7336 web site

Cafergot®
(ergotamine tartrate and
caffeine tablets, USP)
WARNING: Serious and/or life-threatening peripheral ischemia
has been associated with the coadministration of CAFERGOT®
with potent CYP 3A4 inhibitors including protease inhibitors and
macrolide antibiotics. Because CYP 3A4 inhibition elevates the
serum levels of CAFERGOT®, the risk for vasospasm leading to
cerebral ischemia and/or ischemia of the extremities is increased.
Hence, concomitant use of these medications is contraindicated
(see also CONTRAINDICATIONS and WARNINGS section).
DESCRIPTION: Each tablet for oral administration contains 1 mg ergotamine
tartrate, USP, and 100 mg caffeine, USP.
Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl- [R-(R*,R*)]-2,3-dihydroxy-butanedioate (2:1) (salt).
1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-.
Inactive ingredients include black iron oxide, compressible sugar, iron oxide red, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, polyvinyl alcohol, sodium starch glycolate, talc, titanium dioxide and
yellow iron oxide.
CLINICAL PHARMACOLOGY: Ergotamine is an alpha adrenergic blocking
agent with a direct stimulating effect on the smooth muscle of peripheral
and cranial blood vessels and produces depression of central vasomotor
centers. The compound also has the properties of serotonin antagonism.
In comparison to hydrogenated ergotamine, the adrenergic blocking actions
are less pronounced and vasoconstrictive actions are greater.
Caffeine, also a cranial vasoconstrictor, is added to further enhance the vasoconstrictive effect without the necessity of increasing ergotamine dosage.
Many migraine patients experience excessive nausea and vomiting dur- ing attacks, making it impossible for them to retain any oral medication. In
such cases, therefore, the only practical means of medication is through the
rectal route where medication may reach the cranial vessels directly, evad-
ing the splanchnic vasculature and the liver.
Pharmacokinetics:
Interactions: Pharmacokinetic interactions (increased blood levels of
ergotamine) have been reported in patients treated orally with ergotamine
and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythro-
mycin), and in patients treated orally with ergotamine and protease inhibitors
(e.g. ritonavir) presumably due to inhibition of cytochrome P450 3A meta-
bolism of ergotamine (see CONTRAINDICATIONS). Ergotamine has also been
shown to be an inhibitor of cytochrome P450 3A catalyzed reactions. No
pharmacokinetic interactions involving other cytochrome P450 isoenzymes
are known.
INDICATIONS AND USAGE: CAFERGOT® (ergotamine tartrate and caffeine
tablets, USP) are indicated as therapy to abort or prevent vascular headache,
e.g., migraine, migraine variants, or so-called “histaminic cephalalgia”.
CONTRAINDICATIONS: Coadministration of ergotamine with potent CYP 3A4
inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, and
troleandomycin) has been associated with acute ergot toxicity (ergotism)
characterized by vasospasm and ischemia of the extremities (see PRE-
CAUTIONS: Drug Interactions), with some cases resulting in amputation.
There have been rare reports of cerebral ischemia in patients on protease
inhibitor therapy when CAFERGOT® (ergotamine tartrate and caffeinetablets, USP) was coadministered, at least one resulting in death. Becauseof the increased risk for ergotism and other serious vasospastic adverseevents, ergotamine use is contraindicated with these drugs and otherpotent inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole) (see WARN-INGS: CYP 3A4 Inhibitors).
CAFERGOT® (ergotamine tartrate and caffeine tablets, USP) may cause fetal harm when administered to pregnant women. CAFERGOT® (ergota-mine tartrate and caffeine tablets, USP) is contraindicated in women whoare or may become pregnant. If this drug is used during pregnancy or if thepatient becomes pregnant while taking this product, the patient should beapprised of the potential hazard to the fetus.
Peripheral vascular disease, coronary heart disease, hypertension, impaired hepatic or renal function and sepsis.
Hypersensitivity to any of the components.
