Cafergot

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Caffeine 100 mg (anhydrous); Ergotamine tartrate 1 mg;  ;  
Available from:
AFT Pharmaceuticals Ltd
INN (International Name):
Caffeine 100 mg (anhydrous)
Dosage:
100 mg/1 mg
Pharmaceutical form:
Tablet
Composition:
Active: Caffeine 100 mg (anhydrous) Ergotamine tartrate 1 mg     Excipient: Iron oxide yellow Magnesium stearate Microcrystalline cellulose Purified talc Starch Tartaric acid
Units in package:
Bottle, glass, 100-tablet amber glass, 100 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Siegfried PharmaChemikalien Minden GmbH
Therapeutic indications:
Treatment of acute attacks of migraine with or without aura in adults.
Product summary:
Package - Contents - Shelf Life: Bottle, glass, Amber glass - 100 tablets - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-2856
Authorization date:
1969-12-31

Cafergot

Ergotamine tartrate 1 mg and Caffeine 100 mg Tablets

What is in this leaflet

Please read this leaflet carefully before you start taking Cafergot.

This leaflet answers some common questions about Cafergot tablets

It does not contain all the available information. It does not take the place of talking to

your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you

using Cafergot against the benefits it can provide.

If you have any concerns about Cafergot, ask your doctor or pharmacist. Keep this

leaflet with the medicine. You may need to read it again.

What Cafergot is used for

Cafergot is used to treat attacks of migraine with or without aura.

These headaches are thought to be caused by temporary changes in the size of small

blood vessels in the brain. These blood vessels swell, causing the pain and visual

disturbances that often happen during an attack. Cafergot stops the attack by causing

the blood vessels to constrict (shrink) back to normal size.

Cafergot is only taken to treat migraine attacks. It is not taken to prevent attacks from

happening.

There are some types of headaches which must not be treated with Cafergot. Your

doctor will determine the best treatment for your headache.

Cafergot tablets contain the active ingredients, ergotamine tartrate and caffeine.

Ergotamine belongs to a group of medicines known as the "ergot alkaloids." Caffeine

helps ergotamine work better and faster by increasing its absorption into the body.

Ask your doctor if you have any questions about why Cafergot has been prescribed

for you.

Your doctor may have prescribed Cafergot for another reason.

Cafergot is only available with a doctor's prescription.

There is not enough information to recommend this medicine for children under 6 years

of age.

Before you take Cafergot

When you must not take Cafergot

Do not take Cafergot if you have ever had an allergic reaction to any of the

following:

ergotamine or caffeine, the active ingredients in Cafergot tablets

any of the other ingredients listed at the end of this leaflet

any other ergot alkaloids (e.g. Ergodryl

, Ergometrine

, Syntometrine

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing

or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash,

itching or hives on the skin.

Do not take Cafergot if you have any of the following health problems/medical

conditions:

problems with your heart, especially if you have angina that is not controlled or

you have had a heart attack

high blood pressure that is not controlled

severe liver or kidney disease

poor blood circulation or other blood vessel disorders (e.g. varicose veins, fluid

buildup in legs or feet, or conditions that make your fingers and toes unusually

sensitive to cold)

you are being treated with mexiletine (a medicine for irregular heartbeats)

you are being treated with fluvoxamine ( a medicine for mental disorder)

you are being treated for cough and cold or increased weight with medicines such

as phenylephrine, amphetamine, cocaine or phentermine

a serious infection

you are being treated for HIV/AIDS with a medicine called ritonavir, nelfinavir,

indinavir or delavirdine

you are taking a contraceptive pill to prevent pregnancy

you are being treated for an infection with a medicine called ketoconazole,

itraconazole,

erythromycin,

clarithromycin,

quinupristin,

dalfopristim,

ciprofloxacin, norfloxacin

When previously treated with ergotamine derivative, if you had developed scarring and

thickening of any of the following: the abdominal cavity, lungs tissue or lining that

surrounds the lungs, heart tissue or lining that surrounds the heart, do not take this

medicine.

