Mylatrip 2.5mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Frovatriptan succinate monohydrate
Available from:
Mylan
ATC code:
N02CC07
INN (International Name):
Frovatriptan succinate monohydrate
Dosage:
2.5mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04070401; GTIN: 5016695006789
Authorization number:
PL 04569/1335

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PACKAGE LEAFLET

Package leaflet: Information for the patient

Mylatrip 2.5 mg film-coated tablets

frovatriptan

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even

if their signs of illness are the same as yours

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What Mylatrip is and what it is used for

What you need to know before you take Mylatrip

How to take Mylatrip

Possible side effects

How to store Mylatrip

Contents of the pack and other information

1.

What Mylatrip is and what it is used for

Mylatrip contains the active ingredient frovatriptan which belongs to a group of medicines called triptans.

Mylatrip is used to treat migraine headache in adults.

Migraine symptoms may be caused by the widening of blood vessels in the head. Mylatrip is

thought to reduce the widening of these blood vessels. This helps to take away the headache and

other symptoms of a migraine attack, such as feeling or being sick (nausea or vomiting) and being

sensitive to light and sound.

Mylatrip works only when a migraine headache has started. You should not take Mylatrip to prevent

migraines occuring.

2.

What you need to know before you take Mylatrip

Do not take Mylatrip

if you are allergic to frovatriptan or any of the other ingredients of this medicine (listed in section 6).

if you have moderately high or very high blood pressure or mild high blood pressure that is not being

treated.

if you have or have had heart disease, a heart attack, angina (chest pain as a result of lack of oxygen in

the heart muscle) or other signs of coronary heart disease such as breathlessness, extreme tiredness or

ankle swelling.

if you have peripheral vascular disease (narrowing of the vessels that carry blood to the legs and arms)

if you have had a stroke or if you have had the symptoms of a stroke, which only lasted a short time and

from which you made a complete recovery (transient ischaemic attack).

if you are taking medicines containing ergotamine or medicines similar to ergotamine to treat migraine

(including methysergide) or other triptans (see “Other medicines and Mylatrip” for further

information).

if you have severe problems with your liver.

Warnings and precautions

Talk to your doctor or pharmacist before taking Mylatrip if:

you are at a higher risk of heart disease for example if you are a heavy smoker or you use nicotine

replacement therapy. Your doctor should make additional checks especially if you are a woman after

menopause or a man older than 40 years old.

you have unusual forms of migraine caused by brain or eye problems

you are taking herbal medicines containing St John’s wort (side effects may be more frequent)

During treatment

If you get a serious allergic reaction when taking Mylatrip such as flushing of the skin, nettle rash, swelling

of the mouth, lips, tongue or throat causing difficulty breathing or swallowing, feeling sick (nausea) or being

sick (vomiting), collapse or unconsciousness stop taking this medicine and contact your doctor or go

immediately to the nearest hospital emergency department (see section 4 ‘Possible side effects’).

When taking Mylatrip, you may notice pain or a feeling of tightness in your chest and throat. If these

symptoms do not pass quickly, stop taking Mylatrip and tell your doctor immediately.

If you have frequent or daily headaches while taking this medicine, stop taking Mylatrip and contact your

doctor. Using painkillers to treat headaches for longer than normal can make the headaches worse.

Children and adolescents

Mylatrip should not be given to children and adolescents under the age of 18 as it is not known how this

medicine may affect them.

Other medicines and Mylatrip

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

In particular, inform your doctor if you are taking:

Triptans other than frovatriptan (such as sumatriptan, almotriptan, eletriptan, naratriptan, rizatriptan or

zolmitriptan). Do not take these medicines at the same time as Mylatrip. After taking Mylatrip, leave 24

hours before taking other triptans as this may result in high blood pressure, narrowing of the blood

vessels of the heart or serotonin syndrome, a potentially life threatening drug reaction (see section 4

‘Possible side effects’).

Ergotamine or medicines similar to ergotamine (used to treat migraines including methysergide and

methylergometrine). Do not take these medicines at the same time as Mylatrip as this may also result in

high blood pressure, narrowing of the veins of the heart or serotonin syndrome. Wait at least 24 hours

after taking Mylatrip before taking these medicines or similarly, wait at least 24 hours after taking these

medicines before taking Mylatrip.

