AURADOL - PACKAGE LEAFLET - LEAFLETS

Home / leaflets / 2021

Auradol - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Frovatriptan

URADOL 2.5 mg film-coated tablets

Why is Auradol used? What is it for?

Auradol 2.5 mg tablets contain frovatriptan, a drug for the treatment of migraine belonging to the class of triptans (selective 5-hydroxytryptamine (5HT1) receptor agonists).

Auradol 2.5 mg tablets is a medicine to treat the headache phase of a migraine attack or crisis, with or without aura (a strange momentary sensation you get before a "migraine, which varies from person to person, but can alter, for example, sight, "smell or" hearing).

Auradol 2.5 mg tablets should not be taken to prevent a migraine attack.

Contraindications When Auradol should not be used

Your doctor must have made a clear diagnosis of migraine.

Do not take Auradol:

if you are allergic (hypersensitive) to frovatriptan or any of the other ingredients of Auradol 2.5 mg tablets;
if you have had a heart attack or if you have or have suffered from known cardiovascular disease, such as angina pectoris (characterized by squeezing pain in the chest, which can extend to the left arm) or blood circulation disorders in the legs or arms (especially in the fingers and toes);
if you have had a stroke or transient ischemic attack (TIA);
if you have severely or moderately high blood pressure or if your blood pressure is not properly controlled;
if you have severe liver disease (liver disease);
in combination with certain other drugs also used to treat migraine (ergotamine and ergotamine derivatives (including methysergide) or other triptans (5-hydroxytryptamine (5HT1) agonists).

Precautions for use What you need to know before taking Auradol

Take special care with Auradol:

if you are a patient at risk for coronary heart disease, including:
if you are a regular smoker or are on nicotine replacement therapy
if you are a menopausal woman or a man over 40 years of age.

In all these cases, ask your doctor before taking Auradol.

In very rare cases, taking triptans can cause a sensation of compression or pain in the chest, even in patients who have never had cardiovascular disease. If this occurs, contact your doctor and do not take other doses of the drug.

Interactions What medications or foods can change the effect of Auradol

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those obtained without a prescription.

You should not take this medicine together with certain other medicines used to treat migraines:

in particular ergotamine, ergotamine derivatives (including methysergide); at least 24 hours must elapse between stopping therapy with these drugs and taking Auradol 2.5 mg tablets. Similarly, you should not take these drugs within 24 hours. after taking a dose of Auradol 2.5 mg tablets;
particularly other triptans (5-HT1 agonists, such as sumatriptan, almotriptan, eletriptan, naratriptan, rizatriptan or zolmitriptan). Unless otherwise directed by your doctor, you should not take this drug together with monoamine oxidase inhibitors (MAOIs) used to treat depression (phenelzine, isocarboxazide, tranylcypromine, moclobemide).
Tell your doctor or pharmacist if you are taking an oral contraceptive or selective serotonin reuptake inhibitor drugs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline).

It is recommended not to take Auradol 2.5 mg tablets at the same time as St. John's wort (Hypericum perforatum).

Concomitant use of Auradol with the drugs listed above (especially monoamine oxidase inhibitors, selective serotonin reuptake inhibitors and St. John's wort) may also increase the risk of serotonin syndrome (symptoms of which include: chills, sweating, agitation, tremor and sudden contraction of muscles, nausea, fever, confusion).

If you are unsure about taking other medicines with Auradol 2.5 mg tablets, consult your doctor or pharmacist.

Using Auradol with food and drink

Auradol 2.5 mg tablets can be taken with food or on an empty stomach, always with an appropriate amount of water.

Warnings It is important to know that:

Pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.

Auradol 2.5 mg tablets should not be taken during pregnancy or breastfeeding unless advised to by your doctor. However, you should not breastfeed for 24 hours after taking Auradol and discard any leaking milk during this time.

Driving and using machines

Auradol 2.5 mg tablets and migraine itself can make you drowsy. In these cases driving a vehicle or using a machine can be dangerous and should be avoided.

Important information about some of the ingredients of Auradol

This product contains lactose. If you have been told by your doctor that you have an "intolerance to some sugars, please contact him before taking this drug.