Do not take Cafergot if you are pregnant or intend to become pregnant.

This medicine may affect your developing baby if you take it while you are pregnant.

Do not breast-feed if you are using Cafergot.

The active ingredients in Cafergot may pass into breast milk and may affect your baby.

Do not take Cafergot after the expiry date printed on the pack or if the packaging is

torn or shows signs of tampering.

In that case, return it to your pharmacist.

Before you start to take Cafergot

Tell your doctor if you smoke.

Nicotine in cigarettes may increase the chance of you having an unwanted side effect

called "ergotism" (excessive constriction of blood vessels). See Side Effects section for

more information.

Tell your doctor if you are allergic to any other medicines, foods, dyes or

preservatives.

Your doctor will want to know if you are prone to allergies.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy

without a prescription from a pharmacy, supermarket or health food store. You

should also tell your health professional who is prescribing a new medication for

you that you are taking Cafergot.

Some medicines and Cafergot may interfere with each other. These include:

some medicines used to treat HIV/AIDS, including ritonavir, nelfinavir, indinavir,

delavirdine, saquinavir or nevirapine

some medicines for infections, including ketoconazole, itraconazole, fluconazole,

voriconazole,

clotrimazole,

rifampicin,

erythromycin,

clarithromycin,

troleandomycin, quinupristin, dalfopristim, ciprofloxacin, norfloxacin, ofloxacin

some medicines used to treat mental disorders, including nefazodone, fluoxetine,

fluvoxamine, amitriptyline, sertraline

zileuton, a medicine used to prevent asthma attacks

mexiletene, a medicine used to treat irregular heartbeats

other ergot alkaloids

oral contraceptives

other medicines used to treat migraine such as sumatriptan

nicotine in medicines used to help you quit smoking, such as nicotine patches or

chewing gum

some medicines for cough and cold or increased weight such as phenylephrine,

amphetamine, cocaine or phentermine

beta-blocker medicines such as propranolol, which are used to prevent migraine

and also to treat heart problems and high blood pressure

any other medicine that can cause blood vessels to contract (shrink).

You may need to take different amounts of your medicines or to take different

medicines while you are taking Cafergot. Your doctor and pharmacist have more

information.

If you have not told your doctor about any of these things, tell him/her before you

start taking Cafergot.

How to use Cafergot

Follow all directions given to you by your doctor and pharmacist carefully.

These directions may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or

pharmacist for help.

Adults

At the first sign of a migraine attack, swallow two Cafergot tablets.

This dose is usually enough to stop an attack but, if the migraine doesn't go away, you

can have another dose every half an hour to a maximum of 6 tablets in one day.

Do not take more than 6 tablets in one day.

Do not take more than 10 tablets in one week.

Children

At the first sign of a migraine attack, swallow one Cafergot tablet.

This dose is usually enough to stop an attack but, if the migraine doesn't go away, you

can have another dose every half an hour to a maximum of 3 tablets in one day.

Do not take more than 5 tablets in one week.

If you take too much Cafergot or if you take it too often, you may have an increased risk

of serious side effects such as "ergotism" or retroperitoneal or pleuropulmonary fibrosis

(see Side Effects section for more information). You may also have side effects such as

headaches, tiredness, runny nose and muscle pain when you stop using it.

Do not take sumatriptan, zolmitriptan or naratriptan or any medicine containing

ergot alkaloids (e.g. Dihydergot

®

or Ergodryl

®

) at the same time as you take

Cafergot.

If you wish to take one of these other medicines following a dose of Cafergot, your doctor

or pharmacist can advise you how long to wait before you take it.

Things you must do while taking Cafergot

If you become pregnant while using Cafergot, tell your doctor.

Your doctor can discuss with you the risks of using it while you are pregnant.

If you are about to be started on any new medicine, remind your doctor and

pharmacist that you are using Cafergot.

Tell any other doctor, dentist or pharmacist who treats you that you are using

Cafergot.