Medicines for depression called selective serotonin re-uptake inhibitors (SSRIs) such as fluoxetine,

citalopram, fluvoxamine, paroxetine or sertraline) as this may result in high blood pressure, narrowing

of the blood vessels of the heart or serotonin syndrome.

St John’s wort (

Hypericum perforatum

), a herbal remedy used to treat depression, as this may result in

serotonin syndrome.

Medicines used to treat depression called monoamine oxidase inhibitors (MAOIs) such as

moclobemide, phenelzine, isacarboxazid and tranylcypromine as these may cause high blood pressure

or serotonin syndrome.

Oral contraceptives as these may increase the amount of frovatriptan in your body.

Pregnancy and breast-feeding

Pregnancy

Mylatrip is not recommended in pregnant women and in women of child bearing age who do not use

contraception unless clearly necessary as it is not known if it is safe to use.

Breast-feeding

Frovatriptan may be present in breast milk. Breast-feeding is not recommended unless necessary, in which

case avoid breast-feeding for 24 hours after taking Mylatrip.

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.

Driving and using machines

This medicine and the migraine itself may make you feel drowsy. Do not drive or operate machinery if you

feel drowsy, are affected by a migraine attack or after taking Mylatrip.

Mylatrip contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before

taking this medicine.

3.

How to take Mylatrip

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or

pharmacist if you are not sure.

The recommended dose is 2.5 mg to treat a migraine attack. Take this medicine as soon as possible after you

start to get a headache. Do not take this medicine before you start to have a headache.

If the symptoms of migraine return within 24 hours, you may take a second dose of Mylatrip. The second

dose should not be taken within 2 hours of your first dose.

You should not take more than 2 doses of Mylatrip a day. The maximum daily dose is 5 mg Mylatrip in 24

hours.

The tablets should be swallowed whole and with water. You can take this medicine with or without food as

it does not affect the way the medicine works.

Use in older patients (over 65 years)

The use of Mylatrip is not recommended.

Patients with liver problems

Do not take Mylatrip if you have serious liver problems (see section 2 ‘Do not take Mylatrip’).

If you take more Mylatrip than you should

Contact your doctor or nearest hospital casualty department immediately. Take the container and any

remaining tablets with you.

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

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Contact your doctor immediately or go to your nearest hospital emergency department if you get the

following:

Rare

(may affect up to 1 in 1,000 people):

Burning stomach pain, usually immediately or 1 to 2 hours after eating. This may be a sign of an

ulcer in the stomach or upper part of the small intestine

Not known

(frequency cannot be estimated from the available data):

Serious allergic reactions such as flushing of the skin, nettle rash, swelling of the mouth, lips,

tongue or throat causing difficulty breathing or swallowing, feeling sick (nausea) or being sick

(vomiting), collapse or unconsciousness

Sudden chest pain that may spread to the neck or arms with a clammy feeling or a shortness of

breath. These may be signs of a heart attack (myocardial infarction)

A pressing, tight or heavy sensation on your chest with chest pain that lasts for a short period of

time. These may be signs of a temporary narrowing of the blood vessels of the heart (coronary artery

spasm)

Other possible side effects include:

Common (may affect up to 1 in 10 people):

Dizziness, headache, abnormal or lack of feeling when touching, tingling, pins and needles in the

fingers or toes, sleepiness

Warm sensation (flushing)

Problems with your sight

Increased sweating

Stomach pain, feeling sick (nausea), indigestion problems, dry mouth

Tiredness, chest discomfort, tightness in the throat

Uncommon side effects (may affect up to 1 in 100 people)

Change in sense of taste, trembling, poor concentration, lethargy, increased sensitivity to touching,

twitching muscles

Diarrhoea, difficulty in swallowing, wind, stomach upset, bloated stomach

Fast heartbeat that feels like a thumping in your chest (palpitations), increased heartbeat, chest pain

Coldness in feet and hands

Feeling hot, reduced tolerance of heat and cold, pain, weakness, thirst, sluggishness, increased

energy, general feeling of being unwell

Foggy head or feeling lightheaded, with a sensation of spinning when sitting or standing (vertigo)

