Rifater (Rifampin, Isoniazid and Pyrazinamide)

RIFATER™

Hoechst Marion Roussel

Rifampin – Isoniazid – Pyrazinamide

Antituberculous Antibiotic

Action And Clinical Pharmacology: Rifater is an antibacterial fixed combination product containing 120 mg rifampin, 50 mg isoniazid and 300 mg pyrazinamide used for the treatment of tuberculosis. Rifampin, isoniazid and pyrazinamide are bactericidal agents active against both intracellular and extracellular tuberculosis organisms.

Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase, but does not inhibit the mammalian enzyme. Cross-resistance to rifampin has only been shown with other rifamycins. Isoniazid kills actively growing tubercle bacilli by inhibition of mycolic acid synthesis. The mechanism of action of pyrazinamide is unknown. In vitro and in vivo the drug is active only at a slightly acidic pH.

Pharmacokinetics: Pharmacokinetic studies in normal volunteers have shown that the 3 ingredients in Rifater have comparable bioavailability whether they are given together as individual dose forms or as Rifater.

Once daily doses of 4 to 7 tablets in tuberculosis patients resulted in the following steady-state pharmacokinetics.

Indications And Clinical Uses: 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. When indicated, the addition of other antituberculosis drugs, such as streptomycin and/or ethambutol, should be considered.

Following the initial phase and treatment with Rifater, treatment should be continued with rifampin and isoniazid 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. Susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment.

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.

Contra-Indications: In patients with a history of hypersensitivity to rifampin, isoniazid, pyrazinamide, or any of the components of the product. 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.

Manufacturers’ Warnings In Clinical States: Rifater is a combination of 3 drugs, each of which has been associated with liver dysfunction.

Isoniazid: Severe and sometimes fatal hepatitis associated with isoniazid 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: 0/1 000 for persons under 20 years of age, 3/1 000 for persons in the 20 to 34 year age group, 12/1 000 for persons in the 35 to 49 year age group, 23/1 000 for persons in the 50 to 64 year age group, and 8/1 000 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 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 the 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, isoniazid 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 must be reinstituted, it should be reinstituted only after symptoms and laboratory abnormalities have cleared. The drug 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.

Ophthalmologic examinations (including ophthalmoscopy) should be done before isoniazid is started and periodically thereafter, even without occurrence of visual symptoms.

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. Patients with impaired liver function should only be given rifampin in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially serum ALT and serum AST should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, Rifater, because it contains rifampin should be withdrawn.

In some cases, hyperbilirubinemia resulting from competition between rifampin and bilirubin for excretory pathways of the liver at the cell levels 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 aminolevulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration.

Pyrazinamide: Patients started on pyrazinamide should have baseline serum uric acid and liver function determinations. Patients with pre-existing 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, patients 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 management may be more difficult.

A complete blood count (CBC), liver function tests, and blood uric acid determinations should be obtained prior to instituting therapy and periodically throughout the course of therapy. Because of a possible transient rise in transaminase and bilirubin values, blood for baseline clinical chemistries should be obtained before Rifater dosing.

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 isoniazid should be carefully monitored in the following:

1. Patients who are receiving phenytoin 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.

2. Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis.

3. Patients with current chronic liver disease or severe renal dysfunction.

Rifampin: For treatment of tuberculosis, rifampin is usually administered on a daily basis. High doses of rifampin (greater than 600 mg) given once or twice weekly have resulted in a high 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 and renal failure. Rifampin has been observed to increase the requirements for anticoagulant drugs of the coumarin type. In patients receiving anticoagulants and rifampin 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.

The patient should be advised that the reliability of oral contraceptives may be affected; consideration should be given to using alternative contraceptive measures.

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.

Pregnancy: It is not known whether Rifater can affect reproduction capacity. 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.

Teratogenic Effects: Animal reproduction studies have not been conducted with Rifater. It is also not known whether Rifater can cause fetal harm when administered to a pregnant woman. Rifater should be given to a pregnant woman only if clearly needed.

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). Rifater, because it contains isoniazid, should be prescribed during pregnancy only when therapeutically necessary. The benefit of preventive therapy should be weighed against a possible risk to the fetus. Preventive treatment generally should be started after delivery because of the increased risk of tuberculosis for new mothers.