Things you must not do

Do not take Cafergot to prevent a migraine attack from happening.

This medicine should only be taken to treat a migraine once it has started.

Avoid drinking grapefruit juice while you are using Cafergot.

Grapefruit juice may interfere with the action of Cafergot in your body.

Do not give this medicine to anyone else, even if their condition seems similar to

yours.

Do not take it to treat any other complaints unless your doctor tells you to.

This medicine is not appropriate for common 'tension' headaches.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert

until you know how Cafergot affects you.

This medicine may

cause

dizziness or vertigo (spinning sensation) in some people.

Make sure you know how it affects you before you drive a car, operate machinery, or do

anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you

are taking Cafergot, even if you do not think it is connected with the medicine.

All medicines can have side effects. Sometimes they are serious, but most of the time

they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by these lists of possible side effects. You may not experience

any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Stop using Cafergot and tell your doctor immediately if you notice any of the

following:

signs of allergy such as rash, itching or hives on the skin; swelling of the face,

lips, tongue or other part of the body; wheezing or troubled breathing

signs of "ergotism" (excessive constriction of blood vessels) such as numbness,

coldness, tingling or a pale or bluish colour in the fingers or toes, pain or spasms

in muscles, chest pain

pain in the lower back or side, associated with difficulty in passing urine or pain

on urinating, which may be a sign of retroperitoneal fibrosis, a thickening of the

abdominal lining that can cause obstruction of the urinary tract

shortness of breath, dry cough, pain in the chest or rib area, which may be a sign

of pleuropulmonary fibrosis, a scarring and thickening of lung tissue

chest pain as this may be a sign of too little blood and oxygen getting to the heart

muscle or in rare cases, a heart attack.

you feel faint or look pale, which could be signs of shock

The above are serious side effects that need medical attention.

Tell your doctor if you notice any of the following and they worry you:

nausea (feeling sick) or vomiting

stomach pain

diarrhoea

dizziness

dull headaches

Intensifying headache with autonomic disturbances after Cafergot withdrawal

fast, slow or irregular heart beat

increase in your blood pressure

muscular pain or spasm

pain or weakness in your arms or legs

Tell your doctor if you notice anything else that is making you feel unwell.

Some people may have other side effects not yet known or mentioned in this leaflet.

Overdose

Immediately

telephone

your

doctor

or

the

National

Poisons

and

Hazardous

Chemicals Information Centre, Dunedin (telephone 0800 POISON OR 0800 764 766),

or go to the Accident and Emergency Department at your nearest hospital if you

think that you or anyone else may have taken too much Cafergot. Do this even if

there are no signs of discomfort or poisoning. Keep the telephone numbers for

these places handy.

Some of the symptoms of an overdose may include nausea, vomiting, fast heart-beat,

numbness or tingling in the fingers and toes, abnormal blue discoloration of the skin and

mucous membranes, weak pulse, dizziness, drowsiness, confusion, difficulty breathing,

low blood pressure, fits and coma.

Storage

Keep your medicine in the original container until it is time to take it.

Store it in a cool place where the temperature stays below 25°C.

Do not store Cafergot or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Keep this medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place

store medicines.

Disposal

If your doctor tells you to stop using Cafergot or the expiry date has passed, ask

your pharmacist what to do with any medicine that is left over.

Other ingredients

Cafergot tablets also contain the following inactive ingredients:

tartaric acid

magnesium stearic

purified talc

maize starch

cellulose, microcrystalline

iron oxide yellow (E172)

talc

If you want to know more

Talk to your doctor or pharmacist. They will be able to answer your questions.

Distributor

Cafergot is supplied in New Zealand by:

AFT Pharmaceuticals Ltd.