Anxiety, inability to sleep, confusion, nervousness, agitation, depression, loss of sense of personal

identity

Runny or stuffy nose, possibly with pain or tenderness in the face, sore throat

Muscle or joint stiffness, muscle or joint pain, pain in the hands and feet, back pain

Pain in the eye, eye irritation, painful oversensitivity to light

Itchiness

Ringing in the ears, earache

Dehydration

Passing abnormally large amounts of urine; urinating more frequently

Increase in blood pressure

Rare side effects (may affect up to 1 in 1,000 people)

An increase or decrease in muscle tone, delay in reflexes, movement problems

Constipation, belching, heartburn, irritable bowel syndrome, lip blisters, lip pain, spasm of the food

pipe, blisters in the mouth, pain in the salivary gland, redness, irritation or swelling of the mouth,

toothache

Fever

Loss of memory, abnormal dreams, changes to your personality

Nosebleed, hiccups, very quick shallow breathing (hyperventilation), other breathing problems, sore

throat

Night blindness

Skin reddening, sensation of hairs standing on end, purplish spots or patches on skin and mucous

surfaces of the body, hives

Slow heart beat

Ear discomfort, earache, ear itchiness, sensitive hearing

Increase in bilirubin (a substance produced in the liver) in the blood or a decrease of calcium in the

blood which can be seen in a blood test, abnormal urine test results

Low sugar in the blood

Passing urine frequently at night, pain in the kidneys

Self-inflicted injury (bite)

Swollen lymph nodes

Breast tenderness

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 Yellow Card Scheme at

www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the

safety of this medicine.

5.

How to store Mylatrip

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 after ‘EXP’. The expiry date

refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Mylatrip contains

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

The other ingredients are

:

Tablet core: anhydrous lactose (see section 2 ‘Mylatrip contains lactose’), microcrystalline

cellulose, sodium starch glycolate (type A), magnesium stearate and colloidal anhydrous silica

Film-coating: hypromellose, titanium dioxide (E 171), macrogol 8000, macrogol 400.

What Mylatrip looks like and contents of the pack

The tablets are white to off white, film-coated, round tablets with two sides that curve out marked with “M”

on one side of the tablet and “FR” over “2.5” on the other side.

Mylatrip is available in blister packs containing 2, 6 and 12 film-coated tablets and in perforated blister

packs containing 2 x 1, 6 x 1 and 12 x 1 film-coated tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Mylan, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom

Manufacturers

Gerard Laboratories, 35/36 Baldoyle Industrial Estate, Grange Road, Dublin 13, Ireland

Mylan Hungary Kft, H-2900 Komárom, Mylan utca 1, Hungary

This leaflet was last revised in October 2015.

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Object 1

Mylatrip 2.5 mg film-coated tablets

Summary of Product Characteristics Updated 25-Sep-2017 | Generics UK T/A Mylan

1. Name of the medicinal product

Mylatrip 2.5 mg film-coated tablets

2. Qualitative and quantitative composition

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

Excipient with known effect:

Each film-coated tablet contains 107.09 mg lactose.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet

White to off white, film-coated, round, biconvex tablet debossed with “M” on one side of the tablet “FR”

over “2.5” on the other side.

4. Clinical particulars

4.1 Therapeutic indications

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

Frovatriptan is indicated in adults.

4.2 Posology and method of administration

Posology

Frovatriptan should be taken as early as possible after the onset of a migraine attack but it is also effective

when taken at a later stage. Frovatriptan should not be used prophylactically.

If a patient does not respond to the first dose of frovatriptan, a second dose should not be taken for the

same attack, since no benefit has been shown. Frovatriptan may be used for subsequent migraine attacks.

Adults (18 to 65 years of age)

The recommended dose of frovatriptan is 2.5 mg.

If the migraine recurs after initial relief, a second dose may be taken, providing there is an interval of at

least 2 hours between the two doses.

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

Paediatric population (under 18 years)

The safety and efficacy of frovatriptan in children and adolescents below the age of 18 years have not

been established. Therefore, its use in this age group is not recommended. No data are available.