Dose, Method and Time of Administration How to use Auradol: Posology

Always take Auradol 2.5 mg tablets exactly as your doctor has told you. If in doubt you should consult your doctor.

Take Auradol 2.5 mg tablets as soon as possible after the onset of migraine with headache. Swallow the tablet whole with water.

If the first dose has no effect, do not take a second dose during the same seizure. For other subsequent crises, Auradol 2.5 mg tablets can be taken.

If you have relief after the first dose and then the migraine returns within 24 hours, you can take a second dose as long as there is at least 2 hours between the 2 doses.

Do not exceed the maximum dose of 5 mg (two tablets) in 24 hours.

Excessive use (repeated for several consecutive days) of Auradol 2.5 mg tablets constitutes improper use of the drug and can cause increased side effects and lead to chronic daily headache, for which treatment must be temporarily interrupted. Consult your doctor if you start to have too frequent or daily headaches, as this could mean you are suffering from drug abuse migraines.

Auradol should not be used in patients under 18 years of age.

As there is little experience in patients over the age of 65, the use of Auradol is not recommended for patients in this age group.

Overdose What to do if you have taken too much Auradol

If you take more Auradol than you should

If you accidentally take an overdose of this drug, tell your doctor or pharmacist immediately or go to the nearest hospital emergency room, remembering to take the drug pack or this leaflet with you.

If you stop taking Auradol

No special precautions are needed to stop taking the drug.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Side Effects What are the side effects of Auradol

Like all medicines, Auradol 2.5 mg tablets can cause side effects, although not everybody gets them.

After a few minutes of taking the drug, it is possible to experience a sensation of compression or pain in the chest, sometimes even intense and potentially extending up to the throat; when this happens, contact your doctor and do not take any more doses of the medicine.

The undesirable effects reported during clinical trials with Auradol 2.5 mg tablets were temporary, generally mild to moderate, and disappeared spontaneously. Some of the symptoms reported may be caused by the migraine itself.

The following side effects have been observed commonly (estimated frequency: more than 1 in 100 people and less than 1 in 10 people):

nausea (malaise), dry mouth, digestive problems, stomach pain;
fatigue, chest discomfort (feeling of slight heaviness, pressure or compression in the chest);
headache, dizziness, tingling and tingling sensation, especially in the arms and legs, reduction or exaggeration of tactile sensations, severe sleepiness;
hot flashes;
constriction in the throat;
vision disturbances;
increased sweating;

The following side effects have been observed uncommonly (estimated frequency: more than 1 in 1000 people and less than 1 in 100 people):

altered taste, tremor, poor concentration, lethargy, heightened tactile sensations, drowsiness, involuntary muscle contractions;
diarrhea, difficulty swallowing, gas in the stomach or intestines, stomach discomfort, swollen belly;
increased perception of heartbeat (palpitations), rapid heartbeat, increased blood pressure, chest pain (intense compression or feeling of pressure in the chest);
feeling hot, reduced tolerance to heat and cold, pain, weakness, thirst, sluggishness, increased strength, general feeling of being unwell, light-headed or foggy feeling, spinning sensation (vertigo);
anxiety, insomnia, confusion, nervousness, agitation, depression, loss of a sense of personal identity;
feeling of cold in the hands and feet;
nose irritation, sinus inflammation (sinusitis), sore throat and / or vocal cords;
muscle stiffness, muscle-joint pain, pain in the hands and feet, back pain, joint pain;
eye pain, eye irritation, light hypersensitivity pain;
sensations of itching;
ringing in the ears, earache;
dehydration;
frequent urge to urinate, increased amount of urine produced;
high blood pressure.

