endorsed [50:<50 kg or 600 mg of rifampin and 300 mg of isoniazid per day for 4 months if the patient weighed 50 kg. Patients were followed for occurrence of relapses for up to 30 months after the end of therapy. There were no significant differences in the negative bacteriological sputum results (available in a subset of patients) between the two treatments at 2 and 6 months during the trial and during the follow-up period. See table below. Negative Sputa/No. of Patients (Percent Negative) Treatment 2 Months 6 Months Follow-up Period * * The median follow-up time for all the Rifater patients was 756 days with a range of 42 to 1325 days and 745 days with a range of 50 to 1427 days for the patients dosed with separate tablets and capsules. Isoniazid, rifampin, and pyrazinamide dosed as separate tablets and capsules. Rifater 91/96 (95%) 100/104 (96%) 99/101 (98%) Separate 99/108 (92%) 95/96 (99%) 105/106 (99%) For adverse events, see ADVERSE REACTIONS . Indications and Usage for Rifater Rifater is indicated in the initial phase of the short-course treatment of pulmonary tuberculosis. During this phase, which should last 2 months, Rifater should be administered on a daily, continuous basis (see DOSAGE AND ADMINISTRATION ). Following the initial phase and treatment with Rifater, treatment should be continued with rifampin and isoniazid (e.g., RIFAMATE) for at least 4 months. Treatment should be continued for a longer period of time if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive. 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, isoniazid, and pyrazinamide and they should be repeated throughout therapy to monitor response to the treatment. If test results show resistance to any of the components of Rifater and the patient is not responding to therapy, the drug regimen should be modified. Contraindications Rifater is contraindicated in patients with a history of hypersensitivity to rifampin, isoniazid, pyrazinamide or any of the components, or to any of the rifamycins. Rifampin Rifampin is contraindicated in patients who are also receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity. (See PRECAUTIONS, Drug Interactions .) Rifampin is contraindicated in patients who are also receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance. Isoniazid Other contraindications include patients with severe hepatic damage; severe adverse reactions to isoniazid, such as drug fever, chills, and arthritis; patients with acute liver disease of any etiology; and patients with acute gout. 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, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, may occur in patients receiving Rifater (see ADVERSE REACTIONS ). 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). These reactions may be severe and DRESS may be fatal. 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. Rifampin Rifampin has been shown to produce liver dysfunction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking rifampin with other hepatotoxic agents. Because Rifater 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, Rifater 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 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 (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. Precautions General Rifater should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult. Rifampin For treatment of tuberculosis, rifampin is usually administered on a daily basis. Doses of rifampin (> 600 mg) given once or twice weekly have resulted in a higher incidence of adverse reactions, including the "flu syndrome" (fever, chills and malaise); hematopoietic reactions (leukopenia, thrombocytopenia, or acute hemolytic anemia); cutaneous, gastrointestinal, and hepatic reactions; shortness of breath; shock, anaphylaxis, and renal failure. Recent studies indicate that regimens using twice-weekly doses of rifampin 600 mg plus isoniazid 15 mg/kg are much better tolerated. Rifampin is not recommended for intermittent therapy; the patient should be cautioned against intentional or accidental interruption of the daily dosage regimen since rare renal hypersensitivity reactions have been reported when therapy was resumed in such cases. Rifampin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D. Isoniazid All drugs should be stopped and an evaluation of the patient should be made at the first sign of a hypersensitivity reaction. Use of Rifater, because it contains isoniazid, should be carefully monitored in the following: Patients who are receiving phenytoin (diphenylhydantoin) concurrently. Isoniazid may decrease the excretion of phenytoin or may enhance its effects. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant dose should be made. Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis. Patients with current chronic liver disease or severe renal dysfunction. Pyrazinamide Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia which is usually asymptomatic. If hyperuricemia is accompanied by acute gouty arthritis, Rifater, because it contains pyrazinamide, should be discontinued. Information for Patients Food Interactions Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Tyramine and histamine-containing foods should be avoided in patients receiving Rifater. Rifater, because it contains rifampin, may produce a discoloration (yellow, orange, red, brown) of the teeth, urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained. The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures. Patients should be instructed to take Rifater either 1 hour before or 2 hours after a meal with a full glass of water. Patients should be instructed to notify their physician immediately if they experience any of the following: rash with fever or blisters, with or without peeling skin, fever or swollen lymph nodes, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, cough, shortness of breath, wheezing, pain or swelling of the joints. Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed. Laboratory Tests Adults treated for tuberculosis with Rifater should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count (CBC) and platelet count (or estimate), and blood uric acid. Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not necessary. Drug Interactions Rifampin Healthy subjects who received rifampin 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity. Therefore, concomitant use of these medications is contraindicated. (See CONTRAINDICATIONS .) Enzyme Induction Rifampin is known to induce certain cytochrome P-450 enzymes. Coadministration of Rifater, because it contains rifampin, with drugs that undergo biotransformation through these metabolic pathways may accelerate elimination. To maintain optimum therapeutic blood levels, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered rifampin. Rifampin has been reported to substantially decrease the plasma concentrations of the following antiviral drugs: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. These antiviral drugs must not be coadministered with rifampin. (See CONTRAINDICATIONS .) Rifampin has been reported to accelerate the metabolism of the following drugs: anticonvulsants (e.g., phenytoin), digitoxin, antiarrhythmics (e.g., disopyramide, mexiletine, quinidine, tocainide), oral anticoagulants, antifungals (e.g., fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (e.g., diltiazem, nifedipine, verapamil), chloramphenicol, clarithromycin, fluoroquinolones (e.g., ciprofloxacin), corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral or other systemic hormonal contraceptives, dapsone, diazepam, doxycycline, haloperidol, oral hypoglycemic agents (sulfonylureas), levothyroxine, methadone, narcotic analgesics, progestins, quinine, tacrolimus, theophylline, tricyclic antidepressants (e.g., amitriptyline, nortriptyline), and zidovudine. It may be necessary to adjust dosages of these drugs if they are given concurrently with Rifater since it contains rifampin. Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during rifampin therapy. Rifampin has been observed to increase the requirements for anticoagulant drugs of the coumarin type. In patients receiving anticoagulants and Rifater concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant. When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampin were observed. Concurrent use of ketoconazole and rifampin has resulted in decreased serum concentration of both drugs. Concurrent use of rifampin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Since Rifater contains rifampin, dosage adjustments should be made if Rifater is concurrently administered with ketoconazole or enalapril if indicated by the patient's clinical condition. Other Interactions Concomitant antacid administration may reduce the absorption of rifampin. Daily doses of Rifater, because it contains rifampin, should be given at least 1 hour before the ingestion of antacids. Probenecid and cotrimoxazole have been reported to increase the blood level of rifampin. When rifampin is given concomitantly with either halothane or isoniazid the potential for hepatotoxicity is increased. The concomitant use of Rifater, because it contains both rifampin and isoniazid, and halothane should be avoided. Patients receiving both rifampin and isoniazid as in Rifater should be monitored closely for hepatotoxicity. (See the boxed WARNING .) Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and Rifater, because it contains rifampin. This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine. Isoniazid Enzyme Inhibition Isoniazid is known to inhibit certain cytochrome P-450 enzymes. Coadministration of isoniazid with drugs that undergo biotransformation through these metabolic pathways may decrease elimination. Consequently, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered Rifater, because it contains isoniazid, to maintain optimum therapeutic blood levels. Isoniazid has been reported to inhibit the metabolism of the following drugs: anticonvulsants (e.g., carbamazepine, phenytoin, primidone, valproic acid), benzodiazepines (e.g., diazepam), haloperidol, ketoconazole, theophylline, and warfarin. It may be necessary to adjust the dosages of these drugs if they are given concurrently with Rifater because it contains isoniazid. The impact of the competing effects of rifampin and isoniazid on the metabolism of these drugs is unknown. Other Interactions Concomitant antacid administration may reduce the absorption of isoniazid. Ingestion with food may also reduce the absorption of isoniazid. Daily doses of Rifater, because it contains isoniazid, should be given on an empty stomach at least 1 hour before the ingestion of antacids or food. Corticosteroids (e.g., prednisolone) may decrease the serum concentration of isoniazid by increasing acetylation rate and/or renal clearance. Para-aminosalicylic acid may increase the plasma concentration and elimination half-life of isoniazid by competition of acetylating enzymes. Pharmacodynamic Interactions Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis. Isoniazid, when given concomitantly with rifampin, has been reported to increase the hepatotoxicity of both drugs. Patients receiving both rifampin and isoniazid as in Rifater should be monitored closely for hepatotoxicity. The CNS effects of meperidine (drowsiness), cycloserine (dizziness, drowsiness), and disulfiram (acute behavioral and coordination changes) may be exaggerated when concomitant Rifater, because it contains isoniazid, is given. Concurrent Rifater, because it contains isoniazid, and levodopa administration may produce symptoms of excess catecholamine stimulation (agitation, flushing, palpitations) or lack of levodopa effect. Isoniazid may produce hyperglycemia and lead to loss of glucose control in patients on oral hypoglycemics. Fast acetylation of isoniazid may produce high concentrations of hydrazine that facilitate defluorination of enflurane. Renal function should be monitored in patients receiving both Rifater and enflurane. Food Interactions Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Tyramine and histamine-containing foods should be avoided by patients receiving Rifater. Drug/Laboratory Test Interactions Rifampin Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving rifampin when using the KIMS (Kinetic Interaction of Microparticles in Solution) method (e.g., Abuscreen OnLine opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish rifampin from opiates. Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B 12 . Therefore, alternative assay methods should be considered. Transient abnormalities in liver function tests (e.g., elevation in serum bilirubin, alkaline phosphatase and serum transaminases), and reduced biliary excretion of contrast media used for visualization of the gallbladder have also been observed. Therefore, these tests should be performed before the morning dose of Rifater. Rifampin and isoniazid have been reported to alter vitamin D metabolism. In some cases, reduced levels of circulating 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D have been accompanied by reduced serum calcium and phosphate, and elevated parathyroid hormone. Pyrazinamide Pyrazinamide has been reported to interfere with ACETEST and KETOSTIX urine tests to produce a pink-brown color. Carcinogenesis, Mutagenesis, Impairment of Fertility Increased frequency of chromosomal aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide. Rifampin A few cases of accelerated growth of lung carcinoma have been reported in man, but a causal relationship with the drug has not been established. Hepatomas were increased in female (C3Hf/DP) mice dosed for 60 weeks with rifampicin followed by an observation period of 46 weeks, at 20 to 120 mg/kg (equivalent to 0.1 to 0.5 times the maximum dosage used clinically, based on body surface area comparisons). There was no evidence of tumorigenicity in male C3Hf/DP mice or, in similar studies in BALB/c mice, or in two year studies in Wistar rats. There was no evidence of mutagenicity in both prokaryotic ( Salmonella typhi, Escherichia coli ) and eukaryotic ( Saccharomyces cerevisiae ) bacteria, Drosophila melanogaster , or ICR/Ha Swiss mice. An increase in chromatid breaks was noted when whole blood cell cultures were treated with rifampin. Increased frequency of chromosomal aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide. Isoniazid Isoniazid has been reported to induce pulmonary tumors in a number of strains of mice. Pyrazinamide Pyrazinamide was not carcinogenic in lifetime bioassays in rats (at doses up to 500 mg/kg, about three times the recommended human dose, based on body surface area comparisons) or mice (at doses up to 2000 mg/kg, about five times the recommended human dose, based on body surface area comparisons). Pyrazinamide was not mutagenic in the Ames bacterial test, but induced chromosomal aberrations in human lymphocyte cell cultures. Pregnancy Teratogenic Effects Category C. Although animal reproduction studies have not been conducted with Rifater teratogenic effects (including cleft palate and spina bifida) have been observed in rodents treated with rifampin at doses 0.2 to 2 times the maximum recommended human dose, based on body surface area comparisons. There are no adequate and well-controlled studies of Rifater in pregnant women. Rifater should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rifampin Congenital malformations, primarily spina bifida were increased in the offspring of pregnant rats given rifampin during organogenesis at oral doses of 150 to 250 mg/kg/day (about 1 to 2 times the maximum recommended human dose based on body surface area comparisons). Cleft palate was increased in a dose-dependent fashion in fetuses of pregnant mice treated at oral doses of 50 to 200 mg/kg (about 0.2 to 0.8 times the maximum recommended human dose based on body surface area comparisons). Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given rifampin at oral doses up to 200 mg/kg/day (about 3 times the maximum recommended daily human dose based on body surface area comparisons). Although there are no adequate and well-controlled studies in pregnant women, rifampin has been reported to cross the placental barrier and appear in cord blood. Isoniazid It has been reported that in both rats and rabbits, isoniazid may exert an embryocidal effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, and rabbits). Pyrazinamide Animal reproductive studies have not been conducted with pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm when administered to a pregnant woman. Pregnancy Non-Teratogenic Effects When administered during the last few weeks of pregnancy, rifampin can cause post-natal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated. Rifampin When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant. In this case, treatment with vitamin K may be indicated for postnatal hemorrhage. Nursing Mothers Since rifampin, isoniazid, and pyrazinamide are known to pass into maternal breast milk, a decision should be made whether to discontinue nursing or to discontinue Rifater, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients under the age of 15 have not been established. (See CLINICAL PHARMACOLOGY, General ; See also DOSAGE AND ADMINISTRATION .) Geriatric Use Clinical studies of Rifater did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using rifampin and isoniazid in elderly patients. (See WARNINGS .) 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 * Adverse Events by Body Systems During First 2 Months of Trial Rifater n=122 Separate n=123 * A given patient may have experienced 1 adverse event. 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. Isoniazid, rifampin and pyrazinamide dosed as separate tablets and capsules. 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 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 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 s encouraged
be sure that Rifater the actuality
EmoticonEmoticon