Older people (over 65 years)

Frovatriptan data in patients over 65 years remain limited. Therefore, its use in this category of patients is

not recommended.

Renal impairment

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

Hepatic impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment (see section 5.2).

Frovatriptan is contraindicated in patients with severe hepatic impairment (see section 4.3).

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Patients with a history of myocardial infarction, ischaemic heart disease, coronary vasospasm (e.g.

Prinzmetal's angina), peripheral vascular disease, patients presenting with symptoms or signs compatible

with ischaemic heart disease.

- Moderately severe or severe hypertension, uncontrolled mild hypertension.

- Previous cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

- Severe hepatic impairment (Child-Pugh C).

- Concomitant administration of frovatriptan with ergotamine or ergotamine derivatives (including

methysergide) or other 5-hydroxytryptamine (5-HT

) receptor agonists.

4.4 Special warnings and precautions for use

Frovatriptan should only be used where a clear diagnosis of migraine has been established.

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

As with other treatments of migraine attack, it is necessary to exclude other, potentially serious,

neurological conditions before treating the headache of patients without a previous diagnosis of migraine,

or migraine patients presenting with atypical symptoms. It should be noted that migraineurs present an

increased risk of certain cerebral vascular events (e.g. CVA or TIA).

The safety and efficacy of frovatriptan administered during the aura phase, before the headache phase of

migraine, has not been established.

As with other 5-HT

receptor agonists, frovatriptan must not be administered to patients at risk of

coronary artery disease (CAD), including heavy smokers or users of nicotine substitution therapy without

a prior cardiovascular evaluation (see section 4.3). Specific attention should be given to post- menopausal

women and men over 40 years of age presenting with these risk factors.

However, cardiac evaluations may not identify every patient who has cardiac disease. In very rare cases

serious cardiac events have occurred in patients with no underlying cardio-vascular disease when taking

5-HT

receptor agonists.

Frovatriptan administration can be associated with transient symptoms including chest pain or 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 doses of frovatriptan

should be taken and additional investigations should be carried out.

Patients should be informed of the early signs and symptoms of hypersensitivity reactions including

cutaneous disorders, angioedema and anaphylaxis (see section 4.8). In case of serious allergic /

hypersensitivity reactions, frovatriptan treatment should be discontinued immediately and it should not be

administered again.

It is advised to wait 24 hours following the use of frovatriptan before administering an ergotamine- type

medication. At least 24 hours should be elapse after administration of an ergotamine-containing

preparation before frovatriptan is given (see sections 4.3 and 4.5).

In case of too frequent use (repeated administration several days in a row corresponding to a misuse of

the product), the active substance can accumulate leading to an increase of the side-effects.

Prolonged use of any type of 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

possibility of Medication Overuse Headache (MOH) should be taken into consideration in patients who

have frequent or daily headaches despite (or because of) the regular use of headache medications.

Do not exceed the recommended dose of frovatriptan.

Undesirable effects may be more common during concomitant use of triptans (5HT agonists) and herbal

preparations containing St John's wort (Hypericum perforatum).

Mylatrip contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp

lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use contraindicated

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

Risks of hypertension and coronary artery constriction due to additive vasospastic effects when used

concomitantly for the same migraine attack (see section 4.3).

Effects can be additive. It is recommended to wait at least 24 hours after administration of ergotamine-

type medication before administering frovatriptan. Conversely it is recommended to wait 24 hours after

frovatriptan administration before administering an ergotamine-type medication (see section 4.4).

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 section 5.2).

Concomitant use requiring caution

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

Potential risk of hypertension, coronary vasoconstriction or serotonin syndrome.

Strict adherence to the recommended dose is an essential factor to prevent this syndrome.

Methylergometrine

Risks of hypertension, coronary artery constriction.

Fluvoxamine

Fluvoxamine is a potent inhibitor of cytochrome CYP1A2 and has been shown to increase the blood

levels of frovatriptan by 27-49%.

Oral contraceptives

In female subjects taking oral contraceptives, concentrations of frovatriptan were 30% higher than in

females not taking oral contraceptives. No increased incidence in the adverse event profile was reported.