The following side effects have been observed rarely (estimated frequency: more than 1 in 10,000 people and less than 1 in 1,000 people): -

muscle cramps, muscle flaccidity, decreased reflexes (hyporeflexia), movement disorders;
constipation, belching, heartburn, irritable bowel syndrome, blistering of the lips, lip pain, spasm of the esophagus, blistering in the mouth, ulcer in the stomach or upper small intestine, pain in the glands salivary, sore mouth, toothache;
fever;
memory loss, abnormal dreams, personality disorders;
nosebleeds, hiccups, wheezing, breathing problems, sore throat;
night blindness;
redness of the skin, lifting of hair, purple spots or spots on the skin and mucous surfaces of the body, hives;
slow heartbeat;
ear discomfort, ear discomfort, itchy ear, sensitive hearing;
increase in bilirubin (a substance produced by the liver) in the blood, decrease in calcium in the blood, abnormal urinalysis;
low blood sugar;
need to urinate frequently at night, kidney pain;
self-inflicted injuries (for example, bite or bruise);
swollen lymph nodes;
breast pain or discomfort.

There have been cases of allergic reactions to Auradol, with skin irritation and some serious allergic reactions throughout the body (anaphylaxis), with possible sudden difficulty in breathing, rapid heartbeat and palpitations. If necessary, get medical help immediately.

If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Expiry and Retention

Do not use Auradol 2.5 mg tablets after the expiry date stated on the carton. The expiry date refers to the last day of the month.

Do not store above 30 ° C.

Blisters: Store in the original package.

Bottle: keep the container tightly closed.

Keep out of the reach and sight of children.

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.

What Auradol contains

The active substance is frovatriptan 2.5 mg per tablet in the form of succinate monohydrate.

The other ingredients are: anhydrous lactose, microcrystalline cellulose, magnesium stearate, sodium starch glycolate (type A), anhydrous colloidal silica. Coating: white OPADRY: titanium dioxide (E171), anhydrous lactose, hypromellose (E464), macrogol 3000, triacetin.

What Auradol looks like and contents of the pack

Auradol is available as round film-coated tablets, with the letter "m" debossed on one side and the number "2.5" debossed on the other.

Each pack contains 1, 2, 3, 4, 6 or 12 tablets.

Each bottle with safety cap contains 30 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.

Further information on Auradol can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 AUTHORIZATION NUMBER" PLACING ON MARKET09.0 DATE OF PR IMA AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIOPharmaceuticals, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORAN PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

AURADOL 2.5 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 2.5 mg of frovatriptan (as succinate monohydrate).

Excipients with known effects: approximately 100 mg of lactose per tablet

For the full list of excipients see section 6.1

03.0 PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Round, biconvex, coated with white film, with the mark "m" on one side and "2.5" on the other.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Acute treatment of the headache phase of the migraine attack with or without aura.

AURADOL is indicated in adults.

04.2 Posology and method of administration

Dosage

Frovatriptan should be taken as soon as possible after the onset of the migraine attack but is also effective when taken at an advanced stage. Frovatriptan should not be used as a prophylaxis.

If the patient does not benefit after the first dose of frovatriptan, a second dose should not be taken for the same attack because no benefit has been shown.

Frovatriptan can be used for subsequent migraine attacks.

Adults (18 to 65 years of age)

The recommended dose of frovatriptan is 2.5 mg.

If after initial relief the headache reappears, a second dose can be taken with an interval of at least 2 hours between the two doses.

The total daily dose should not exceed 5 mg per day.

Pediatric population (under 18 years)

The safety and efficacy of AURADOL in children and adolescents under the age of 18 have not been established. Therefore, use in this age group is not recommended. No data are available.

Elderly (over 65 years)

Data on the use of frovatriptan in patients over the age of 65 are limited. Therefore, use in this patient group is not recommended.

Kidney damage

No dosage adjustment is required in patients with renal impairment (see 5.2 Pharmacokinetic properties).

Impaired liver function

No dosage adjustment is required in patients with mild or moderate hepatic impairment (see 5.2 Pharmacokinetic properties). Frovatriptan is contraindicated in patients with severe hepatic impairment (see 4.3 Contraindications).

Method of administration

Oral use.

The tablet should be swallowed whole with water.

04.3 Contraindications

• Hypersensitivity to frovatriptan or to any of the excipients listed in section 6.1

• Patients with a history of myocardial infarction, ischemic heart disease, coronary vasospasm (eg Prinzmetal's angina), peripheral vascular disease, patients with symptoms or signs consistent with ischemic heart disease.

