Rifampin and isoniazid

In the treatment of tuberculosis, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type. Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment. Bacteriologic smears or cultures should be obtained before the start of therapy to confirm the susceptibility of the organism to rifampin and isoniazid, and they should be repeated throughout therapy to monitor response to the treatment. If test results show resistance to any of the components of RIFAMATE and the patient is not responding to therapy, the drug regimen should be modified. RIFAMATE is indicated for pulmonary tuberculosis in which organisms are susceptible, and when the patient has been titrated on the individual components and it has therefore been established that this fixed dosage is therapeutically effective.

This fixed-dosage combination drug is not recommended for initial therapy of tuberculosis or for preventive therapy.

A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide (e.g., RIFATER®) is recommended in the initial phase of short-course therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin, and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered. Following the initial phase, treatment should be continued with RIFAMATE for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

This drug is not indicated for the treatment of meningococcal infections or asymptomatic carriers of Neisseria meningitidis to eliminate meningococci from the nasopharynx.

RIFAMATE (rifampin and isoniazid capsules USP) is a combination of two drugs, each of which has been associated with liver dysfunction.

Rifampin

Rifampin has been shown to produce liver dysfunction. There have been fatalities associated with jaundice in patients with liver disease or receiving rifampin concomitantly with other hepatotoxic agents. Because RIFAMATE contains both rifampin and isoniazid, it should only be given with caution and under strict medical supervision to patients with impaired liver function. In these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, RIFAMATE should be withdrawn.

In some cases, hyperbilirubinemia resulting from competition between rifampin and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels, and considering them in conjunction with the patient's clinical condition.

Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration.

Isoniazid

(See the BOXED WARNING).

Since RIFAMATE contains isoniazid, ophthalmologic examinations (including ophthalmoscopy) should be done before treatment is started and periodically thereafter, even without occurrence of visual symptoms.

Signs And Symptoms

Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after ingestion; actual unconsciousness may occur with severe hepatic involvement. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces is proportional to amount ingested. Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage, bilirubin levels may increase and jaundice may develop rapidly. Hepatic involvement may be more marked in patients with prior impairment of hepatic function. Other physical findings remain essentially normal. A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely.

Facial or periorbital edema has also been reported in pediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours. Nausea, vomiting, dizziness, slurring of speech, blurring of vision, visual hallucinations (including bright colors and strange designs), are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma, are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria, and hyperglycemia are typical laboratory findings.

Acute Toxicity

The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 gm rifampin. Fatal acute overdoses in adults have been reported with doses ranging from 14 to 60 gm. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in pediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses has been reported.

Untreated or inadequately treated cases of gross isoniazid overdosage can be fatal, but good response has been reported in most patients treated within the first few hours after drug ingestion. Ingested acutely, as little as 1.5 g isoniazid may cause toxicity in adults. Doses of 35 to 40 mg/kg have resulted in seizures. Ingestion of 80 to 150 mg/kg isoniazid has been associated with severe toxicity and, if untreated, significant mortality.

The airway should be secured and adequate respiratory exchange established. Only then should gastric emptying (lavage-aspiration) be attempted; this may be difficult because of seizures. Since nausea and vomiting are likely to be present, gastric lavage is probably preferable to induction of emesis.

Blood samples should be obtained for immediate determination of gases, electrolytes, BUN, glucose, etc. Blood should be typed and crossmatched in preparation for possible hemodialysis.

Gastric lavage within the first 2 to 3 hours after ingestion should not be attempted until convulsions are under control. To treat convulsions, administer IV diazepam or short-acting barbiturates, and IV pyridoxine (usually 1 mg/1 mg isoniazid ingested). Activated charcoal slurry instilled into the stomach following evacuation of gastric contents can help absorb any remaining drug in the GI tract. Antiemetic medication may be required to control severe nausea and vomiting.

RAPID CONTROL OF METABOLIC ACIDOSIS IS FUNDAMENTAL TO MANAGEMENT. Intravenous sodium bicarbonate should be given at once and repeated as needed, adjusting subsequent dosage on the basis of laboratory findings (i.e., serum sodium, pH, etc.).