PO Box 33.203

Takapuna

AUCKLAND

Date of preparation: 13 February 2018

New Zealand Data Sheet

1

CAFERGOT (ERGOTAMINE TARTRATE 1 MG AND

CAFFEINE 100 MG TABLET)

CAFERGOT

ergotamine tartrate 1 mg and caffeine 100 mg tablet

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Ergotamine tartrate 1 mg and Caffeine 100 mg

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Cafergot tablets are round, flat with bevelled edge, 9 mm diameter, speckled

yellow/white, inscribed with a breakline and XL on one side and plain on the other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of acute attacks of migraine with or without aura in adults.

4.2

Dose and method of administration

Cafergot should be given at the first signs of a migraine attack.

Dose

Adults

First attack

The first time Cafergot is taken, an initial dose of 2 Cafergot tablets orally, is

recommended. If relief is not obtained within half an hour, a further tablet should be

administered; this may be repeated at half-hourly intervals, but the maximum daily dose

of 6 tablets should not be exceeded.

Subsequent attacks:

If the pain persists, take 1 tablet every half an hour up to the maximum daily dose of 6

tablets. The maximum weekly dose is 10 tablets.

Children under 18 years

Not recommended.

Maximum dose per attack or per day

Adults: 6 mg ergotamine tartrate = 6 tablets.

Maximum weekly dose

Adults: 10 mg ergotamine tartrate = 10 tablets.

Special populations

Renal impairment

Cafergot is contraindicated in patients with severe renal impairment (see

Contraindications).

Hepatic impairment

Cafergot is contraindicated in patients with severe hepatic impairment (see

Contraindications). Patients with mild to moderate hepatic impairment, especially

patients with cholestasis, should be appropriately monitored (see Warnings and

Precautions).

Pediatrics

Cafergot is not recommended in children and adolescents under the age of 18 years.

Safety and efficacy have not been established in pediatric patients.

Geriatrics

Cafergot is not recommended for patients aged over 65 years. No studies have been

performed in elderly patients (65 years age and above).

Method of administration

The following restriction must be observed

If supplementary antimigraine medication is required, the use of any ergotamine-

containing preparations, intranasal or parenteral dihydroergotamine or sumatriptan or

other 5HT

-receptor agonists must be avoided (see Contraindications).

Taking Cafergot repeatedly over extended periods must be avoided.

The concomitant use of an anti-emetic may enhance the action of the tablets.

4.3

Contraindications

Known hypersensitivity to ergot alkaloids, caffeine, or any other components of

the formulation

Pregnancy and breast-feeding

Impaired peripheral circulation, obliterative vascular disease, coronary heart

disease, inadequately controlled hypertension, septic conditions, shock

Severe renal impairment

Severe hepatic impairment

Temporal arteritis

Hemiplegic or basilar migraine

Concomitant treatment with cytochrome P450 3A4 (CYP3A4) inhibitors such as

macrolide

antibiotics

(all

except

spiramycin),

protease

reverse

transcriptase inhibitors and azole antifungals

Concomitant treatment with vasoconstrictor agents including ergot alkaloids,

sumatriptan, other 5HT

receptor agonists, nicotine (e.g. heavy smoking) and

sympathomimetics

Concomitant treatment with fluoroquinolones, mexiletine, fluvoxamine, and oral

contraceptives

modulate

metabolic

clearance

caffeine

consequently may translate to increase in absorption of ergotamine

Patients

developed

fibrosis

(retroperitoneal

fibrosis,

pleurisy,

pleural

effusion, pleural fibrosis, pericarditis, pericardial effusion or similar condition)

under previous treatment with an ergotamine derivative.

4.4

Special warnings and precautions for use

Cafergot is indicated only for the treatment of acute migraine attacks and not for

prevention.

Cardiovascular effects

Continued daily use of Cafergot or its use in excess of the recommended doses must be

avoided since this may cause vasospasm. If signs of vascular spasms are observed,

Cafergot should be discontinued and treatment with a peripheral vasodilator initiated.

Owing to its vasoconstrictor properties, ergotamine may cause myocardial ischaemia or,

in rare cases, infarction, even in patients with no known history of coronary heart

disease. If chest pain occurs treatment should be withdrawn.

