Rifater (Tablet, Sugar Coated)
Adults: Patients should be given the following single daily dose of RIFATER either 1 hour before or 2 hours after a meal with a full glass of water. Patients weighing���44 kg���4 tablets Patients weighing between 45���54 kg���5 tablets Patients weighing���55 kg���6 tablets<br/>Pediatric Patients: The ratio of the drugs in RIFATER may not be appropriate in pediatric patients under the age of 15 (eg, higher mg/kg doses of isoniazid are usually given in pediatric patients than adults). 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 the 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 or rifampin 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 rifampin and isoniazid (eg, 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. Concomitant administration of pyridoxine (B) is recommended in the malnourished, in those predisposed to neuropathy (eg, alcoholics and diabetics), and in adolescents. See CLINICAL PHARMACOLOGY: General for dosing information in patients with renal failure.
RIFATER (rifampin/isoniazid/pyrazinamide) tablets are combination tablets containing 120 mg rifampin, 50 mg isoniazid, and 300 mg pyrazinamide for use in antibacterial therapy. The tablets also contain as inactive ingredients: povidone, carboxymethylcellulose sodium, calcium stearate, sodium lauryl sulfate, sucrose, talc, acacia, titanium dioxide, kaolin, magnesium carbonate, colloidal silicon dioxide, dried aluminum hydroxide gel, ferric oxide, black iron oxide, carnauba wax, white beeswax, colophony, hard paraffin, lecithin, shellac, and propylene glycol. The RIFATER triple therapy combination was developed for dosing convenience. Rifampin is a semisynthetic antibiotic derivative of rifamycin SV. Rifampin is a red-brown crystalline powder very slightly soluble in water at neutral pH, freely soluble in chloroform, soluble in ethyl acetate and methanol. Its molecular weight is 822.95 and its chemical formula is CHNO. The chemical name for rifampin is either: 3-[[(4-methyl-1-piperazinyl)imino]-methyl]-rifamycin; or 5,6,9,17,19,21-hexahydroxy-23methoxy-2,4,12,16,18,20,22 heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate. Its structural formula is: Isoniazid is the hydroxide of isonicotinic acid. It is a colorless or white crystalline powder or white crystals. It is odorless and slowly affected by exposure to air and light. It is freely soluble in water, sparingly soluble in alcohol and slightly soluble in chloroform and in ether. Its molecular weight is 137.14 and its chemical formula is CHNO. The chemical name for isoniazid is 4-pyridinecarboxylic acid, hydrazide and its structural formula is: Pyrazinamide, the pyrazine analogue of nicotinamide, is a white, crystalline powder, stable at room temperature, and sparingly soluble in water. The chemical name for pyrazinamide is pyrazinecarboxamide and its molecular weight is 123.11. Its chemical formula is CHNO and its structural formula is:
General:<br/>Rifampin: Rifampin is readily absorbed from the gastrointestinal tract. Peak serum levels in normal adults and pediatric populations vary widely from individual to individual. Following a single 600 mg oral dose of rifampin in healthy adults, the peak serum level averages 7 mcg/mL but may vary from 4 to 32 mcg/mL. Absorption of rifampin is reduced when the drug is ingested with food. In normal subjects, the biological half-life of rifampin in serum averages about 3 hours after a 600 mg oral dose, with increases up to 5.1 hours reported after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2 to 3 hours. The half-life does not differ in patients with renal failure at doses not exceeding 600 mg daily and, consequently, no dosage adjustment is required. The half-life of rifampin at a dose of 720 mg daily has not been established in patients with renal failure. Following a single 900 mg oral dose of rifampin in patients with varying degrees of renal insufficiency, the half-life increased from 3.6 hours in normal subjects to 5.0, 7.3, and 11.0 hours in patients with glomerular filtration rates of 30���50 mL/min, less than 30 mL/min, and in anuric patients, respectively. Refer to the WARNINGS section for information regarding patients with hepatic insufficiency. After absorption, rifampin is rapidly eliminated in the bile, and an enterohepatic circulation ensues. During this process, rifampin undergoes progressive deacetylation so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite has antibacterial activity. Intestinal reabsorption is reduced by deacetylation, and eliminationis facilitated. Up to 30% of a dose is excreted in the urine, with about half as unchanged drug. Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore is diffused freely in tissues.<br/>Isoniazid: After oral administration, isoniazid is readily absorbed from the GI tract and produces peak blood levels within 1 to 2 hours. