Rifamate

• Sanofi-Aventis U.S. LLC

You should not use this medicine if you are allergic to isoniazid or rifampin, or if you have active liver disease (including hepatitis or cirrhosis), or a history of liver problems caused by taking isoniazid.

To make sure isoniazid and rifampin is safe for you, tell your doctor if you have:

• liver disease;

• kidney disease;

• diabetes;

• gout;

• seizures; or

• if you drink alcohol every day.

Serious and sometimes fatal liver problems may occur during treatment with isoniazid and rifampin or after you stop taking this medication, even months after stopping. The risk of liver problems is highest in adults between the ages of 35 and 65. Your liver function may need to be checked every month while you are taking this medicine.

It is not known whether isoniazid and rifampin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Isoniazid and rifampin can make birth control pills less effective. Ask your doctor about using non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking isoniazid and rifampin.

Isoniazid and rifampin can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Do not wear soft contact lenses while taking isoniazid and rifampin. Rifampin may turn your tears a red-orange color. This effect could permanently discolor soft contact lenses.

Avoid drinking alcohol. It may increase your risk of liver damage while you are taking isoniazid and rifampin.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with isoniazid and rifampin, especially:

• an anticoagulant (warfarin, Coumadin).

This list is not complete. Other drugs may interact with isoniazid and rifampin, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

It is very important that your doctor check your progress at regular visits. In addition, you should check with your doctor immediately if blurred vision or loss of vision, with or without eye pain, occurs during treatment. He or she may want you to have your eyes checked by an ophthalmologist (eye doctor).

If your symptoms do not improve within 2 to 3 weeks, or if they become worse, check with your doctor.

Oral contraceptives (birth control pills) containing estrogen may not work properly if you take them while you are taking rifampin and isoniazid combination. Unplanned pregnancies may occur. You should use a different means of birth control while you are taking this medicine. If you have any questions about this, check with your health care professional.

Liver problems may be more likely to occur if you drink alcoholic beverages regularly while you are taking this medicine. Also, the regular use of alcohol may keep this medicine from working properly. Therefore, you should strictly limit the amount of alcoholic beverages you drink while you are taking this medicine.

Certain foods such as cheese (Swiss or Cheshire) or fish (tuna, skipjack, or Sardinella) may rarely cause reactions in some patients taking isoniazid-containing medicines. Check with your doctor if redness or itching of the skin, hot feeling, fast or pounding heartbeat, sweating, chills or clammy feeling, headache, or lightheadedness occurs after eating these foods while you are taking this medicine.

This medicine will cause the urine, stool, saliva, sputum, sweat, and tears to turn reddish-orange to reddish-brown. This is to be expected while you are taking this medicine. This effect may cause soft contact lenses to become permanently discolored. Standard cleaning solutions may not take out all the discoloration. Therefore, it is best not to wear soft contact lenses while taking this medicine. This condition will return to normal once you stop taking this medicine. Hard contact lenses are not discolored by this medicine. If you have any questions about this, check with your doctor.

If this medicine causes you to feel very tired or very weak; or causes clumsiness; unsteadiness; a loss of appetite; nausea; numbness, tingling, burning, or pain in the hands and feet; or vomiting, stop taking it and check with your doctor immediately. These may be early warning symptoms of more serious liver or nerve problems that could develop later.

Rifampin and isoniazid combination may cause blood problems. These problems may result in a greater chance of certain infections, slow healing, and bleeding of the gums. Therefore, you should be careful when using regular toothbrushes, dental floss, and toothpicks. Dental work should be delayed until your blood counts have returned to normal. Check with your medical doctor or dentist if you have any questions about proper oral hygiene (mouth care) during treatment.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Change in color of body fluids to orange or red.
• Belly pain.
• Loose stools (diarrhea).
• Gas.
• Headache.
• Heartburn.
• Upset stomach or throwing up.
• Feeling sleepy.
• Feeling tired or weak.
• Dizziness.
• Not hungry.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Rifampin

Gastrointestinal: heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea have been noted in some patients. Although Clostridium difficile has been shown in vitro to be sensitive to rifampin, pseudomembranous colitis has been reported with the use of rifampin (and other broad spectrum antibiotics). Therefore, it is important to consider this diagnosis in patients who develop diarrhea in association with antibiotic use.