Ergotism

Long-term use of ergotamine can cause ergotism, including severe cases of symptoms of

constriction of peripheral blood vessels, with possible fatal outcome.

To avoid the risk of ergotism patients who are being treated with Cafergot should be

informed of the maximum doses allowed and of the first symptoms of overdosage:

hypoaesthesia, paresthesia, e.g. numbness, tingling in the fingers and toes, non-

migraine-related nausea and vomiting, and symptoms of myocardial ischaemia e.g.

precordial pain. If symptoms such as tingling in the fingers or toes occur, the drug

should be discontinued at once and the physician consulted

Fibrotic complications

If, contrary to recommendations, ergotamine-containing drugs including Cafergot are

used excessively over years, they may induce fibrotic changes, including pleural,

retroperitoneal and pulmonary fibrosis. There have also been rare reports of fibrotic

changes of the cardiac valves.

Hepatic impairment

Patients with mild to moderate hepatic impairment, especially cholestatic patients should

be appropriately monitored.

Drug-induced headache

The occurrence of drug-induced headaches has been reported during prolonged and

uninterrupted treatment with Cafergot.

Visual disturbances

Cases with sudden and transient loss of vision have been reported in post-marketing use.

This adverse event may be related to vasospasm and ischaemic episodes. Patents should

stop using Cafergot immediately if they experience visual disturbances and seek medical

help.

4.5

Interaction with other medicines and other forms of interaction

Potent CYP3A4 inhibitors

The concomitant use of Cafergot with cytochrome P450 3A (CYP3A) inhibitors such as

macrolide antibiotics (e.g. troleandomycin, erythromycin, clarithromycin; except

spiramycin); HIV protease or reverse transcriptase inhibitors (e.g. amprenavir,

atazanavir, fosamprenavir, ritonavir, indinavir, lopinavir, nelfinavir, saquinavir,

tipranavir, delavirdine, efavirenz); or azole antifungals (e.g. ketoconazole, itraconazole,

voriconazole) must be avoided (see Contraindications). Concomitant use can result in an

elevated exposure to ergotamine and ergot toxicity (vasospasm and ischemia of the

extremities and other tissues). Ergot alkaloids have also been shown to be both inhibitors

and substrates of CYP3A.

Moderate/weak CYP3A4 inhibitors

Moderate to weak CYP3A4 inhibitors such as cimetidine, fluconazole, quinupristin/

dalfopristin, zileuton and grapefruit juice can also increase exposure to ergotamine and

caution is required for concomitant use.

No pharmacokinetic interactions between ergotamine and cytochrome P450 isoenzymes

are known.

Vasoconstrictors

Concurrent use of vasoconstrictor agents including preparations containing ergot

alkaloids (bromocriptine, cabergoline, pergolide, lisuride), sumatriptan and other 5HT1

receptor agonists (almotriptan, fovatriptan, naratriptan, rizatriptan, zolmitriptan,

eletriptan), nicotine (e.g. heavy smoking) and sympathomimetics must be avoided since

this may result in enhanced vasoconstriction, (see Contraindications). Allow 24 hours

between the discontinuation of the triptans and the use of the alkaloid.

CYP3A4 inducers

Drugs (e.g. nevirapine, rifampicin) inducing CYP3A4 can lead to decrease in

pharmacological action of ergotamine.

Beta-blockers

A few cases of vasospastic reactions have been reported among patients treated

concomitantly with ergotamine-containing preparations and propranolol.

Antidepressants

Some antidepressants such as fluoxetine, fluvoxamine or nefazodone may increase the

levels of the ergot derivatives. Concurrent use of ergotamine with serotonin reuptake

inhibitors (e.g. amitriptyline) including selective agents (e.g. sertraline) can lead to

serotonin syndrome, caution is required for concurrent use.

CYP1A2

Caffeine undergoes extensive metabolism by CYP1A2. Concurrent use with substances

like fluoroquinolones, mexiletine, fluvoxamine, oral contraceptives and

sympathomimetics, that can reduce CYP1A2 activity may modulate the metabolic

clearance of caffeine and consequently may translate to increase in absorption of

ergotamine, see Contraindications.

