MIGERGOT- ergotamine tartrate and caffeine suppository

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ERGOTAMINE TARTRATE (UNII: MRU5XH3B48) (ERGOTAMINE - UNII:PR834Q503T), CAFFEINE (UNII: 3G6A5W338E) (CAFFEINE - UNII:3G6A5W338E)
Available from:
Cosette Pharmaceuticals, Inc.
INN (International Name):
Ergotamine Tartrate
Composition:
Ergotamine Tartrate 2 mg
Administration route:
RECTAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Ergotamine Tartrate and Caffeine Indicated as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants or so-called “histaminic cephalalgia”. 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 PRECAUTIONS: Drug Interactions), with some cases resulting in amputation. There have been rare reports of cerebral ischemia in patients on protease inhibitor therapy when ergotamine tartrate and caffeine was coadministered, at least one resulting in death. Because of the increased risk for ergotism and other serious vasospastic adverse events, ergotamine use is contraindicated with these drugs and other potent inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole) (see WARNINGS: CYP 3A4 Inhibitors). Ergotamine tartrate and caffeine may cause fetal harm when administered to pregnant
Product summary:
HOW SUPPLIED: Ergotamine Tartrate and Caffeine Suppositories USP are supplied in boxes of 12 foil wrapped suppositories. NDC 0713-0166-12
Authorization status:
Abbreviated New Drug Application
Authorization number:
0713-0166-12

MIGERGOT- ergotamine tartrate and caffeine suppository

Cosette Pharmaceuticals, Inc.

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ERGOTAMINE TARTRATE and

CAFFEINE SUPPOSITORIES USP

(For Rectal Administration)

Rx only

WARNING

Serious and/or life-threatening peripheral ischemia has been associated with the

coadministration of ergotamine tartrate and caffeine with potent CYP 3A4 inhibitors

including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition

elevates the serum levels of ergotamine tartrate and caffeine, 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: Ergotamine Tartrate and Caffeine Suppository

ergotamine tartrate USP 2 mg

caffeine USP 100 mg

Inactive Ingredients: tartaric acid NF, and hard fat NF

Ergotamine Tartrate and Caffeine Suppositories are for rectal administration only.

Ergotamine Tartrate and Caffeine Suppositories are sealed in foil to afford protection from leakage. If

an unavoidable period of exposure to heat softens the suppository, it should be chilled in ice-cold

water to solidify it before removing the foil.

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 during 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, evading 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,

erythromycin), and in patients treated orally with ergotamine and protease inhibitors (e.g. ritonavir)

presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine (See

CONTRAINDICATIONS). Ergotamine has also been shown to be an inhibitor of cytochrome P450 3A

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

Ergotamine Tartrate and Caffeine

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 PRECAUTIONS: Drug

Interactions), with some cases resulting in amputation. There have been rare reports of cerebral

ischemia in patients on protease inhibitor therapy when ergotamine tartrate and caffeine was

coadministered, at least one resulting in death. Because of the increased risk for ergotism and other

serious vasospastic adverse events, ergotamine use is contraindicated with these drugs and other potent

inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole) (see WARNINGS: CYP 3A4 Inhibitors).

Ergotamine tartrate and caffeine may cause fetal harm when administered to pregnant women.

Ergotamine tartrate and caffeine is contraindicated in women who are or may become pregnant. If this

drug is used during pregnancy or if the patient becomes pregnant while taking this product, the patient

should be apprised 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 protease inhibitors or

macrolide antibiotics has been associated with serious adverse events; for this reason, these drugs

should not be given concomitantly with ergotamine (See CONTRAINDICATIONS). While these

reactions 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 suppositories 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

rectally 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 induces vasoconstriction by a direct action on vascular smooth muscle.

In chronic intoxication with ergot derivatives, headache, intermittent claudication, muscle pains,

numbness, coldness and pallor of the digits may occur. If the condition 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 hypersensitivity. 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.

Rare cases of a solitary rectal or anal ulcer have occurred from abuse of ergotamine suppositories

usually in higher than recommended doses or with continual use at the recommended dose for many

years. Spontaneous healing occurs within usually 4-8 weeks after drug withdrawal.

Information for Patients

Patients should be advised that one suppository of ergotamine tartrate and caffeine should be taken at the

first sign of a migraine headache. No more than 2 suppositories should be taken for any single migraine

attack. No more than 5 suppositories should be taken during any 7-day period. Administration of

Ergotamine Tartrate and Caffeine Suppositories should not exceed the dosing guidelines and should not

be used for chronic daily administration (see DOSAGE AND ADMINISTRATION). Ergotamine

tartrate and caffeine 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 physician

immediately any of the following: numbness or tingling in the fingers or 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.