Hypericum perforatum (St. John's wort) (oral route)

As with other triptans the risk of the occurence of serotonin syndrome may be increased.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is

unknown. Frovatriptan is not recommended during pregnancy and in women of child bearing potential

not using contraception unless clearly necessary.

Breast-feeding

Frovatriptan and/or its metabolites are excreted in the milk of lactating rats with the maximum

concentration in milk being four-fold higher than maximum blood levels. A risk to the breast-feeding

newborns/infants cannot be excluded.

Although it is not known whether frovatriptan or its metabolites are excreted in human breast milk, the

administration of frovatriptan to women who are breastfeeding is not recommended, unless is clearly

needed. In this case, a 24 hours interval must be observed.

4.7 Effects on ability to drive and use machines

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

Migraine or treatment with frovatriptan may cause somnolence. Patients should be advised to evaluate

their ability to perform complex tasks such as driving during migraine attacks and following

administration of frovatriptan.

4.8 Undesirable effects

Frovatriptan has been administered to over 2700 patients at the recommended dose of 2.5 mg and the

most common side effects (<10%) include dizziness, fatigue, paraesthesia, headache and vascular

flushing. The undesirable effects reported in clinical trials with frovatriptan were transient, generally mild

to moderate and resolved spontaneously. Some of the symptoms reported as undesirable effects may be

associated symptoms of migraine.

The table below shows all the adverse reactions that are considered to be related to treatment with 2.5 mg

frovatriptan and showed a greater incidence than with placebo in the 4 placebo controlled trials. They are

listed in decreasing incidence by body-system. Adverse reactions collected in the post-marketing

experience are noted with an asterisk *.

System organ

class

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

<1/10,0

00

Not known

(cannot be

estimated from

the available

data)

Blood and

lymphatic

system disorders

Lymphadenopathy

Immune system

disorders

Hypersensitivit

y reactions*

(including

cutaneous

disorders,

angioedema and

anaphylaxis)

Metabolism and

nutrition

disorders

Dehydration,

Hypoglycaemia

Psychiatric

disorders

Anxiety,

insomnia,

confusional

state,

nervousness,

agitation,

depression,

depersonalisatio

Abnormal dreams,

personality

disorder

Nervous system

disorders

Dizziness,

paraesthesia,

headache,

somnolence,

dysaesthesia,

hypoaesthesia

Dysgeusia,

tremor,

disturbance in

attention,

lethargy,

hyperaesthesia,

sedation,

vertigo,

involuntary

muscle

contractions

Amnesia,

Hypertonia,

Hypotonia,

hyporeflexia,

movement

disorder

Eye disorders

Visual

disturbance

Eye pain, eye

irritation,

photophobia

Night blindness

Ear and labyrinth

disorders

Tinnitus, ear

pain

Ear discomfort,

ear disorder, ear

pruritus,

hyperacusis

Cardiac

disorders

Palpitations,

tachycardia

Bradycardia

Myocardial

infarction*,

arteriospasm

coronary*

Vascular

disorders

Flushing

Peripheral

coldness,

Hypertension

Respiratory,

thoracic and

mediastinal

disorders

Throat

tightness

Rhinitis,

sinusitis,

pharyngolaryng

eal pain

Epistaxis, hiccups,

hyperventilation,

respiratory

disorder, throat

irritation

Gastrointestinal

disorders

Nausea, dry-

mouth,

dyspepsia,

abdominal

pain

Diarrhoea,

dysphagia,

flatulence,

stomach

discomfort,

abdominal

distension

Constipation,

eructation, gastro-

oesophageal reflux

disease, irritable

bowel syndrome,

lip blister, lip pain,

oesophageal

spasm, oral

mucosal blistering,

peptic ulcer,

salivary gland

pain, stomatitis,

toothache

Skin and

subcutaneous

tissue disorders

Hyperhidrosis

Pruritus

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, renal

pain

Reproductive

system and

Breast tenderness

breast disorders

General

disorders and

administration

site conditions

Fatigue, chest

discomfort

Chest pain,

feeling hot,

temperature

intolerance,

pain, asthaenia,

thirst,

sluggishness,

energy

increased,

malaise

Pyrexia

Investigations

Blood bilirubin

increased, blood

calcium decreased,

urine analysis

abnormal

Injury, poisoning

and procedural

complications

Bite

In two open long-term clinical studies the observed effects were not different from those listed above.