Forced osmotic diuresis must be started early and should be continued for some hours after clinical improvement to hasten renal clearance of drug and help prevent relapse. Fluid intake and output should be monitored.

Bile drainage may be indicated in presence of serious impairment of hepatic function lasting more than 24–48 hours. Under these circumstances and for severe cases, extracorporeal hemodialysis may be required; if this is not available, peritoneal dialysis can be used along with forced diuresis. Along with measures based on initial and repeated determination of blood gases and other laboratory tests as needed, meticulous respiratory and other intensive care should be utilized to protect against hypoxia, hypotension, aspiration, pneumonitis, etc.

Untreated or inadequately treated cases of gross isoniazid overdosage can terminate fatally, but good response has been reported in most patients brought under adequate treatment within the first few hours after drug ingestion.

Before taking this medication, tell your doctor if you have

• ever had an allergic reaction to isoniazid or rifampin;
• disease;
• liver disease; or
• porphyria.

You may not be able to take isoniazid and rifampin, or you may require a lower dose or special monitoring during treatment if you have any of the conditions listed above.

It is not known whether isoniazid and rifampin will harm an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant.

It is also not known whether isoniazid and rifampin will harm a nursing baby. Do not take this medication without first talking to your doctor if you are breast-feeding a baby.

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 rifampin and isoniazid. 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 rifampin and isoniazid. Also, the regular use of alcohol may keep rifampin and isoniazid from working properly. Therefore, you should strictly limit the amount of alcoholic beverages you drink while you are taking rifampin and isoniazid.

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 rifampin and isoniazid.

rifampin and isoniazid 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 rifampin and isoniazid. 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 rifampin and isoniazid. This condition will return to normal once you stop taking rifampin and isoniazid. Hard contact lenses are not discolored by rifampin and isoniazid. If you have any questions about this, check with your doctor.

If rifampin and isoniazid 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.

• Tell all of your health care providers that you take rifampin and isoniazid. This includes your doctors, nurses, pharmacists, and dentists.
• Have an eye exam as you have been told by your doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
• Talk with your doctor before you drink alcohol.
• Take vitamin B6 (pyridoxine) as you were told by your doctor.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Tell your doctor if you have signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Some foods and drinks like cheese and red wine, when taken with rifampin and isoniazid, may cause very risky effects such as sudden high blood pressure. To avoid these problems, get a list of foods to avoid.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking this medicine with your other drugs.
• This medicine may stain contact lenses.
• A very bad and sometimes deadly reaction has happened with rifampin and isoniazid. Most of the time, this reaction has signs like fever, rash, or swollen glands with problems in body organs like the liver, kidney, blood, heart, muscles and joints, or lungs. Talk with the doctor.
• A very bad skin reaction (toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
• Birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Use some other kind of birth control also like a condom when taking this medicine.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using rifampin and isoniazid while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of lupus like a rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs.
• Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
• Signs of too much acid in the blood (acidosis) like confusion; fast breathing; fast heartbeat; a heartbeat the does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; or feeling very tired or weak.
• Fever or chills.
• Sore throat.
• Period (menstrual) changes.
• Muscle pain or weakness.
• Any unexplained bruising or bleeding.
• Purple spots or redness of the skin.
• Feeling very tired or weak.
• A burning, numbness, or tingling feeling that is not normal.
• Seizures.
• Feeling confused.
• Memory problems or loss.
• Change in eyesight.
• Mood changes.
• Change in balance.
• Not able to focus.
• It is common to have diarrhea when taking rifampin and isoniazid. Rarely, a very bad form of diarrhea called Clostridium difficile (C diff)–associated diarrhea (CDAD) may occur. Sometimes, this has led to a deadly bowel problem (colitis). CDAD may happen while you are taking this medicine or within a few months after you stop taking it. Call your doctor right away if you have stomach pain or cramps, very loose or watery stools, or bloody stools. Do not try to treat loose stools without first checking with your doctor.

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 your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about rifampin and isoniazid, please talk with your doctor, nurse, pharmacist, or other health care provider.
• 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.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about rifampin and isoniazid. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using rifampin and isoniazid.

Review Date: October 4, 2017