FDA label 7b9c0dd6-b8d1-4599-8626-60e94bce91fe

WARNING Severe and sometimes fatal hepatitis associated with isoniazid, a component of RIFATER, therapy may occur and may develop even after many months of treatment. The risk of developing hepatitis is age related. Approximate case rates by age are: 0 per 1,000 for persons under 20 years of age, 3 per 1,000 for persons in the 20 to 34 year age group, 12 per 1,000 for persons in the 35 to 49 year age group, 23 per 1,000 for persons in the 50 to 64 year age group, and 8 per 1,000 for persons over 65 years of age. The risk of hepatitis is increased with daily consumption of alcohol. Precise data to provide a fatality rate for isoniazid-related hepatitis is not available; however, in a U.S. Public Health Service Surveillance Study of 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis. Therefore, patients given RIFATER, which contains isoniazid, should be carefully monitored and interviewed at monthly intervals. Serum transaminase concentration becomes elevated in about 10% to 20% of patients, usually during the first few months of therapy, but it can occur at any time. Usually enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs. Patients should be instructed to report immediately any of the prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, RIFATER, should be discontinued promptly since continued use of the drug in these cases has been reported to cause a more severe form of liver damage. Patients with tuberculosis should be given appropriate treatment with alternative drugs. If isoniazid, a component of RIFATER, must be reinstituted, it should be reinstituted only after symptoms and laboratory abnormalities have cleared. RIFATER should not be restarted and instead, isoniazid should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent liver involvement. Treatment should be deferred in persons with acute hepatic diseases.

WARNINGS RIFATER is a combination of the three drugs, rifampin, isoniazid, and pyrazinamide. Each of these individual drugs has been associated with liver dysfunction. Systemic hypersensitivity reactions were reported with all three components of RIFATER (rifampin, isoniazid, and pyrazinamide). Signs and symptoms of hypersensitivity reactions may include fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). Manifestations of hypersensitivity, such as fever, lymphadenopathy or laboratory abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. Monitor patients receiving RIFATER for signs and/or symptoms of hypersensitivity reactions. If these signs or symptoms occur, discontinue RIFATER and administer supportive measures. Cases of severe cutaneous adverse reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with all three components of RIFATER (rifampin, isoniazid, and pyrazinamide). If symptoms or signs of severe cutaneous adverse reactions develop, discontinue RIFATER immediately and institute appropriate therapy. Rifampin Hepatotoxicity of hepatocellular, cholestatic, and mixed patterns has been reported in patients treated with rifampin, a component of RIFATER. Severity ranged from asymptomatic elevations in liver enzymes, isolated jaundice/hyperbilirubinemia, symptomatic self-limited hepatitis to fulminant liver failure and death. Severe hepatic dysfunction including fatalities were reported in patients with liver disease and in patients taking rifampin, a component of RIFATER, with other hepatotoxic agents. Monitor for symptoms and clinical/laboratory signs of liver injury, especially if treatment is prolonged or given with other hepatotoxic drugs. Patients with impaired liver function should be given RIFATER only in cases of necessity and then under strict medical supervision. In these patients, careful monitoring of liver function should be done prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatic damage occur or worsen, discontinue RIFATER. Rifampin, a component of RIFATER, has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin (a component of RIFATER) administration. Cases of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with rifampin. If symptoms or signs of severe cutaneous adverse reactions develop, discontinue RIFATER immediately and institute appropriate therapy. Rifampin, a component of RIFATER, may cause vitamin K–dependent coagulation disorders and bleeding (see ADVERSE REACTIONS ). Monitor coagulation tests during RIFATER treatment (prothrombin time and other coagulation tests) in patients at risk of vitamin K deficiency (such as those with chronic liver disease, poor nutritional status, on prolonged antibacterial drugs or anticoagulants). Consider discontinuation of RIFATER if abnormal coagulation tests and/or bleeding occur. Supplemental vitamin K administration should be considered when appropriate. Postmarketing reports suggest that concomitant administration of high doses of cefazolin and rifampin, a component of RIFATER, may prolong the prothrombin time, leading to severe vitamin K–dependent coagulation disorders that may be life-threatening or fatal. Avoid concomitant use of cefazolin and RIFATER in patients at increased risk for bleeding. If no alternative treatment options are available, closely monitor prothrombin time and other coagulation tests, and administer vitamin K as indicated. Isoniazid (See the boxed WARNING .) Since RIFATER contains isoniazid, ophthalmologic examinations (including ophthalmoscopy) should be done before treatment is started and periodically thereafter, even without occurrence of visual symptoms. Severe cutaneous reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some with a fatal outcome, have been reported with the use of isoniazid, a component of RIFATER (see ADVERSE REACTIONS ). Monitor for skin reactions and advise patients to report skin rashes or mucosal lesions immediately. Discontinue RIFATER, if these reactions occur. Pyrazinamide Since RIFATER contains pyrazinamide, patients started on RIFATER should have baseline serum uric acid and liver function determinations. Patients with preexisting liver disease or those patients at increased risk for drug related hepatitis (e.g., alcohol abusers) should be followed closely. Because it contains pyrazinamide, RIFATER should be discontinued and not be resumed if signs of hepatocellular damage or hyperuricemia accompanied by an acute gouty arthritis appear. If hyperuricemia accompanied by an acute gouty arthritis occurs without liver dysfunction, the patient should be transferred to a regimen not containing pyrazinamide.