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 Yellow Card Scheme at

www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

There is limited data on overdose with frovatriptan tablets. The maximum single oral dose of frovatriptan

given to male and female patients with migraine was 40 mg (16 times the recommended clinical dose of

2.5 mg) and the maximum single dose given 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, one post-marketing serious case of coronary vasospasm has been reported,

following intake of 4 times the recommended dose of frovatriptan on three consecutive days, in a patient

taking migraine prophylactic treatment with a tricyclic antidepressant. The patient recovered.

Treatment

There is no specific antidote for frovatriptan. The elimination half-life of frovatriptan is approximately 26

hours (see section 5.2.).

The effects of haemodialysis or peritoneal dialysis on serum concentrations of frovatriptan are unknown.

In case of overdose with frovatriptan, the patient should be monitored closely for at least 48 hours and be

given any necessary supportive therapy

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, antimigraine preparations, selective serotonin (5HT

) agonists.

ATC code: N02CC07

Frovatriptan is a selective agonist for 5-HT receptors, which shows high affinity for 5-HT

and 5-HT

binding sites in radioligand assays and exhibits potent agonist effects at 5-HT

and 5-HT

receptors in

functional bioassays. It exhibits marked selectivity for 5-HT

receptors and has no significant affinity

for 5-HT

, 5-HT

, 5-HT

, 5-HT

, α- adrenoreceptors, or histamine receptors. Frovatriptan has no

significant affinity for benzodiazepine binding sites.

Frovatriptan is believed to act selectively on extracerebral, intracranial arteries to inhibit the excessive

dilatation of these vessels in migraine. At clinically relevant concentrations, frovatriptan produced

constriction of human isolated cerebral arteries with little or no effect on isolated human coronary

arteries.

The clinical efficacy of frovatriptan for treatment of migraine headache and accompanying symptoms was

investigated in three multicenter placebo controlled studies. In these studies frovatriptan 2.5 mg was

consistently superior to placebo in terms of headache response at 2 and 4 hours post-dosing and time to

first response. Pain relief (reduction from moderate-or severe headache to no or mild pain) after 2 hours

was 37-46% for frovatriptan and 21-27% for placebo.

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

with 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 was slightly lower than that of sumatriptan 100 mg at 2 hours and 4 hours. The frequency of

undesirable events was slightly lower with frovatriptan 2.5 mg compared to sumatriptan 100 mg. No

study comparing frovatriptan 2.5 mg and sumatriptan 50 mg has been carried out.

In elderly subjects in good health, transient changes in systolic arterial pressure (within normal limits)

have been observed in some subjects, following a single oral dose of frovatriptan 2.5 mg.

5.2 Pharmacokinetic properties

Absorption

After administration of a single oral 2.5 mg dose to healthy subjects, the mean maximum blood

concentration of frovatriptan (C

), reached between 2 and 4 hours, was 4.2 ng/ml in males and 7.0

ng/mL in females. The mean area under the curve (AUC) was 42.9 and 94.0 ng.h/ml for males and

females respectively.

The oral bioavailability was 22% in males and 30% in females. The pharmacokinetics of frovatriptan

were similar between healthy subjects and migraine patients and there was no difference in

pharmacokinetic parameters in the patients during a migraine attack or between attacks.

Frovatriptan displayed generally linear pharmacokinetics over the dose range used in clinical studies (1

mg to 40 mg).

Food had no significant effect on the bioavailability of frovatriptan, but delayed t

slightly by

approximately 1 hour.

Distribution

The steady state volume of distribution of frovatriptan following intravenous administration of 0.8 mg

was 4.2 L/kg in males and 3.0 L/kg in females.

Binding of frovatriptan to serum proteins was low (approximately 15%). Reversible binding to blood cells

at steady state was approximately 60% with no difference between males and females. The blood : plasma

ratio was about 2:1 at equilibrium.