• Severe or moderately severe arterial hypertension, mild uncontrolled hypertension.

• Previous cerebrovascular accident (CVA) or transient ischemic attack (TIA).

• Severe hepatic insufficiency (Child-Pugh C).

• Simultaneous administration of frovatriptan with ergotamine, ergotamine derivatives (including methysergide) or with other 5-hydroxytryptamine (5-HT1) receptor agonists.

04.4 Special warnings and appropriate precautions for use

Frovatriptan should only be used when a clear diagnosis of migraine has been made.

Frovatriptan is not indicated for the treatment of hemiplegic, basilar or ophthalmoplegic migraine.

As with other treatments for migraine attacks, other potentially serious neurological conditions need to be ruled out before treating the headache of patients without a previous diagnosis of migraine or patients diagnosed with migraine but who have atypical symptoms. & EGRAVE; It should be noted that patients with migraine are at increased risk for some cerebro-vascular events (eg CVA or TIA).

The safety and efficacy of frovatriptan during the aura phase, preceding the migraine headache phase, has not been established.

Like other 5-HT1 receptor agonists, frovatriptan should not be given to patients who are at risk of coronary artery disease (CAD), including heavy smokers or patients on nicotine replacement treatment, without prior cardiovascular evaluation (see 4.3 Contraindications). Particular attention should be paid to postmenopausal women and men over 40 years of age who have these risk factors.

However, a cardiovascular evaluation may not identify all patients with cardiovascular disease. Serious cardiac events have occurred very rarely in patients taking 5-HT1 receptor agonists in the absence of underlying cardiovascular disease.

Administration of frovatriptan may be associated with transient symptoms such as chest pain or a sensation of chest tightness which may be intense and extend to the throat (see 4.8 Undesirable Effects).

In cases where the above symptoms lead to suspicion of ischemic heart disease, no further doses of frovatriptan should be taken and further investigations should be conducted.

Patients should be informed of the early signs and symptoms of hypersensitivity reactions, including skin disorders, angioedema and anaphylaxis (see section 4.8). In the event of serious allergic / hypersensitivity reactions, treatment with frovatriptan must be stopped immediately and must not be re-administered.

You must wait 24 hours after taking frovatriptan before administering an ergotamine-like product. At least 24 hours after administering an ergotamine-containing product must elapse before taking frovatriptan (see 4.3 Contraindications and 4.5 Interactions with other medicinal products and other forms of interaction) .

In case of too frequent use (repeated administrations, for several consecutive days, correspond to an incorrect use of the drug), the active substance can accumulate and cause an increase in side effects.

Prolonged use of any type of pain reliever for headache can worsen the condition. If this situation is experienced or suspected, the patient should consult a doctor and discontinue treatment. In patients who suffer from frequent or daily headache despite (or due to) regular use of headache medications the possibility of MOH (drug overuse headache) should be considered.

Do not exceed the recommended dose of frovatriptan.

This medicine contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Undesirable effects may be seen more commonly during concomitant administration of triptans (5HT agonists) and preparations containing St John's wort (Hypericum perforatum).

04.5 Interactions with other medicinal products and other forms of interaction

CONCOMITANT USE IS CONTRAINDICATED

Ergotamine and ergotamine derivatives (including methysergide) and other 5 HT1 agonists.

Risks of hypertension, constriction of the coronary arteries due to the additive vasospastic effect, when used simultaneously for the same migraine attack (see 4.3 Contraindications).

Effects can be additive. It is recommended to wait at least 24 hours after administration of ergotamine products before administering frovatriptan. Instead, it is recommended to wait 24 hours after administration of frovatriptan before administering an ergotamine product (see 4.4. Special warnings and precautions for use).

CONCOMITANT USE NOT RECOMMENDED

Monoamine oxidase inhibitors

Frovatriptan is not a substrate for MAO-A, however a potential risk of serotonin syndrome or hypertension cannot be excluded (see 5.2 Pharmacokinetic properties).

CONCOMITANT USE THAT REQUIRES CAUTION

Selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Potential risk of hypertension, coronary vasoconstriction or serotonin syndrome.