ADVERSE REACTIONS Adverse Experiences during the Clinical Trial Adverse event data reported for the RIFATER and the separate drug treatment groups during the first 2 months of the trial are shown in the table below. Adverse Events Reported During the Clinical Study Number of Patients with Adverse Events A given patient may have experienced ≥1 adverse event. Adverse Events by Body Systems During First 2 Months of Trial RIFATER n=122 A total of 250 patients (124 RIFATER; 126 separate) were originally enrolled in the study. Five patients (2 RIFATER; 3 separate) were excluded due to admission errors. Separate Isoniazid, rifampin, and pyrazinamide dosed as separate tablets and capsules. n=123 Cutaneous (rash, erythroderma, erythema, exfoliative dermatitis, Lyell syndrome, urticaria, localized skin rash, diffuse skin rash, pruritus, generalized hypersensitivity) 8 (7%) 21 (17%) Gastrointestinal (nausea, vomiting, digestive pain, diarrhea) 8 (7%) 14 (11%) Musculoskeletal (arthralgia, long bones pain, phlebitis, localized joint pain, diffuse joint pain, edema of the legs) 5 (4%) 8 (7%) Hearing and Vestibular (tinnitus, vertigo, vertigo with loss of equilibrium) 3 (2%) 6 (5%) Liver and Biliary (hepatitis with conjunctival jaundice, hepatitis with deep jaundice) 0 (0%) 2 (2%) Central and Peripheral Nervous System (sweating, headache, insomnia, diffuse paresthesia of the legs, anxiety, diabetic coma) 5 (4%) 4 (3%) Total Body (spiking fever, persistent fever) 2 (2%) 4 (3%) Cardiorespiratory (tightness in chest, coughing, diffuse chest pain, hemoptysis, angina, palpitation, total pneumothorax) 8 (7%) 3 (2%) Total number of patients with one or more adverse events 29 43 No serious adverse events were reported in the patients receiving RIFATER tablets. Three serious adverse events were reported in the patients given isoniazid, rifampin, and pyrazinamide as separate tablets and capsules. The three serious adverse events were two general hypersensitivity reactions and one jaundice reaction. There were no significant differences between the two treatment groups in standard liver function, renal function, and hematological laboratory test values measured at baseline and after 8 weeks of treatment. As would be expected for these drugs, there were alterations in liver enzymes (SGOT, SGPT) and serum uric acid levels. The adverse reactions reported during therapy with RIFATER are consistent with those described below for the individual components. Adverse Reactions Reported for Individual Components of RIFATER 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. Tooth discoloration (which may be permanent) may occur. Hepatic Hepatotoxicity including transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, alkaline phosphatase, serum transaminases, gamma-glutamyl transferase), hepatitis, a shock-like syndrome with hepatic involvement and abnormal liver function tests, and cholestasis have been reported (see WARNINGS ). 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, decreased hemoglobin, bleeding, and vitamin K–dependent coagulation disorders (abnormal prolongation of prothrombin time or low vitamin K–dependent coagulation factors) 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, acute generalized exanthematous pustulosis, 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 Paradoxical drug reaction (tuberculosis infection exacerbation in a patient who had previously shown improvement with appropriate antituberculosis therapy, in the absence of evidence of disease relapse or the presence of another diagnosis) has been reported. 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 Paradoxical drug reaction (tuberculosis infection exacerbation in a patient who had previously shown improvement with appropriate antituberculosis therapy, in the absence of evidence of disease relapse or the presence of another diagnosis) has been reported, rheumatic syndrome, and systemic lupus erythematosus-like syndrome. Pyrazinamide The principal adverse effect is a hepatic reaction (see WARNINGS ). Hepatotoxicity appears to be dose related and may appear at any time during therapy. Pyrazinamide can cause hyperuricemia and gout (see PRECAUTIONS ). Gastrointestinal GI disturbances including nausea, vomiting, and anorexia have also been reported. Hematologic and Lymphatic Thrombocytopenia and sideroblastic anemia with erythroid hyperplasia, vacuolation of erythrocytes and increased serum concentration have occurred rarely with this drug. Adverse effects on blood clotting mechanisms have also been rarely reported. Other Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (see WARNINGS ), rashes, urticaria, pruritus, and erythema have been reported. Paradoxical drug reaction (tuberculosis infection exacerbation in a patient who had previously shown improvement with appropriate antituberculosis therapy, in the absence of evidence of disease relapse or the presence of another diagnosis) has been reported. Angioedema has been reported rarely. Fever, acne, photosensitivity, porphyria, dysuria, and interstitial nephritis have been reported rarely.