Biotransformation

Following oral administration of radiolabelled frovatriptan 2.5 mg to healthy male subjects, 32% of the

dose was recovered in urine and 62% in faeces. Radiolabelled compounds excreted in urine were

unchanged frovatriptan, hydroxy frovatriptan, N-acetyl desmethyl frovatriptan, hydroxy N-acetyl

desmethyl frovatriptan, and desmethyl frovatriptan, together with several other minor metabolites.

Desmethyl frovatriptan had about 3-fold lower affinity at 5-HT

receptors than the parent compound. N-

acetyl desmethyl frovatriptan had negligible affinity at 5-HT

receptors. The activity of other metabolites

has not been studied.

The results of in vitro studies have provided strong evidence that CYP1A2 is the cytochrome P450

isoenzyme primarily involved in the metabolism of frovatriptan. Frovatriptan does not inhibit or induce

CYP1A2 in vitro.

Frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes or cytochrome P450

isozymes and therefore has little potential for drug-drug interactions (see section 4.5). Frovatriptan is not

a substrate for MAO.

Elimination

The elimination of frovatriptan is biphasic with a distribution phase prevailing between 2 and 6 hours.

Mean systemic clearance was 216 and 132 ml/min in males and females, respectively. Renal clearance

accounted for 38% (82 ml/min) and 49% (65 ml/min) of total clearance in males and females,

respectively. The terminal elimination half-life is approximately 26 hours, irrespective of the sex of the

subjects, however the terminal elimination phase only becomes dominant after about 12 hours.

Gender

AUC and C

values for frovatriptan are lower (by 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, dosage adjustment with respect to gender is not necessary (see section 4.2).

Older people

In healthy elderly subjects (65 to 77 years) AUC is increased by 73% in males and by 22% in females,

compared to younger subjects (18 to 37 years). There was no difference in t

or t

between the two

populations (see 4.2 Posology and method of administration).

Renal impairment

Systemic exposure to frovatriptan and its t

were not significantly different in male and female subjects

with renal impairment (creatinine clearance 16 - 73 ml/min), compared to that in healthy subjects.

Hepatic impairment

Following oral administration in male and female subjects aged 44 to 57, with mild or moderate hepatic

impairment (Child-Pugh grades A and B), mean blood concentrations of frovatriptan were within the

range observed in healthy young and elderly subjects. There is no pharmacokinetic or clinical experience

with frovatriptan in subjects with severe hepatic impairment (see section 4.3).

5.3 Preclinical safety data

During toxicity studies after single or repeated administration, preclinical effects were only observed at

exposure levels in excess of the maximum exposure level in man.

Standard genotoxicity studies did not reveal a clinically relevant genotoxic potential of frovatriptan.

Frovatriptan was foetotoxic in rats, but in rabbits foetotoxicity was observed only at maternally toxic dose

levels.

Frovatriptan was not potentially carcinogenic in standard rodent carcinogenicity studies and in p53 (+/-)

mouse studies at exposures considerably higher than anticipated in humans.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core:

Lactose, anhydrous

Cellulose microcrystalline

Sodium starch glycolate (type A)

Magnesium stearate

Silica, colloidal anhydrous

Film-coating:

Hypromellose

Titanium dioxide (E 171)

Macrogol 8000

Macrogol 400

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

OPA/Alu/PVC blisters in pack sizes of 2, 6 and 12 film-coated tablets.

OPA/Alu/PVC – aluminium perforated unit dose blisters in pack sizes of 2 x 1, 6 x 1, 12 x 1 film-coated

tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Generics [UK] Ltd. t/a Mylan

Potters Bar, Hertfordshire, EN6 1TL, United Kingdom

8. Marketing authorisation number(s)

PL 04569/1335

9. Date of first authorisation/renewal of the authorisation

20/03/2013

10. Date of revision of the text

15/10/2015

Company Contact Details

Generics UK T/A Mylan

Address

Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL

Telephone

+44 (0)1707 853 000

Medical Information Direct Line

+44 (0)1707 853 000

Customer Care direct line

+44 (0)1707 853 000 select option 2

Stock Availability

+44 (0)1707 853 000 select option 2

http://www.mylan.com

+44 (0)1707 261 803

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)1707 261 803

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