Absolute observance of the recommended doses is an essential factor in preventing this syndrome.

Methylergometrine

Risks of hypertension, constriction of the coronary arteries.

Fluvoxamine

Fluvoxamine is a potent inhibitor of cytochrome CYP1A2 and has been shown to increase blood levels of frovatriptan by 27-49%.

Oral contraceptives

In women taking oral contraceptives, the concentration of frovatriptan is 30% higher than in women not taking contraceptives. There was no reported increased incidence of adverse events.

Hypericum perforatum (St. John's wort) (by mouth)

As with other triptans, it may increase the risk of developing serotonin syndrome.

04.6 Pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of frovatriptan in pregnant women.

Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for men is unknown. AURADOL is not recommended during pregnancy and in women of childbearing potential who do not use contraceptives, unless clearly needed.

Feeding time

It is unknown whether Frovatriptan or its metabolites are excreted in human milk. Frovatriptan and / or its metabolites are excreted in the milk of lactating rats with a maximum concentration up to four times higher than that found in blood.

A breastfeeding risk to the newborns / infants cannot be excluded.

AURADOL is not recommended during breastfeeding unless absolutely necessary. In this case an interval of 24 hours should be observed.

04.7 Effects on ability to drive and use machines

No studies on the ability to drive and use machines have been performed.

Migraine or treatment with frovatriptan can cause drowsiness. Patients should be advised in order to assess their ability to perform complex actions, such as driving, during migraine attacks or after taking frovatriptan.

04.8 Undesirable effects

Frovatriptan has been administered to more than 2700 patients at the recommended dose of 2.5 mg and the most common side effects (dizziness, fatigue, paraesthesia, headache and hot flashes. Undesirable effects reported in clinical protocols with frovatriptan were transient, generally mild or moderate and resolved spontaneously Some of the symptoms reported as side effects may be symptoms associated with migraine.

The table below shows all adverse reactions that were considered related to treatment with frovatriptan 2.5 mg and that showed a higher incidence than placebo in 4 placebo-controlled clinical trials. They are listed according to decreasing incidence and by system.Adverse reactions collected after the drug was placed on the market are indicated with an asterisk *.

System and organ classification Very common (> 1/10) Common (> 1/100 Uncommon (> 1/1000 Rare (> 1/10000 Very rare ( Not known (frequency cannot be estimated from the available data) Disorders of the blood and lymphatic system Lymphadenopathy Disorders of the immune system Hypersensitivity reactions * (including skin disorders, angioedema and anaphylaxis) Metabolism and nutrition disorders Dehydration Hypoglycemia Psychiatric disorders Anxiety, insomnia, confusion, nervousness, agitation, depression, depersonalization Abnormal dreams, personality disorders Nervous system disorders Dizziness, paraesthesia, headache, somnolence, dysesthesia, hypoesthesia Dysgeusia, tremor, attention disturbance, lethargy, hyperesthesia, sedation, dizziness, involuntary muscle contractions Amnesia, hypertonia, hypotonia, hyporeflexia, movement disorders Eye disorders Visual disturbances Eye pain, eye irritation, photophobia Night blindness Ear and labyrinth disorders Tinnitus, ear pain Ear discomfort, discomfort and itching, hyperacusis Cardiac pathologies Palpitations, tachycardia Bradycardia Myocardial infarction *, Coronary arteriospasm * Vascular pathologies Redness Sensation of cold in the extremities, hypertension Respiratory, thoracic and mediastinal disorders Constriction in the throat Rhinitis, sinusitis, pharyngolaryngeal pain Epistaxis, hiccups, hyperventilation, breathing disorders, throat irritation Gastrointestinal disorders Nausea, dry mouth, dyspepsia, abdominal pain Diarrhea, dysphagia, flatulence, stomach discomfort, abdominal distension Constipation, belching, gastroesophageal reflux disease, irritable bowel syndrome, blistering of the lips, lip pain, oesophageal spasm, blistering of the oral mucosa, peptic ulcer, salivary gland pain, stomatitis, odontalgia Skin and subcutaneous tissue disorders Hyperhidrosis Itching Erythema, piloerection, purpura, urticaria Musculoskeletal and connective tissue disorders Musculoskeletal stiffness, musculoskeletal pain, pain in extremity, back pain, arthralgia Renal and urinary disorders Pollakiuria, polyuria Nocturia, kidney pain Diseases of the reproductive system and breast Mastodynia General disorders and administration site conditions Fatigue, chest discomfort Chest pain, sensation of heat, intolerance to heat and cold, pain, asthenia, thirst, weakness, increased strength, malaise Pyrexia Diagnostic tests Increased blood bilirubin, decreased blood calcium, abnormal urinalysis Injury, poisoning and procedural complications bite

