Cafergot

Each tablet for oral administration contains 1 mg ergotamine tartrate, USP, and 100 mg caffeine, USP.

ERGOTAMINE TARTRATE:

Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenyl-methyl)-,(5' α)-, [R-(R*,R*)]-2,3- dihydroxy-butanedioate (2:1) (salt).

CAFFEINE:

1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-.

Inactive ingredients include acacia, calcium carbonate, compressible sugar, confectioner's sugar (sucrose and corn starch), magnesium stearate, methylparaben, microcrystalline cellulose, povidone, propylparaben, sodium benzoate, sodium starch glycolate, starch (potato), sucrose, synthetic iron oxide, titanium dioxide and other ingredients.

CAFERGOT® (ergotamine tartrate and caffeine tablets, USP) for oral administration are available as:

1 mg/100 mg: round tablets, sugar coated beige and imprinted CAFERGOT (ergotamine tartrate and caffeine) in black ink.

Bottles of 100...................................................NDC 0078-0349-05

Store at controlled room temperature 15° -30° C (59° -86° F).

Dispense in a tight, light-resistant container.

Manufactured By: Geneva Pharmaceuticals, Inc. Broomfield, CO 80020. Distributed By: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. Rev 03-2003. FDA Rev date: 7/26/1999

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 and caffeine tablets should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).

Do not use this medication if you are allergic to caffeine or ergotamine, or other ergot medicine such as dihydroergotamine (D.H.E. 45, Migranal), ergonovine (Ergotrate), methylergonovine (Methergine), or methysergide (Sansert).

Do not use caffeine and ergotamine if you are pregnant or breast-feeding, or if you have:

• a history of heart disease, angina (chest pain), blood circulation problems, or history of a heart attack or stroke;
• coronary artery disease or "hardening of the arteries";
• uncontrolled high blood pressure;
• severe liver disease;
• severe kidney disease; or
• a serious infection called sepsis.

Using certain medications together with caffeine and ergotamine can cause even greater decreases in blood flow than caffeine and ergotamine used alone. A severe decrease in blood flow to the brain and other parts of the body can lead to dangerous side effects. Do not use caffeine and ergotamine if you are also using any of the following medications:

• conivaptan (Vaprisol);
• diclofenac (Arthrotec, Cataflam, Voltaren, Flector Patch, Solareze);
• imatinib (Gleevec);
• isoniazid (for treating tuberculosis);
• an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), telithromycin (Ketek), or troleandomycin (Tao);
• an antifungal medication such as clotrimazole (Mycelex Troche), itraconazole (Sporanox), ketoconazole (Nizoral), or voriconazole (Vfend);
• an antidepressant such as nefazodone;
• heart or blood pressure medication such as diltiazem (Cardizem, Dilacor, Tiazac), nicardipine (Cardene), quinidine (Quinaglute, Quinidex, Quin-Release), or verapamil (Calan, Covera, Isoptin, Verelan); or
• HIV/AIDS medicine such as amprenavir (Agenerase), atazanavir (Reyataz), delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase, Fortovase), or ritonavir (Norvir).

Caffeine and ergotamine can cause rare but serious side effects on the heart, including heart attack or stroke. If you have certain conditions, you may need a dose adjustment or special tests to safely use this medication. Before using caffeine and ergotamine, tell your doctor if you have:

• breathing problems;
• high blood pressure;
• liver disease;
• kidney disease; or
• coronary artery disease (or risk factors that include diabetes, menopause, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, being older than 40 and a man, or being a woman who has had a hysterectomy).

FDA pregnancy category X. This medication can cause birth defects. Do not use caffeine and ergotamine if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use an effective form of birth control while you are using caffeine and ergotamine.

Caffeine and ergotamine passes into breast milk and may be harmful to a nursing infant. Do not use caffeine and ergotamine without telling your doctor if you are breast-feeding a baby.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

For dihydroergotamine and ergotamine: These medicines are used to relieve severe, throbbing headaches in children 6 years of age or older. They have not been shown to cause different side effects or problems in children than they do in adults. However, these medicines can cause serious side effects in any patient. Therefore, it is especially important that you discuss with the child's doctor the good that this medicine may do as well as the risks of using it.

For belladonna alkaloids: Young children, especially children with spastic paralysis or brain damage, may be especially sensitive to the effects of belladonna alkaloids. This may increase the chance of side effects during treatment.

For dimenhydrinate, diphenhydramine, and pentobarbital: Although these medicines often cause drowsiness, some children become excited after taking them.

For dihydroergotamine and ergotamine: The chance of serious side effects caused by decreases in blood flow is increased in elderly people receiving these medicines.

For belladonna alkaloids, dimenhydrinate, diphenhydramine, and pentobarbital: Elderly people are more sensitive than younger adults to the effects of these medicines. This may increase the chance of side effects such as excitement, depression, dizziness, drowsiness, and confusion.

Geriatric

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Many medicines can add to or decrease the effects of the belladonna alkaloids, caffeine, dimenhydrinate, diphenhydramine, or pentobarbital present in some of these headache medicines. Therefore, you should tell your health care professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine. This is especially important if any medicine you take causes excitement, trouble in sleeping, dryness of the mouth, dizziness, or drowsiness.