WARNINGS:
CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors):
Coadministration of ergotamine with potent CYP 3A4 inhibitors such as pro-
tease inhibitors or macrolide antibiotics has been associated with serious
adverse events; for this reason, these drugs should not be given con-
comitantly with ergotamine (see CONTRAINDICATIONS). While these reac-
tions have not been reported with less potent CYP 3A4 inhibitors, there is
a potential risk for serious toxicity including vasospasm when these drugs
are used with ergotamine. Examples of less potent CYP 3A4 inhibitors
include: saquinavir, nefazodone, fluconazole, fluoxetine, grapefruit juice,
fluvoxamine, zileuton, metronidazole, and clotrimazole. These lists are not
exhaustive, and the prescriber should consider the effects on CYP 3A4 of
other agents being considered for concomitant use with ergotamine.
Fibrotic Complications: There have been a few reports of patients on
ergotamine tartrate and caffeine therapy developing retroperitoneal and/or
pleuropulmonary fibrosis. There have also been rare reports of fibrotic
thickening of the aortic, mitral, tricuspid, and/or pulmonary valves with long-
term continuous use of ergotamine tartrate and caffeine. Ergotamine tartrate
and caffeine tablets should not be used for chronic daily administration (see
DOSAGE AND ADMINISTRATION).
PRECAUTIONS:
General: Although signs and symptoms of ergotism rarely develop even after
long-term intermittent use of the orally administered drug, care should be
exercised to remain within the limits of recommended dosage.
Ergotism is manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia. Ergotamine inducesvasoconstriction by a direct action on vascular smooth muscle. In chronicintoxication with ergot derivatives, headache, intermittent claudication,muscle pains, numbness, coldness and pallor of the digits may occur. If thecondition is allowed to progress untreated, gangrene can result.
While most cases of ergotism associated with ergotamine treatment result from frank overdosage, some cases have involved apparent hyper-
sensitivity. There are few reports of ergotism among patients taking doses
within the recommended limits or for brief periods of time. In rare instances,
patients, particularly those who have used the medication indiscriminately
over long periods of time, may display withdrawal symptoms consisting of
rebound headache upon discontinuation of the drug.
Information for Patients: Patients should be advised that two tablets of
CAFERGOT® (ergotamine tartrate and caffeine tablets, USP) should be taken
at the first sign of a migraine headache. No more than 6 tablets should be
taken for any single migraine attack. No more than 10 tablets should be taken
during any 7-day period. Administration of ergotamine tartrate and caffeine
tablets should not exceed the dosing guidelines and should not be used for
chronic daily administration (see DOSAGE AND ADMINISTRATION). CAFER-
GOT® (ergotamine tartrate and caffeine tablets, USP) should be used only
for migraine headaches. It is not effective for other types of headaches and
it lacks analgesic properties. Patients should be advised to report to the physi-
cian immediately any of the following: numbness or tingling in the fingers
and toes, muscle pain in the arms and legs, weakness in the legs, pain in
the chest or temporary speeding or slowing of the heart rate, swelling
or itching.
Drug Interactions:
CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors):
See CONTRAINDICATIONS and WARNINGS.
CAFERGOT® (ergotamine tartrate and caffeine tablets, USP) should not be administered with other vasoconstrictors. Use with sympathomimetics(pressor agents) may cause extreme elevation of blood pressure. The beta-blocker Inderal (propranolol) has been reported to potentiate the vaso-constrictive action of CAFERGOT® (ergotamine tartrate and caffeine tablets,USP) by blocking the vasodilating property of epinephrine. Nicotine may pro-voke vasoconstriction in some patients, predisposing to a greater ischemicresponse to ergot therapy.
The blood levels of ergotamine-containing drugs are reported to be elevated by the concomitant administration of macrolide antibiotics and
vasospastic reactions have been reported with therapeutic doses of the
ergotamine-containing drugs when coadministered with these antibiotics.
Pregnancy:
Teratogenic Effects:
Pregnancy Category X: There are no studies on the placental transfer or ter-
atogenicity of the combined products of CAFERGOT® (ergotamine tar-
trate and caffeine tablets, USP). Caffeine is known to cross the placenta and
has been shown to be teratogenic in animals. Ergotamine crosses the pla-
centa in small amounts, although it does not appear to be embryotoxic in
this quantity. However, prolonged vasoconstriction of the uterine vessels
and/or increased myometrial tone leading to reduced myometrial and pla-
cental blood flow may have contributed to fetal growth retardation observed
in animals (see CONTRAINDICATIONS).
