodialysis patients (creatinine clearance <10 ml/min/1.73 m²), the AUC for rizatriptan was approximately 44% greater than that in patients with normal renal function. The maximal plasma concentration of rizatriptan in patients with all degrees of renal impairment was similar to that in healthy subjects.

5.3 Preclinical safety data

Preclinical data indicate no risk for humans based on conventional studies of repeat dose toxicity, genotoxicity, carcinogenic potential, reproductive and developmental toxicity, safety pharmacology, and pharmacokinetics and metabolism.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose,microcrystalline

Maizestarch

Silica,colloidalanhydrous

Aspartame(E951)

Mintpowder

Magnesiumstearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PA/Aluminium/PVC/Aluminium blisters with 2, 3, 6 or 18 orodispersible tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

2016-04-18