4.6

Fertility, pregnancy and lactation

Pregnancy

Category C

Cafergot is contraindicated during pregnancy because ergotamine has oxytocic and

vasoconstrictor effects on the placenta and umbilical cord.

In a reproductive performance study and a peri-/post-natal study in female rats, an

increased number of stillbirths and/or peri-/post-natal mortality were observed following

administration of oral ergotamine/caffeine (1:100). At high oral doses, ergotamine

induced fetal retardation in experimental animals. The observation has been attributed to

reduced uteroplacental blood flow.

Women with the potential to become pregnant must use effective birth control

throughout the treatment period.

Breastfeeding

Ergotamine and caffeine are excreted in breast milk. Ergotamine may cause symptoms

of vomiting, diarrhoea, weak pulse and unstable blood pressure in infants. Cafergot is

thus contraindicated in nursing mothers.

Fertility

In male rats receiving the combination of oral ergotamine and caffeine (1:100), fertility

was not impaired.

4.7

Effects on ability to drive and use machines

Patients experiencing dizziness, visual disturbance or impaired reactions, should not

drive or operate machinery.

4.8

Undesirable effects

The most common of all side-effects are nausea and vomiting. Depending on the dose of

ergotamine, signs and symptoms of vasoconstriction may occur.

Adverse reactions are listed by MedDRA system organ class and ranked under heading

of frequency, the most frequent first, using the following convention: very common (≥

1/10); common (≥1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, <

1/1,000), very rare (< 1/10,000), not known (frequency cannot be estimated from the

available data).

Immune system disorders

Rare: Hypersensitivity reactions

Nervous system disorders

Common: Dizziness

Uncommon: Paraesthesia (e.g. tingling) in fingers and toes, hypoaesthesia (e.g.

numbness)

Rare: Drowsiness

Not known: Somnolence, drug-induced headache, an intensifying headache with

autonomic disturbances occurs within 24-48 hours of ergotamine withdrawal and may

continue for 72 hours or longer. Headache is also a recognised symptom of caffeine

withdrawal.

Eye Disorders

Not known: Visual impairment

Ear and labyrinth disorders

Rare: Vertigo

Cardiac disorders

Uncommon: Cyanosis

Rare: Bradycardia, tachycardia

Very rare: Myocardial ischaemia, myocardial infarction

Not known: Endocardial fibrosis

Vascular disorders

Uncommon: Peripheral vasoconstriction

Rare: Hypertension

Very rare: Gangrene

Respiratory, thoracic and mediastinal disorders

Rare: Dyspnoea

Not known: Pleural fibrosis

Gastrointestinal disorders

Common: Nausea and vomiting (not migraine related), abdominal pain

Uncommon: Diarrhoea

Not known: Retroperitoneal fibrosis

Skin and subcutaneous tissue disorders

Rare: Rash, face oedema, urticaria

Musculoskeletal and connective tissue disorders

Uncommon: Pain in extremity, weakness in extremity

Rare: Myalgia, muscle spasms

Investigations

Rare: Pulse absent

Injury, poisoning and procedural complications

Rare: Ergot poisoning

Hypersensitivity reactions such as skin rash, face oedema, urticaria and dyspnoea.

Ergotism is defined as an intense arterial vasoconstriction, producing signs and

symptoms of peripheral vascular ischemia of the extremities and other tissues.

If ergotamine-containing drugs are used excessively over years, they may induce fibrotic

changes, in particular of the pleura and the retroperitoneum. There have also been rare

reports of fibrotic changes of the cardiac valves (see Special warnings and special

precautions). The occurrence of drug-induced headaches has been reported during

prolonged and uninterrupted treatment with Cafergot.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

professionals are asked to report any suspected adverse reactions

https://nzphvc.otago.ac.nz/reporting/

4.9

Overdose

Symptoms

Nausea, vomiting, drowsiness, confusion, tachycardia, dizziness, respiratory depression,

hypotension, convulsion, shock, coma, symptoms and complications of ergotism.