In two long-term clinical studies the observed effects were not different from those reported in the table.

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 https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

Data on frovatriptan tablet overdose are limited. The maximum single oral dose of frovatriptan administered to male and female migraine patients was 40 mg (16 times the recommended clinical dose of 2.5 mg) and the maximum single dose administered to healthy male subjects was 100 mg (40 times the recommended clinical dose). Both were not associated with side effects other than those mentioned in section 4.8. However, a severe case of coronary vasospasm has been reported post-marketing after taking four times the recommended dose of frovatriptan for three consecutive days in a patient taking a tricyclic antidepressant as a prophylactic therapy for migraine. he recovered.

There is no specific antidote for frovatriptan. The elimination half-life of frovatriptan is approximately 26 hours (see 5.2 Pharmacokinetic properties).

The effects of hemodialysis or peritoneal dialysis on plasma concentrations of frovatriptan are not known.

Treatment

In the event of an overdose of frovatriptan, the patient should be carefully monitored for at least 48 hours and any necessary supportive treatment given.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: selective 5-HT1 receptor agonist

(N: central nervous system)

ATC code: NO2C C07

Frovatriptan is a selective 5-HT receptor agonist, showing high affinity for 5-HT1B and 5-HT1D binding sites in radioligand assays and exhibiting potent agonist effects on 5-HT1B and 5-HT1D receptors in functional biological assays. It exhibits marked selectivity for 5-HT1B / 1D receptors and has no significant affinity for 5-HT2, 5-HT3, 5-HT4, 5-HT6, a-adrenergic or histamine receptors. Frovatriptan has no significant affinity for benzodiazepine binding sites.

Frovatriptan appears to act selectively on the extracerebral, intracranial arteries, inhibiting the excessive dilation of these vessels during migraine. At clinically active concentrations, frovatriptan produced constriction of isolated human cerebral arteries with little or no effect on isolated human coronary arteries.

The clinical efficacy of frovatriptan for the treatment of migraine headache and accompanying symptoms was studied in three placebo-controlled multicenter studies. In these studies, frovatriptan 2.5 mg was significantly superior to placebo both in terms of first response to headache, at 2 and 4 hours after administration, both in terms of time to initial response.

Pain relief (reduction in moderate-severe to mild headache or its disappearance) after 2 hours was 37-46% with frovatriptan and 21-27% with placebo.

Complete pain relief after 2 hours was 9-14% with frovatriptan and 2-3% with placebo.

The maximum efficacy of frovatriptan is reached in 4 hours.

In a clinical study comparing frovatriptan 2.5 mg with sumatriptan 100 mg, the efficacy of frovatriptan 2.5 mg at 2 and 4 hours was slightly lower than the efficacy of sumatriptan 100 mg. The incidence of undesirable effects was slightly lower with frovatriptan 2.5 mg compared to sumatriptan 100 mg.

No comparison study has been conducted between frovatriptan 2.5 mg and sumatriptan 50 mg.

In some healthy elderly subjects, transient changes in systolic blood pressure (within normal limits) have been reported following a single oral dose of 2.5 mg frovatriptan.

05.2 "Pharmacokinetic properties

Absorption

Following administration of a single 2.5 mg oral dose to healthy subjects, the mean maximum plasma concentrations of frovatriptan (Cmax), achieved between 2 and 4 hours, is 4.2 ng / mL in males and 7.0 ng / mL in females. The mean area under the curve (AUC) is 42.9 and 94.0 ng.h / mL for males and females, respectively.