Nonteratogenic Effects: CAFERGOT® (ergotamine tartrate and caffeine
tablets, USP) is contraindicated in pregnancy due to the oxytocic effects of
ergotamine (see CONTRAINDICATIONS).
Labor and Delivery: CAFERGOT® (ergotamine tartrate and caffeine tablets,
USP) is contraindicated in labor and delivery due to its oxytocic effect
which is maximal in the third trimester (see CONTRAINDICATIONS).
Nursing Mothers: Ergot drugs are known to inhibit prolactin but there are
no reports of decreased lactation with CAFERGOT® (ergotamine tartrate and
caffeine tablets, USP). Ergotamine is excreted in breast milk and may
cause symptoms of vomiting, diarrhea, weak pulse and unstable blood pres-
sure in nursing infants. Because of the potential for serious adverse reac-
tions in nursing infants from CAFERGOT® (ergotamine tartrate and caffeine
tablets, USP), a decision should be made whether to discontinue nursing
or discontinue the drug, taking into account the importance of the drug to
the mother.
Pediatric Use: Safety and effectiveness in pediatric patients have not been
established.
ADVERSE REACTIONS:
Cardiovascular: Vasoconstrictive complications of a serious nature may
occur at times. These include ischemia, cyanosis, absence of pulse, cold
extremities, gangrene, precordial distress and pain, EKG changes and
muscle pains. Although these effects occur most commonly with long-term
therapy at relatively high doses, they have also been reported with short-
term or normal doses. Other cardiovascular adverse effects include tran-
sient tachycardia or bradycardia and hypertension.
Gastrointestinal: Nausea and vomiting.
Neurological: paresthesias, numbness, weakness, and vertigo.
Allergic: Localized edema and itching.
Fibrotic Complications (see WARNINGS).
DRUG ABUSE AND DEPENDENCE: There have been reports of drug abuse
and psychological dependence in patients on CAFERGOT® (ergotamine tar-
trate and caffeine tablets, USP) therapy. Due to the chronicity of vascular
headaches, it is imperative that patients be advised not to exceed recom-
mended dosages with long-term use to avoid ergotism (see PRECAUTIONS).
OVERDOSAGE: The toxic effects of an acute overdosage of CAFERGOT®
(ergotamine tartrate and caffeine tablets, USP) are due primarily to the
ergotamine component. The amount of caffeine is such that its toxic effects
will be overshadowed by those of ergotamine. Symptoms include vomit-
ing, numbness, tingling, pain and cyanosis of the extremities associated with
diminished or absent peripheral pulses; hypertension or hypotension;
drowsiness, stupor, coma, convulsions and shock. A case has been reported
of reversible bilateral papillitis with ring scotomata in a patient who received
five times the recommended daily adult dose over a period of 14 days.
Treatment consists of removal of the offending drug by induction of eme- sis, gastric lavage, and catharsis. Maintenance of adequate pulmonary
ventilation, correction of hypotension and control of convulsions and blood
pressure are important considerations. Treatment of peripheral vasospasm
should consist of warmth, but not heat, and protection of the ischemic limbs.
Vasodilators may be beneficial but caution must be exercised to avoid
aggravating an already existent hypotension.
DOSAGE AND ADMINISTRATION:
Procedure: For the best results, dosage should start at the first sign of an
attack. Adults: Take 2 tablets at the start of attack; 1 additional tablet every
1/2 hour, if needed for full relief (maximum 6 tablets per attack, 10 per week).
Maximum Adult Dosage: Total dose for any one attack should not exceed
6 tablets. Total weekly dosage should not exceed 10 tablets. Ergotamine
tartrate and caffeine tablets should not be used for chronic daily adminis-
tration. In carefully selected patients, with due consideration of maximum
dosage recommendations, administration of the drug at bedtime may be an
appropriate short-term preventive measure.
HOW SUPPLIED: CAFERGOT® (ergotamine tartrate and caffeine tablets,
USP) for oral administration are available as:
1 mg/100 mg: round tablets, film coated beige, debossed SZ 183 on one
side and plain on the reverse side and supplied as:
NDC 0781-5405-01 bottles of 100Store at 200-250C (680-770F) (see USP Controlled Room Temperature).
Dispense in a tight, light-resistant container.

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