Ergotism is defined as an intense arterial vasoconstriction, producing signs and

symptoms of peripheral vascular ischemia of the extremities such as numbness, tingling

and pain in the extremities, cyanosis, absence of pulse and if the condition is allowed to

progress untreated, gangrene may result. Furthermore ergotism can also involve signs

and symptoms of vascular ischemia of other tissues such as renal or cerebral vasospasm.

Most cases of ergotism are associated with chronic intoxication and/ or overdose.

Treatment

In the case of orally ingested drug, administration of activated charcoal is recommended.

In the case of very recent oral intake gastric lavage may be considered.

Treatment should be symptomatic. In the event of severe vasospastic reactions, i.v.

administration of a peripheral vasodilator such as nitroprusside, phentolamine or

dihydralazine, local application of warmth to the affected area and nursing care to

prevent tissue damage are recommended. In the event of coronary constriction,

appropriate treatment such as nitroglycerin should be initiated.

For advice on the management of overdose please contact the National Poisons Centre

on 0800 POISON (0800 764766).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antimigraine preparations

ATC code: N02CA52

Ergotamine aborts attacks of migraine with or without aura by its specific vasotonic

action on distended extracranial arteries. Ergotamine can cause vasoconstriction by

stimulating alpha-adrenergic and 5-HT receptors. It displays moderate to high affinity

for various serotonin receptor subtypes however its beneficial effect in migraine are

primarily linked to agonist properties at 5-HT

and 5-HT

Regional changes to cerebral flows resulting from intracranial arterial vasodilatation

accompany the migraine attack. The mechanism seems to be related to a reduction in

systemic levels of serotonin which, in turn, leads to the vasomotor changes observed.

Because of its direct vasoconstrictive effect on the smooth muscles of the dilated

vessels, ergotamine aborts the migraine attack and vascular headaches. Ergotamine also

acts on the vasomotor centres and leads to the blockage of peripheral alpha-adrenergic

receptors.

Ergotamine exerts a tonic effect on the smooth vascular musculature and presents a

particular affinity for arterial monoaminergic receptors (NA and HT), especially in the

external carotid network.

Numerous studies performed in animals and humans have amply demonstrated that the

vasoconstrictive action of ergotamine manifests itself selectively at the carotid and

extracranial arteries and is due mainly to stimulation of serotonergic and alpha-

adrenergic receptors.

As regards any changes in blood pressure, it has been demonstrated that these depend

mainly on the pre-existing pressures: with Cafergot there is a slight and transient

increase in pressure in normotensive subjects and hypotension in hypertensive subjects.

Caffeine accelerates and increases the enteral absorption of ergotamine. Also caffeine

exerts its analgesic activity through blockade of peripheral pronociceptive actions of

adenosine and the activation of central noradrenergic pathways that constitute an

endogenous pain suppressing system.

5.2

Pharmacokinetic properties

Ergotamine

Absorption

Studies using tritium-labelled ergotamine indicate that 62% of an oral dose is absorbed

from the gastrointestinal tract. Peak plasma levels are reached about 2 hours after

ingestion.

Distribution

Protein binding for ergotamine amounts to 98%.

Biotransformation

Ergotamine is extensively metabolized in the liver and is a substrate for the CYP3A4

enzyme system. It has been suggested that the therapeutic effects of the drug are

partially due to active metabolites.

Elimination

Parent drug and metabolites are mainly excreted in the bile. Their elimination from

plasma is biphasic, with half-lives of 2.7 and 21 hours, respectively.

Caffeine

Absorption

After oral administration, caffeine is rapidly and almost completely absorbed from the

GI tract, and peak concentrations achieved after oral administration of 175 mg range

between 5 - 10 μg/mL. Peak plasma concentrations are reached in 15-120 minutes.