Ergotamine tartrate and caffeine 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 vasoconstrictive action of ergotamine tartrate

and caffeine by blocking the vasodilating property of epinephrine. Nicotine may provoke

vasoconstriction in some patients, predisposing to a greater ischemic response 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

There are no studies on the placental transfer or teratogenicity of the combined products of ergotamine

tartrate and caffeine. Caffeine is known to cross the placenta and has been shown to be teratogenic in

animals. Ergotamine crosses the placenta 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 placental blood flow may have

contributed to fetal growth retardation observed in animals. (See CONTRAINDICATIONS)

Nonteratogenic Effects

Ergotamine tartrate and caffeine is contraindicated in pregnancy due to the oxytocic effects of

ergotamine. (See CONTRAINDICATIONS)

Labor and Delivery

Ergotamine tartrate and caffeine 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

ergotamine tartrate and caffeine. Ergotamine is excreted in breast milk and may cause symptoms of

vomiting, diarrhea, weak pulse and unstable blood pressure in nursing infants. Because of the potential

for serious adverse reactions in nursing infants from ergotamine tartrate and caffeine, 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 transient tachycardia or bradycardia and hypertension.

Gastrointestinal: Nausea and vomiting; rectal or anal ulcer (from overuse of suppositories).

Neurological: Paresthesias, numbness, weakness, and vertigo.

Allergic: Localized edema and itching.

Fibrotic Complications: (See WARNINGS).

To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-

800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG ABUSE AND DEPENDENCE

There have been reports of drug abuse and psychological dependence in patients on ergotamine tartrate

and caffeine therapy. Due to the chronicity of vascular headaches, it is imperative that patients be

advised not to exceed recommended dosages with long-term use to avoid ergotism. (See

PRECAUTIONS)

OVERDOSAGE

The toxic effects of an acute overdosage of ergotamine tartrate and caffeine 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 vomiting, 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 enema. 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 best results, dosage should start at the first sign of an attack.

Rectally

Two suppositories is the maximum dose for an individual attack.

Total weekly dosage should not exceed 5 suppositories. Ergotamine Tartrate and Caffeine

Suppositories should not be used for chronic daily administration.

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: Ergotamine Tartrate and Caffeine Suppositories USP are supplied in boxes of 12

foil wrapped suppositories.

NDC 0713-0166-12

Store and Dispense

The suppositories should be refrigerated at 2° to 8°C (36° to

46°F). Iss. 07/2019

0166CP1

Manufactured by:

Cosette Pharmaceuticals, Inc.

111 Coolidge Street

South Plainfield, NJ 07080

PACKAGE LABEL

NDC 0713-0166-12

MIGERGOT

Ergotamine Tartrate and Caffeine Suppositories USP

Each Rectal Suppository Contains: Ergotamine Tartrate, USP 2 mg, Caffeine, USP 100 mg, Tartaric

Acid 21.5 mg

Usual Adult Dose: See Package insert.

Refrigerate at 2º - 8ºC (36º - 46ºF)

12 Rectal Suppositories Rx Only

Cosette Pharmaceuticals, Inc.

®

MIGERGOT - Front Foil

®

MIGERGOT - Back Foil

MIGERGOT

ergotamine tartrate and caffeine suppository

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 713-0 16 6

Route of Administration

RECTAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

®

Cosette Pharmaceuticals, Inc.

ERGO TAMINE TARTRATE (UNII: MRU5XH3B48 ) (ERGOTAMINE - UNII:PR8 34Q50 3T)

ERGOTAMINE TARTRATE

2 mg

CAFFEINE (UNII: 3G6 A5W338 E) (CAFFEINE - UNII:3G6 A5W338 E)

CAFFEINE

10 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

TARTARIC ACID (UNII: W48 8 8 I119 H)

HARD FAT (UNII: 8 334LX7S21)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 713-0 16 6 -12

12 in 1 BOX; Type 0 : No t a Co mbinatio n Pro duct

10 /30 /19 8 3

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 8 6 557

10 /30 /19 8 3

Labeler -

Cosette Pharmaceuticals, Inc. (116918230)

Registrant -

Cosette Pharmaceuticals, Inc. (116918230)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Co sette Pharmaceuticals,

Inc .

116 9 18 230

analysis(0 713-0 16 6 ) , manufacture(0 713-0 16 6 ) , label(0 713-0 16 6 ) , pack(0 713-

0 16 6 )

Revised: 8/2019

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