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excreta (saliva, sputum, and feces). Isoniazid is not substantially bound to plasma proteins. The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. The plasma half-life of isoniazid in patients with normal renal and hepatic function ranges from 1���4 hours, depending on the rate of metabolism. From 50% to 70% of a dose of isoniazid is excreted in the urine within 24 hours, mostly as metabolites. Isoniazid is metabolized in the liver mainly by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50% of African Americans and Caucasians are "slow inactivators" and the rest are "rapid inactivators"; the majority of Eskimos and Asians are "rapid inactivators." The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug, and thus, an increase in toxic reactions. Pyridoxine (B) deficiency is sometimes observed in adults with high doses of isoniazid and is probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase.<br/>Pyrazinamide: Pyrazinamide is well absorbed from the gastrointestinal tract and attains peak plasma concentrations within 2 hours. Plasma concentrations generally range from 30 to 50 mcg/mL with doses of 20 to 25 mg/kg. It is widely distributed in body tissues and fluids including the liver, lungs, and cerebrospinal fluid (CSF). The CSF concentration is approximately equal to concurrent steady-state plasma concentrations in patients with inflamed meninges. Pyrazinamide is approximately 10% bound to plasma proteins. The plasma half-life of pyrazinamide is 9 to 10 hours in patients with normal renal and hepatic function. The half-life of the drug may be prolonged in patients with impaired renal or hepatic function. Pyrazinamide is hydrolyzed in the liver to its major active metabolite, pyrazinoic acid. Pyrazinoic acid is hydroxylated to the main excretory product, 5-hydroxypyrazinoic acid. Within 24 hours, approximately 70% of an oral dose of pyrazinamide is excreted in urine, mainly by glomerular filtration. About 4% to 14% of the dose is excreted as unchanged drug; the remainder is excreted as metabolites.<br/>RIFATER: In a single-dose bioavailability study of five RIFATER tablets (Treatment A, n=23) versus RIFADIN 600 mg, isoniazid 250 mg, and pyrazinamide 1500 mg (Treatment B, n=24) administered concurrently in normal subjects, there was no difference in extent of absorption, as measured by the area under the plasma concentration versus time curve (AUC), of all three components. However, the mean peak plasma concentration of rifampin was approximately 18% lower following the single-dose administration of RIFATER tablets as compared to RIFADIN administered in combination with pyrazinamide and isoniazid. Mean (��SD) pharmacokinetic parameters are summarized in the following table. The effect of food on the pharmacokinetics of RIFATER tablets was not studied.<br/>Microbiology: Rifampin, isoniazid, and pyrazinamide at therapeutic levels have demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms.<br/>Mechanism of Action:<br/>Rifampin: Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms. Specifically, it interacts with bacterial RNA polymerase, but does not inhibit the mammalian enzyme. Organisms resistant to rifampin are likely to be resistant to other rifamycins.<br/>Isoniazid: Isoniazid kills actively growing tubercle bacilli by inhibiting the biosynthesis of mycolic acids which are major components of the cell wall of Mycobacterium tuberculosis.<br/>Pyrazinamide: The exact mechanism of action by which pyrazinamide inhibits the growth of Mycobacterium tuberculosis organisms is unknown. In vitro and in vivo studies have demonstrated that pyrazinamide is only active at a slightly acidic pH (pH 5.5).<br/>Susceptibility Testing: Prior to initiation of therapy, appropriate specimens should be collected for identification of the infecting organism and in vitro susceptibility tests. Two standardized in vitro susceptibility methods are available for testing isoniazid, rifampin, and pyrazinamide against Mycobacterium tuberculosis organisms. The agar proportion method (CDC or NCCLS M24-P) utilizes Middlebrook 7H10 medium impregnated with isoniazid at 0.2 and 1.0 mcg/mL and rifampin at 1.0 mcg/mL for the final concentrations of drug. The final concentration for pyrazinamide is 25.0 mcg/mL at pH 5.5. After 3 weeks of incubation MICvalues are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug���1% of the control indicates resistance. The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 0.2 and 1.0 mcg/mL of isoniazid and 2.0 mcg/mL of rifampin. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay. The radiometric broth method has not been approved for the testing of pyrazinamide. Susceptibility test results obtained by the two different methods can only be compared if the appropriate rifampin or isoniazid concentrations are used for each test method as indicated above. Both test procedures require the use of Mycobacterium tuberculosis H37Rv, ATCC 27294, as a control organism. The clinical relevance of in vitro susceptibility test results for mycobacterial species other than Mycobacterium tuberculosis using either the radiometric broth method or the proportion method has not been determined.