Hepatic: transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, alkaline phosphatase, serum transaminases) have been observed. Rarely, hepatitis or a shock-like syndrome with hepatic involvement and abnormal liver function tests has been reported.

Hematologic: thrombocytopenia has occurred primarily with high dose intermittent therapy, but has also been noted after resumption of interrupted treatment. It rarely occurs during well supervised daily therapy. This effect is reversible if the drug is discontinued as soon as purpura occurs. Cerebral hemorrhage and fatalities have been reported when rifampin administration has been continued or resumed after the appearance of purpura.

Rare reports of disseminated intravascular coagulation have been observed.

Leukopenia, hemolytic anemia, and decreased hemoglobin have been observed.

Agranulocytosis has been reported rarely.

Central Nervous System: headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, muscular weakness, pains in extremities, and generalized numbness have been observed.

Psychoses have been rarely reported.

Rare reports of myopathy have also been observed.

Ocular: visual disturbances have been observed.

Endocrine: menstrual disturbances have been observed.

Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.

Renal: elevations in BUN and serum uric acid have been reported. Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal insufficiency, and acute renal failure have been noted. These are generally considered to be hypersensitivity reactions. They usually occur during intermittent therapy or when treatment is resumed following intentional or accidental interruption of a daily dosage regimen, and are reversible when rifampin is discontinued and appropriate therapy instituted.

Dermatologic: cutaneous reactions are mild and self-limiting and do not appear to be hypersensitivity reactions. Typically, they consist of flushing and itching with or without a rash. More serious cutaneous reactions which may be due to hypersensitivity occur but are uncommon.

Hypersensitivity reactions: occasionally, pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme including Stevens-Johnson syndrome, toxic epidermal necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (see WARNINGS), vasculitis, eosinophilia, sore mouth, sore tongue, and conjunctivitis have been observed.

Anaphylaxis has been reported rarely.

Miscellaneous: edema of the face and extremities has been reported. Other reactions which have occurred with intermittent dosage regimens include "flu" syndrome (such as episodes of fever, chills, headache, dizziness, and bone pain), shortness of breath, wheezing, decrease in blood pressure and shock. The "flu" syndrome may also appear if rifampin is taken irregularly by the patient or if daily administration is resumed after a drug free interval.

Isoniazid

The most frequent reactions are those affecting the nervous system and the liver. (See the boxed WARNING).

Nervous system: peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics), and is usually preceded by paresthesia of the feet and hands. The incidence is higher in "slow inactivators."

Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic psychosis.

Gastrointestinal: pancreatitis, nausea, vomiting, and epigastric distress.

Hepatic: elevated serum transaminases (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms are anorexia, nausea, vomiting, fatigue, malaise, and weakness. Mild and transient elevation of serum transaminase levels occurs in 10 to 20% of persons taking isoniazid. The abnormality usually occurs in the first 4 to 6 months of treatment but can occur at any time during therapy. In most instances, enzyme levels return to normal with no necessity to discontinue medication. In occasional instances, progressive liver damage occurs, with accompanying symptoms. In these cases, the drug should be discontinued immediately. The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3% of those over 50 years of age.

Hematologic: agranulocytosis, hemolytic sideroblastic or aplastic anemia, thrombocytopenia, and eosinophilia.

Hypersensitivity reactions: fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, anaphylactic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (see WARNINGS, Isoniazid), Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (see WARNINGS), and vasculitis.

Metabolic and endocrine: pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and gynecomastia.

Miscellaneous: rheumatic syndrome and systemic lupus erythematosus-like syndrome.

Capsules (opaque red), imprinted "Rifamate" on both ends of the capsule, containing 300 mg rifampin and 150 mg isoniazid; bottles of 60 (NDC 0068-0509-60).

Storage

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from excessive humidity.

Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY

Revised October 2016

©2016 sanofi-aventis U.S. LLC

Applies to isoniazid / rifampin: oral capsule

General

Doses greater than 600 mg of rifampin given once or twice weekly have resulted in a higher incidence of adverse reactions, including the "flu syndrome" (fever, chills, malaise); hematopoietic reactions (leukopenia, thrombocytopenia, acute hemolytic anemia); shortness of breath; shock; anaphylaxis; renal failure; and cutaneous, gastrointestinal, and hepatic reactions.[Ref]

Cardiovascular

Frequency not reported: Vasculitis

Rifampin:
Frequency not reported: Flushing, decreased blood pressure[Ref]

Dermatologic

Frequency not reported: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, Stevens-Johnson syndrome, Toxic Epidermal Necrolysis (TEN), rash

Isoniazid:
Frequency not reported: Acne, exfoliative dermatitis, pemphigus

Rifampin:
Frequency not reported: Erythema multiforme, skin reaction, pruritus, pruritic rash, urticaria, allergic dermatitis, pemphigoid, sweat discoloration, cutaneous reactions[Ref]

Endocrine

Isoniazid:
Frequency not reported: Gynecomastia, hyperglycemia

Rifampin:
Rare (less than 0.1%): Adrenal insufficiency
Frequency not reported: Menstrual disorder/disturbances[Ref]

Gastrointestinal

Frequency not reported: Nausea, vomiting, epigastric distress, diarrhea

Isoniazid:
Frequency not reported: Constipation, dry mouth, pancreatitis

Rifampin:
Frequency not reported: Gastrointestinal disorder, abdominal discomfort, heartburn, flatulence, cramps, pseudomembranous colitis, sore mouth, sore tongue[Ref]

Hematologic

Frequency not reported: Thrombocytopenia, eosinophilia, agranulocytosis, hemolytic anemia

Isoniazid:
Frequency not reported: Anemia, aplastic anemia, lymphadenopathy

Rifampin:
Uncommon (0.1% to 1%): Leukopenia
Rare (less than 0.1%): Disseminated intravascular coagulation
Frequency not reported: Decreased hemoglobin[Ref]

Hepatic

Frequency not reported: Hepatitis, elevated serum transaminases (SGOT, SGPT), bilirubinemia, bilirubinuria, jaundice

Rifampin:
Common (1% to 10%): Elevated alkaline phosphatase
Rare (less than 0.1%): Abnormal liver function, shock-like syndrome with hepatic involvement
Frequency not reported: Hyperbilirubinemia[Ref]

Hypersensitivity

Rifampin:
Rare (less than 0.1%): Anaphylaxis[Ref]

Metabolic

Isoniazid:
Frequency not reported: Pellagra, pyridoxine deficiency, metabolic acidosis

Rifampin:
Frequency not reported: Decreased appetite, anorexia[Ref]

Musculoskeletal

Isoniazid:
Frequency not reported: Systemic lupus erythematosus-like syndrome, rheumatic syndrome

Rifampin:
Rare (less than 0.1%): Myopathy
Frequency not reported: Muscle weakness, bone pain[Ref]

Nervous system

Peripheral neuropathy associated with isoniazid is dose-dependent, most often occurs in malnourished patients and in patients predisposed to neuritis (such as alcoholics and diabetics), and generally follows paresthesias of the hands and feet. The rate is higher in slow acetylators.[Ref]

Isoniazid:
Common (1% to 10%): Peripheral neuropathy
Uncommon (0.1% to 1%): Convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment
Frequency not reported: Vertigo, polyneuritis (presenting as paresthesia, muscle weakness, loss of tendon reflexes)

Rifampin:
Frequency not reported: Headache, drowsiness, cerebral hemorrhage, ataxia, dizziness, inability to concentrate, muscular weakness, pains in extremities, generalized numbness[Ref]

Ocular

Rifampin:
Frequency not reported: Tear discoloration, visual disturbances, conjunctivitis[Ref]

Other

Frequency not reported: Fever

Isoniazid:
Frequency not reported: Anti-nuclear antibodies

Rifampin:
Frequency not reported: Influenza-like syndrome, post-partum hemorrhage, fetal-maternal hemorrhage, porphyria, edema, fatigue, facial edema, edema of the extremities, shock[Ref]

Psychiatric

Isoniazid:
Frequency not reported: Toxic psychosis

Rifampin:
Frequency not reported: Psychotic disorder/psychoses, mental confusion, behavioral changes[Ref]

Renal

Rifampin:
Rare (less than 0.1%): Hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal insufficiency, acute renal failure
Frequency not reported: Acute kidney injury, chromaturia, increased blood creatinine, elevated BUN, elevated serum uric acid[Ref]

Respiratory

Rifampin:
Frequency not reported: Dyspnea, wheezing, discolored sputum, shortness of breath[Ref]

Some side effects of Rifamate may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.