Distribution

Plasma protein binding of caffeine is 35%. Caffeine is distributed relatively uniformly

throughout all body tissues, including cerebrospinal fluid, breast milk, salvia, and

semen. The volume of distribution is about 0.7 L/kg. Caffeine crosses the placental

barrier.

Biotransformation

Caffeine is metabolized to a large extent by CYP1A2 to paraxanthine. Paraxanthine is

further metabolised to uracil and uric acid derivatives by demethylation and

hydroxylation.

Elimination

The metabolites are excreted mainly in the urine. Plasma elimination half-life is about

3.5 hours. The clearance of caffeine is increased by smoking.

5.3

Preclinical safety data

Acute toxicity

values after single intravenous injection of Cafergot (ergotamine/caffeine 1:50)

were found to be 40 mg/kg in rabbits, 124 mg/kg in rats, and 111 mg/kg in mice. After

single oral administration in mice, LD

was 474 mg/kg.

Chronic and subchronic toxicity

In a 26-week oral safety study in beagle dogs, ergotamine induced vomiting, salivation

and decreased heart rate. In addition, superficial necrosis at the ear margin was

observed, which is a common finding in lop-eared dogs and is due to the marked

vasoconstrictor effect of the drug.

Carcinogenicity

There are no data about the carcinogenic potential of ergotamine.

Studies in rodents showed no carcinogenic activity of caffeine.

Reproductive toxicity

Ergotamine showed no evidence for embryonal mortality or teratogenic effects in rabbits

at 1, 3 and 10 mg/kg per day, and in rats at up to 3 mg/kg per day. However, in rats

given 10 mg/kg per day, maternal weight increase was inhibited, fetal ossification

retarded and prenatal mortality increased. High ergotamine doses constricted the uterine

vessels, reduced blood supply and thus induced hypoxia which is known to be

responsible for teratogenic effects in the offspring.

The combination of ergotamine and caffeine (1:100) revealed no teratogenic potential in

pregnant rats and rabbits. At high oral ergotamine doses, developmental toxicity (e.g.

decreased fetal body weight, delayed skeletal ossification or increased prenatal

mortality) was observed in experimental animals. This observation has been attributed to

reduced uteroplacental blood flow resulting from prolonged vasoconstriction of the

uterine vessels and/or increased myometrial tone induced by ergotamine. In a

reproductive performance study in male rats, fertility was not impaired. In a

reproductive performance study and a peri-/post-natal study in female rats, an increased

number of stillbirth and/or peri-/post-natal mortality was observed.

In animal studies, caffeine was found to be teratogenic only at very high doses.

Mutagenicity

No mutagenicity study was performed with ergotamine/caffeine combinations. In vivo

models showed no evidence of mutagenic activity of ergotamine, and therefore is

considered devoid of genotoxic potential. The overall evidence from numerous genetic

toxicity studies indicates that caffeine has no genotoxic potential at exposures relevant to

man.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tartaric acid,

Magnesium stearate

Talc

Maize starch

Cellulose

Iron oxide yellow (E172)

6.2

Incompatibilities

Not known

6.3

Shelf life

24 months

6.4

Special precautions for storage

Protect from light. Store at or below 25°C.

Cafergot must be kept out of the reach and sight of children

6.5

Nature and contents of container

Bottles of 100 tablets

6.6

Special precautions for disposal and other handling

No special requirements

7

MEDICINE SCHEDULE

Prescription medicine

8

SPONSOR

AFT Pharmaceuticals Ltd

PO BOX 33203

Takapuna

Auckland

Contact number: 0800 423 823

Email: customer.service@aftpharm.com

9

DATE OF FIRST APPROVAL

Date of publication in the New Zealand Gazette of consent to distribute the medicine:

31 December 1969

10

DATE OF REVISION OF TEXT

13 February 2018

Summary table of changes

Section changed

Summary of new information

Datasheet format updated

This section has been updated for addition of adverse

effect as a result of signal detection, Analgesic-induced or

rebound headaches after ergotamine withdrawal.

Pharmacotherapeutic group has been added

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