The oral bioavailability is 22% in males and 30% in females.

The pharmacokinetics of frovatriptan are similar in healthy subjects and patients with migraine and there is no difference in pharmacokinetic parameters in patients during the migraine crisis or in the period between attacks.

Frovatriptan generally exhibits linear pharmacokinetics over the dose range used in clinical studies (1 mg to 40 mg).

Food has no significant effect on the bioavailability of frovatriptan, but slightly delays tmax by approximately 1 hour.

Distribution

The equilibrium volume of distribution of frovatriptan following intravenous administration of 0.8 mg is 4.2 L / kg in males and 3.0 L / kg in females.

Serum protein binding of frovatriptan is low (approximately 15%). Reversible binding to blood cells in equilibrium is approximately 60% with no difference between males and females.

The blood: plasma ratio is approximately 2: 1 in equilibrium conditions.

Biotransformation

After oral administration of 2.5 mg radiolabelled frovatriptan to healthy male subjects, 32% of the dose was recovered in the urine and 62% in the faeces. The radiolabelled compounds excreted in the urine consist of unchanged frovatriptan, hydroxy-frovatriptan, N-acetyl-demethyl-frovatriptan, hydroxy-N-acetyl-demethyl-frovatriptan, and demethyl-frovatriptan, along with various other minor metabolites. Demethyl-frovatriptan has approximately three times lower affinity for 5-HT1 receptors than the parent compound. N-acetyl-demethyl frovatriptan has negligible affinity for 5-HT1 receptors. The activity of other metabolites has not been studied.

The results of in vitro studies demonstrated that CYP1A2 is the cytochrome P450 isoenzyme primarily involved in the metabolism of frovatriptan. In vitro frovatriptan does not inhibit or induce CYP1A2.

Frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes or cytochrome P450 isoenzymes and therefore has minimal potential for interaction with other medicinal products. (see 4.5 Interactions with other medicinal products and other forms of interaction). Frovatriptan is not a substrate for MAO.

Elimination

Elimination of frovatriptan is biphasic with a distribution phase prevalent between 2 and 6 hours. The mean systemic clearance is 216 and 132 mL / min in males and females, respectively. Renal clearance is 38% (82 mL / min) and 49% (65 mL / min) of the total clearance in males and females, respectively.

The terminal elimination half-life is approximately 26 hours, regardless of the sex of the subjects. However, the terminal elimination phase becomes dominant only after approximately 12 hours.

Sex

Frovatriptan AUC and Cmax values are lower (approximately 50%) in males than in females. This is due, at least in part, to the concomitant use of oral contraceptives. Based on the efficacy or safety of the 2.5 mg dose in clinical use, no dose adjustment is necessary according to gender (see 4.2 Posology and method of administration).

Senior citizens

In healthy elderly subjects (65 to 77 years) the AUC increases by 73% in males and 22% in females, compared to young subjects (18 to 37 years). There is no difference in tmax or t½ between the two populations (see 4.2 Posology and method of administration).

Kidney failure

The systemic exposure to frovatriptan and its t½ are not significantly different in male and female subjects with renal insufficiency (creatinine clearance 16-73 mL / min) compared to healthy subjects.

Hepatic insufficiency

Following oral administration in male and female subjects 44 to 57 years of age with mild or moderate hepatic impairment (Child-Pugh class A and B), mean blood concentrations of frovatriptan remained within the limits observed for healthy young and healthy subjects. Senior citizens. There are no pharmacokinetic or clinical studies with frovatriptan in subjects with severe hepatic impairment (see 4.3 Contraindications).

05.3 Preclinical safety data

During single and repeated dose toxicity studies, preclinical effects were observed only at exposure levels in excess of the maximum human exposure level.

Standard genotoxicity studies did not reveal any genotoxic potential of frovatriptan.

Frovatriptan showed an embryotoxic effect in mice. In rabbits, a foetotoxic effect was observed only at maternally toxic doses.

Frovatriptan was not potentially carcinogenic in standard rodent carcinogenicity studies and in p53 (+/-) mouse studies at exposure levels considerably higher than expected in humans.