Pregnancy

Use of dihydroergotamine or ergotamine by pregnant women may cause serious harm, including death of the fetus and miscarriage. Therefore, these medicines should not be used during pregnancy.

Breast Feeding

For dihydroergotamine and ergotamine: These medicines pass into the breast milk and may cause unwanted effects, such as vomiting, diarrhea, weak pulse, changes in blood pressure, or convulsions (seizures) in nursing babies. Large amounts of these medicines may also decrease the flow of breast milk.

For caffeine: Caffeine passes into the breast milk. Large amounts of it may cause the baby to appear jittery or to have trouble in sleeping.

For belladonna alkaloids, dimenhydrinate, and diphenhydramine: These medicines have drying effects. Therefore, it is possible that they may reduce the amount of breast milk in some people. Dimenhydrinate passes into the breast milk.

For pentobarbital: Pentobarbital passes into the breast milk. Large amounts of it may cause unwanted effects such as drowsiness in nursing babies.

Be sure that you discuss these possible problems with your doctor before taking any of these medicines.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Atazanavir
• Boceprevir
• Cobicistat
• Darunavir
• Dasabuvir
• Elvitegravir
• Ombitasvir
• Paritaprevir
• Potassium
• Ranolazine
• Rilpivirine
• Riociguat
• Ritonavir
• Telaprevir
• Voriconazole

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol
• Alfentanil
• Alprazolam
• Amobarbital
• Anisindione
• Aprobarbital
• Axitinib
• Bosutinib
• Bromazepam
• Bromopride
• Buprenorphine
• Bupropion
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Carbinoxamine
• Carisoprodol
• Carmustine
• Chloral Hydrate
• Chlordiazepoxide
• Chlorzoxazone
• Clarithromycin
• Clobazam
• Clonazepam
• Clorazepate
• Clozapine
• Cobimetinib
• Codeine
• Daclatasvir
• Dantrolene
• Deferasirox
• Deflazacort
• Delavirdine
• Diazepam
• Dicumarol
• Dihydrocodeine
• Donepezil
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Doxylamine
• Dronedarone
• Elbasvir
• Erlotinib
• Eslicarbazepine Acetate
• Estazolam
• Ethchlorvynol
• Etonogestrel
• Etravirine
• Fentanyl
• Fluconazole
• Flunitrazepam
• Flurazepam
• Grazoprevir
• Halazepam
• Hydrocodone
• Hydromorphone
• Ifosfamide
• Imatinib
• Ketazolam
• Ledipasvir
• Levorphanol
• Lopinavir
• Lorazepam
• Lormetazepam
• Meclizine
• Medazepam
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Methoxyflurane
• Midazolam
• Mifepristone
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Nifedipine
• Nimodipine
• Nitrazepam
• Olaparib
• Orlistat
• Oxazepam
• Oxycodone
• Oxymorphone
• Peginterferon Alfa-2b
• Pentazocine
• Pentobarbital
• Periciazine
• Phenindione
• Phenobarbital
• Phenprocoumon
• Piperaquine
• Pixantrone
• Prazepam
• Primidone
• Quazepam
• Regadenoson
• Remifentanil
• Saquinavir
• Secobarbital
• Simeprevir
• Sirolimus
• Sodium Oxybate
• Sonidegib
• Sufentanil
• Sunitinib
• Tacrolimus
• Tapentadol
• Temazepam
• Teniposide
• Tenofovir Alafenamide
• Thiopental
• Tolvaptan
• Tramadol
• Triazolam
• Ulipristal
• Velpatasvir
• Venetoclax
• Zolpidem

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Using medicines in this class with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use your medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Tobacco

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

• Agoraphobia (fear of open or public places) or
• Panic attacks or
• Stomach ulcer or
• Trouble in sleeping (insomnia)—Caffeine can make your condition worse.

• Diarrhea—Rectal dosage forms (suppositories) will not be effective if you have diarrhea.

• Difficult urination or
• Enlarged prostate or
• Glaucoma (not well controlled) or
• Heart or blood vessel disease or
• High blood pressure (not well controlled) or
• Infection or
• Intestinal blockage or other intestinal problems or
• Itching (severe) or
• Kidney disease or
• Liver disease or
• Mental depression or
• Overactive thyroid or
• Trauma from an accident (broken arm or leg)
• Urinary tract blockage—The chance of side effects may be increased.

Also, tell your doctor if you need, or if you have recently had, an angioplasty (a procedure done to improve the flow of blood in a blocked blood vessel) or surgery on a blood vessel. The chance of serious side effects caused by dihydroergotamine or ergotamine may be increased.

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

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 catalyzed reactions. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

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 Cafergot® (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).

      Cafergot may cause fetal harm when administered to pregnant women. Cafergot 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.

Procedure

For the best results, dosage should start at the first sign of an attack.

           Early Aministration Gives Maximum Effectiveness

Maximum Adult Dosage

Two suppositories is the maximum dose for an individual attack.

      Total weekly dosage should not exceed 5 suppositories. Cafergot® (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.