rifater (rifampin, isoniazid and pyrazinamide) tablet, sugar coated
[sanofi-aventis U.S. LLC]
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 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 The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent liver involvement.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.
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 C43H58N4O12. The chemical name for rifampin is either:
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 C6H7N3O.
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 C5H5N3O and its structural formula is:
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 elimination is 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.
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 (B6) 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.
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.
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.
Rifampin, isoniazid, and pyrazinamide at therapeutic levels have demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms.
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.
Isoniazid kills actively growing tubercle bacilli by inhibiting the biosynthesis of mycolic acids which are major components of the cell wall of Mycobacterium tuberculosis.
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).
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 MIC99 values 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.
A total of 250 patients were enrolled in an open label, prospective, randomized, parallel group, active controlled trial, for the treatment of pulmonary tuberculosis. There were 241 patients evaluable for efficacy, 123 patients received isoniazid, rifampin and pyrazinamide as separate tablets and capsules for 56 days, and 118 patients received 4 to 6 RIFATER tablets based on body weight for 56 days. RIFATER tablets and the drugs dosed as separate tablets and capsules were administered based on body weight during the intensive phase of treatment according to the following table.
|45 to 54 kg||5||250||600||1500|
During the continuation phase, both treatment groups received 450 mg of rifampin and 300 mg of isoniazid per day for 4 months if the patient weighed <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.
|Treatment||2 Months||6 Months||Follow-up Period*|
|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 section.
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 section).
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.
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 is a combination of the three drugs, rifampin, isoniazid, and pyrazinamide. Each of these individual drugs has been associated with liver dysfunction.
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.
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.
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 (eg, 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.
RIFATER should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult.
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 and renal failure.
The patient should be advised that the reliability of oral contraceptives may be affected; consideration should be given to using alternative contraceptive measures.
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:
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.
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 (eg, headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (eg, 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 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.
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.
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 accelerate the metabolism of the following drugs: anticonvulsants (eg, phenytoin), antiarrhythmics (eg, disopyramide, mexiletine, quinidine, tocainide), anticoagulants, antifungals (eg, fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (eg, diltiazem, nifedipine, verapamil), chloramphenicol, ciprofloxacin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral contraceptives, dapsone, diazepam, haloperidol, oral hypoglycemic agents (sulfonylureas), methadone, narcotic analgesics, nortriptyline, progestins, and theophylline. It may be necessary to adjust dosages of these drugs if they are given concurrently with RIFATER since it contains rifampin.
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.
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.
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.
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 (eg, carbamazepine, phenytoin, primidone, valproic acid), benzodiazepines (eg, 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.
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 (eg, 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.
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 deflorination of enflurane. Renal function should be monitored in patients receiving both RIFATER and enflurane.
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 (eg, headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (eg, skipjack, tuna, other tropical fish). Tyramine- and histamine-containing foods should be avoided by patients receiving RIFATER.
Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Therefore, alternative assay methods should be considered. Transient abnormalities in liver function tests (eg, 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 has been reported to interfere with ACETEST® and KETOSTIX® urine tests to produce a pink-brown color.
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.
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 two to ten 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 activity in vitro has also 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.
Isoniazid has been reported to induce pulmonary tumors in a number of strains of mice.
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.
Category C. 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.
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.
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.
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.
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.
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.
Safety and effectiveness in pediatric patients under the age of 15 have not been established.
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 in elderly patients. (See WARNINGS)
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.
|Number of Patients
With Adverse Events*
|Adverse Events by Body Systems|
During First 2 Months of Trial
n = 122†
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.
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. Rarely, hepatitis or a shocklike syndrome with hepatic involvement and abnormal liver function tests has been reported.
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.
Leukopenia, hemolytic anemia, and decreased hemoglobin have been observed. Agranulocytosis has been reported rarely.
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.
Visual disturbances have been observed.
Menstrual disturbances have been observed.
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.
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.
Occasionally pruritus, urticaria, rash, pemphigoid reaction, eosinophilia, sore mouth, sore tongue and conjunctivitis have been observed.
Edema of the face and extremities have 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.
The most frequent reactions are those affecting the nervous system and the liver. See the boxed WARNING.
Peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those predisposed to neuritis (eg, 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.
Nausea, vomiting, and epigastric distress.
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.
Agranulocytosis; hemolytic, sideroblastic, or aplastic anemia; thrombocytopenia; and eosinophilia.
Fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, and vasculitis.
Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and gynecomastia.
Rheumatic syndrome and systemic lupus erythematosus-like syndrome.
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).
GI disturbances including nausea, vomiting, and anorexia have also been reported.
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.
Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including rashes, urticaria, pruritus, and erythema have been reported. Angioedema has been reported rarely. Fever, acne, photosensitivity, porphyria, dysuria, and interstitial nephritis have been reported rarely.
There is no human experience with RIFATER overdosage.
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.
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.
Overdosage experience with pyrazinamide is limited.
The following signs and symptoms have been seen with each individual component in an overdosage situation.
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.
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.
In one case of pyrazinamide overdosage, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped.
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.
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
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 (B6) 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 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).
Store at controlled room temperature 59–86°F (15–30°C). Protect from excessive humidity.
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Rev. April 2008
©2008 sanofi-aventis U.S. LLC
|Rifater (rifampin, isoniazid and pyrazinamide)|