Rifampin: Although rifampin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampin, alone or in combination with other antituberculosis drugs, on the human fetus is not known. An increase in congenital malformations, primarily spina bifida and cleft palate, has been reported in the offspring of rodents given oral doses of 150 to 250 mg/kg/day of rifampin during pregnancy. The possible teratogenic potential in women capable of bearing children should be carefully weighed against the benefits of Rifater therapy.

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. Rifater, because it contains pyrazinamide, should be given to a pregnant woman only if clearly needed.

Non-Teratogenic Effects: it is not known whether Rifater can affect reproduction capacity.

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.

Lactation: 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.

Children: Safety and effectiveness in children have not been established.

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.

Isoniazid: Isoniazid has been reported to induce pulmonary tumors in a number of strains of mice.

Rifampin: There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility. 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. An increase in the incidence of hepatomas in female mice (of a strain known to be particularly susceptible to the spontaneous development of hepatomas) was observed when rifampicin was administered in doses 2 to 10 times the average daily human dose for 60 weeks followed by an observation period of 46 weeks. No evidence of carcinogenicity was found in male mice of the same strain, mice of a different strain, or rats under similar experimental conditions.

Rifampin has been reported to possess immunosuppressive potential in rabbits, mice, rats, guinea pigs, human lymphocytes in vitro, and humans. Antitumor acitvity in vitro has been shown with rifampin.

There was no evidence of mutagenicity in bacteria, Drosophila melanogaster, or mice. An increase in chromatid breaks was noted when whole blood cell cultures were treated with rifampin.

Pyrazinamide: In lifetime bioassays in rats and mice, pyrazinamide was administered in the diet at concentrations of up to 10 000 ppm. This resulted in estimated daily doses of 2 g/kg for the mouse, or 40 times the maximum human dose, and 0.5 g/kg for the rat, or 10 times the maximum human dose. Pyrazinamide was not carcinogenic in rats or male mice and no conclusion was possible for female mice.

Pyrazinamide was not mutagenic in the Ames bacterial test, but induced chromosomal aberrations in human lymphocyte cell cultures.

Drug Interactions: 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. Dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered 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 currently 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 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.

In case reports, the CNS effects of meperidine (drowsiness), cycloserine (dizziness, drowsiness), and disulfiram (acute behavioral and coordination changes) may be exaggerated when concomitant isoniazid is given. Concurrent 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 which facilitates deflorination of enflurane. Renal function should be monitored in patients receiving this drug combination.

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.

Rifampin: Enzyme Induction: Rifampin is known to induce certain cytochrome P-450 enzymes. Coadministration of 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 accelerate the metabolism of the following drugs: anticonvulsants (e.g., phenytoin), antiarrhythmics (e.g., disopyramide, mexiletine, quinidine, tocainide), anticoagulants, antifungals (e.g., fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (e.g., diltiazem, nifedipine, verapamil), chloramphenicol, ciprofloxacin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral contraceptives, dapsone, diazepam, haloperidol, oral hypoglycemic agents (sulfonylureas), narcotic analgesics, nortriptyline, progestins, and theophylline. It may be necessary to adjust the dosages of these drugs if they are given concurrently with Rifater since it contains rifampin.

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. Dosage adjustments should be made if indicated by the patient’s clinical condition.

Other Interactions : Concomitant antacid administration may reduce the absorption of rifampin. Daily doses of 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 and halothane should be avoided. Patients receiving both rifampin and isoniazid as in Rifater should be monitored closely for hepatotoxicity (see Warnings).

Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and rifampin. This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine.

Drug/Laboratory Tests Interaction: Rifampin: Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Therefore, alternate assay methods should be considered. Transient abnormalities in liver function tests (e.g., elevation in serum bilirubin, abnormal bromsulphalein [BSP] excretion, 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.

Rifater, because it contains rifampin may produce a reddish coloration of the urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained.

Patients should be instructed to take Rifater either 1 hour before or 2 hours after a meal.

Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, 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: A complete blood count (CBC), liver function tests, and blood uric acid determinations should be obtained prior to instituting therapy and periodically throughout the course of therapy. Because of a possible transient rise in transaminase and bilirubin values, blood for baseline clinical chemistries should be obtained before Rifater dosing.

Adverse Reactions: The adverse reactions reported during therapy with Rifater are consistent with reactions described or listed below for the individual components.