<table width="100%"><caption>Adverse Events Reported During the Clinical Study</caption><col align="left" width="56%" valign="middle"/><col align="center" width="22%" valign="middle"/><col align="center" width="22%" valign="middle"/><thead><tr><th styleCode="lrule"> </th><th colspan="2" styleCode="lrule rrule">Number of Patients with Adverse Events<footnote>A given patient may have experienced &#x2265;1 adverse event.</footnote></th></tr><tr><th styleCode="lrule toprule">Adverse Events by Body Systems During First 2 Months of Trial</th><th styleCode="lrule toprule">RIFATER n=122<footnote ID="footnote1">A total of 250 patients (124 RIFATER; 126 separate) were originally enrolled in the study. Five patients (2 RIFATER; 3 separate) were excluded due to admission errors.</footnote></th><th styleCode="lrule toprule rrule">Separate<footnote>Isoniazid, rifampin, and pyrazinamide dosed as separate tablets and capsules.</footnote> n=123<footnoteRef IDREF="footnote1"/></th></tr></thead><tbody><tr><td styleCode="lrule botrule"><content styleCode="bold">Cutaneous</content> (rash, erythroderma, erythema, exfoliative dermatitis, Lyell syndrome, urticaria, localized skin rash, diffuse skin rash, pruritus, generalized hypersensitivity)</td><td styleCode="lrule botrule" valign="bottom">8 (7%)</td><td styleCode="lrule botrule rrule" valign="bottom">21 (17%)</td></tr><tr><td styleCode="lrule botrule"><content styleCode="bold">Gastrointestinal</content> (nausea, vomiting, digestive pain, diarrhea)</td><td styleCode="lrule botrule" valign="bottom">8 (7%)</td><td styleCode="lrule botrule rrule" valign="bottom">14 (11%)</td></tr><tr><td styleCode="lrule botrule"><content styleCode="bold">Musculoskeletal</content> (arthralgia, long bones pain, phlebitis, localized joint pain, diffuse joint pain, edema of the legs)</td><td styleCode="lrule botrule" valign="bottom">5 (4%)</td><td styleCode="lrule botrule rrule" valign="bottom">8 (7%)</td></tr><tr><td styleCode="lrule botrule"><content styleCode="bold">Hearing and Vestibular</content> (tinnitus, vertigo, vertigo with loss of equilibrium)</td><td styleCode="lrule botrule" valign="bottom">3 (2%)</td><td styleCode="lrule botrule rrule" valign="bottom">6 (5%)</td></tr><tr><td styleCode="lrule botrule"><content styleCode="bold">Liver and Biliary</content> (hepatitis with conjunctival jaundice, hepatitis with deep jaundice)</td><td styleCode="lrule botrule" valign="bottom">0 (0%)</td><td styleCode="lrule botrule rrule" valign="bottom">2 (2%)</td></tr><tr><td styleCode="lrule botrule"><content styleCode="bold">Central and Peripheral Nervous System</content> (sweating, headache, insomnia, diffuse paresthesia of the legs, anxiety, diabetic coma)</td><td styleCode="lrule botrule" valign="bottom">5 (4%)</td><td styleCode="lrule botrule rrule" valign="bottom">4 (3%)</td></tr><tr><td styleCode="lrule botrule"><content styleCode="bold">Total Body</content> (spiking fever, persistent fever)</td><td styleCode="lrule botrule" valign="bottom">2 (2%)</td><td styleCode="lrule botrule rrule" valign="bottom">4 (3%)</td></tr><tr><td styleCode="lrule botrule"><content styleCode="bold">Cardiorespiratory</content> (tightness in chest, coughing, diffuse chest pain, hemoptysis, angina, palpitation, total pneumothorax)</td><td styleCode="lrule botrule" valign="bottom">8 (7%)</td><td styleCode="lrule botrule rrule" valign="bottom">3 (2%)</td></tr><tr><td styleCode="lrule botrule"><content styleCode="bold">Total number of patients with one or more adverse events</content></td><td styleCode="lrule botrule" valign="bottom">29</td><td styleCode="lrule botrule rrule" valign="bottom">43</td></tr></tbody></table>