RIFATER is contraindicated in patients with a history of hypersensitivity to rifampin, isoniazid, pyrazinamide, or any of the components. 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.
RIFATER tablets are light beige, smooth, round, and shiny sugar-coated tablets imprinted with "RIFATER" in black ink and contain 120 mg rifampin, 50 mg isoniazid, and 300 mg pyrazinamide, and are supplied as: Bottles of 60 tablets (NDC 0088-0576-41).<br/>Storage Conditions: Store at controlled room temperature 59���86��F (15���30��C). Protect from excessive humidity.<br/>Reference:
WARNING: 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 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 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 progressiveliver 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.
dailymed-ingredient:acacia, dailymed-ingredient:black_iron_oxide, dailymed-ingredient:calcium_stearate, dailymed-ingredient:carboxymethylcellulose_sodium, dailymed-ingredient:carnauba_wax, dailymed-ingredient:colloidal_silicon_dioxide, dailymed-ingredient:colophony, dailymed-ingredient:dried_aluminum_hydroxide_gel, dailymed-ingredient:ferric_oxide, dailymed-ingredient:hard_paraffin, dailymed-ingredient:kaolin, dailymed-ingredient:lecithin, dailymed-ingredient:magnesium_carbonate, dailymed-ingredient:povidone, dailymed-ingredient:propylene_glycol, dailymed-ingredient:shellac, dailymed-ingredient:sodium_lauryl_sulfate, dailymed-ingredient:sucrose, dailymed-ingredient:talc, dailymed-ingredient:titanium_dioxide, dailymed-ingredient:white_beeswax
RIFATER: There is no human experience with RIFATER overdosage.<br/>Rifampin: Non-fatal 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.<br/>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.<br/>Pyrazinamide: Overdosage experience with pyrazinamide is limited.<br/>Signs and Symptoms: The following signs and symptoms have been seen with each individual component in an overdosage situation.<br/>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.<br/>Isoniazid: Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours. Nausea, vomiting, dizziness, slurring of speech, blurring of vision, and 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.<br/>Pyrazinamide: In one case of pyrazinamide overdosage, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped.<br/>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 IV diazepam or short-acting barbiturates, and IV 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 IV sodium bicarbonate at once and repeat as needed, adjusting subsequent dosage on the basis of laboratory findings (ie, 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.
rifampin, isoniazid and pyrazinamide
Rifater (Tablet, Sugar Coated)
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. 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.<br/>Adverse Reactions Reported for Individual Components:<br/>Rifampin:<br/>Isoniazid: The most frequent reactions are those affecting the nervous system and the liver. See the boxed WARNING.<br/>Pyrazinamide: The principal adverse effect is a hepatic reaction . Hepatotoxicity appears to be dose related and may appear at any time during therapy. Pyrazinamide can cause hyperuricemia and gout .
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 . Following the initial phase and treatment with RIFATER, treatment should be continued with rifampin and isoniazid (eg, 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.