Isoniazid: The most frequent reactions are those affecting the nervous system and the liver (see Warnings).

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 paresthesias 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: Nausea, vomiting, and epigastric distress.

Hepatic: elevated serum transaminases (ALT, AST), 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, and vasculitis.

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

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

Rifampin: Gastrointestinal: heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea have been noted in some patients. Although C. 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. 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.

Transient leukopenia, hemolytic anemia, and decreased hemoglobin have been observed.

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

Rare reports of myopathy have also been observed.

Ocular: Visual disturbances have been observed.

Endocrine: Menstrual disturbances have been observed.

Renal: Elevations in BUN and serum uric acid have been reported. Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, 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, eosinophilia, sore mouth, sore tongue and conjunctivitis have been observed.

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.

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: Gastrointestinal 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 iron 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 rashes, urticaria, and pruritus have been reported. Fever, acne, photosensitivity, porphyria, dysuria and interstitial nephritis have been reported rarely.

Symptoms And Treatment Of Overdose: There is no human experience with Rifater overdosage.

Isoniazid: 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.

Rifampin: Nonfatal overdoses with as high as 12 g of rifampin have been reported.

One case of fatal overdose is known: a 26-year-old man died after self-administering 60 g of rifampin.

Pyrazinamide: Overdosage experience with pyrazinamide is limited.Symptoms: The following signs and symptoms have been seen with each individual component in an overdosage situation.

Isoniazid: 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.

Rifampin: Nausea, vomiting, and increasing lethargy will probably occur within a short time after rifampin overdosage; unconsciousness may occur when there is severe hepatic disease. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears and feces will occur, and its intensity is proportional to the 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.

Pyrazinamide: In 1 case of pyrazinamide overdosage, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped.

Treatment: The airway should be secured and adequate respiratory exchange should be established in cases of overdosage with Rifater.

Obtain blood samples for immediate determination of gases, electrolytes, BUN, glucose, etc.; type and cross-match blood in preparation for possible hemodialysis.

Gastric lavage within the first 2 to 3 hours after ingestion is advised, but it should not be attempted until convulsions are under control. To treat convulsions, administer i.v. diazepam or short-acting barbiturates, and i.v. pyridoxine (usually 1 mg/1 mg isoniazid ingested). Following evacuation of gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting.

Rapid control of metabolic acidosis is fundamental to management. Give i.v. sodium bicarbonate at once and repeat as needed, adjusting subsequent dosage on the basis of laboratory findings (e.g., 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; monitor fluid intake and output.

Hemodialysis is advised for severe cases; 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, utilize meticulous respiratory and other intensive care to protect against hypoxia, hypotension, aspiration pneumonitis, etc.

Dosage And Administration: Adults: Patients should be given the following single daily dose either 1 hour before or 2 hours after a meal with a full glass of water: Patients weighing 44 kg or less: 4 tablets; patients weighing between 45 to 54 kg: 5 tablets; patients weighing 55 kg or greater: 6 tablets.

Rifater is recommended in the initial phase of short-course therapy which is usually continued for 2 months. When indicated, the addition of other antituberculosis drugs, such as streptomycin and/or ethambutol, should be considered.

Following the initial phase, treatment should be continued with rifampin and isoniazid 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.

Concomitant administration of pyridoxine (B6) is recommended in the malnourished, in those predisposed to neuropathy (e.g., alcoholics and diabetics), and in adolescents.

Children: The ratio of the drugs in Rifater may not be appropriate in children (e.g., higher mg/kg doses of isoniazid are usually given in children than adults) (see Precautions).

Availability And Storage: Each light beige, round, sugar-coated tablet contains: rifampin 120 mg, isoniazid 50 mg and pyrazinamide 300 mg. Nonmedicinal ingredients: acacia, aluminum hydroxide, calcium stearate, carnauba wax, colophony, kaolin, magnesium carbonate, paraffin, povidone, ferric oxide, silicon dioxide, sodium carboxymethylcellulose, sodium lauryl sulfate, sucrose, talc, titanium dioxide and white beeswax. Bottles of 60. Store at controlled room temperature (15 to 30°C). Protect from moisture.

RIFATER™ Hoechst Marion Roussel Rifampin – Isoniazid – Pyrazinamide Antituberculous Antibiotic

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