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Rifater
Overview
What is Rifater?
RIFATER (rifampin/isoniazid/pyrazinamide USP) 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, carboxymethyl cellulose 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.
What does Rifater look like?
What are the available doses of Rifater?
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What should I talk to my health care provider before I take Rifater?
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How should I use Rifater?
RIFATER is indicated in the initial phase of the short-course treatment of pulmonary tuberculosis. During this phase, which should last 2 months, RIFATER should be administered on a daily, continuous basis (see ).
Following the initial phase and treatment with RIFATER, treatment should be continued with rifampin and isoniazid (e.g., RIFAMATE) for at least 4 months. Treatment should be continued for a longer period of time if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.
In the treatment of tuberculosis, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type. Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment. Bacteriologic smears or cultures should be obtained before the start of therapy to confirm the susceptibility of the organism to rifampin, isoniazid, and pyrazinamide and they should be repeated throughout therapy to monitor response to the treatment. If test results show resistance to any of the components of RIFATER and the patient is not responding to therapy, the drug regimen should be modified.
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 (e.g., 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 (e.g., alcoholics and diabetics), and in adolescents.
See , for dosing information in patients with renal failure.
What interacts with Rifater?
RIFATER is contraindicated in patients with a history of hypersensitivity to rifampin, isoniazid, pyrazinamide or any of the components, or to any of the rifamycins.
Rifampin
Rifampin is contraindicated in patients who are also receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity. (See .)
Rifampin is contraindicated in patients who are also receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance.
Isoniazid
Other contraindications include patients with severe hepatic damage; severe adverse reactions to isoniazid, such as drug fever, chills, and arthritis; patients with acute liver disease of any etiology; and patients with acute gout.
What are the warnings of Rifater?
RIFATER is a combination of the three drugs, rifampin, isoniazid, and pyrazinamide. Each of these individual drugs has been associated with liver dysfunction.
Systemic hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, may occur in patients receiving RIFATER (see ). Signs and symptoms of hypersensitivity reactions may include fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). These reactions may be severe and DRESS may be fatal. Manifestations of hypersensitivity, such as fever, lymphadenopathy or laboratory abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. Monitor patients receiving RIFATER for signs and/or symptoms of hypersensitivity reactions. If these signs or symptoms occur, discontinue RIFATER and administer supportive measures.
Rifampin
Rifampin has been shown to produce liver dysfunction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking rifampin with other hepatotoxic agents. Because RIFATER contains both rifampin and isoniazid, it should only be given with caution and under strict medical supervision to patients with impaired liver function. In these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, RIFATER should be withdrawn.
In some cases, hyperbilirubinemia resulting from competition between rifampin and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels, and considering them in conjunction with the patient's clinical condition.
Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration.
Isoniazid
(See the boxed .)
Since RIFATER contains isoniazid, ophthalmologic examinations (including ophthalmoscopy) should be done before treatment is started and periodically thereafter, even without occurrence of visual symptoms.
Severe cutaneous reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some with a fatal outcome, have been reported with the use of isoniazid (see ). Monitor for skin reactions and advise patients to report skin rashes or mucosal lesions immediately. Discontinue RIFATER if these reactions occur.
Pyrazinamide
Since RIFATER contains pyrazinamide, patients started on RIFATER should have baseline serum uric acid and liver function determinations. Patients with preexisting liver disease or those patients at increased risk for drug related hepatitis (e.g., alcohol abusers) should be followed closely.
Because it contains pyrazinamide, RIFATER should be discontinued and not be resumed if signs of hepatocellular damage or hyperuricemia accompanied by an acute gouty arthritis appear. If hyperuricemia accompanied by an acute gouty arthritis occurs without liver dysfunction, the patient should be transferred to a regimen not containing pyrazinamide.
What are the precautions of Rifater?
General
RIFATER should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult.
Rifampin
For treatment of tuberculosis, rifampin is usually administered on a daily basis. Doses of rifampin (>600 mg) given once or twice weekly have resulted in a higher incidence of adverse reactions, including the "flu syndrome" (fever, chills and malaise); hematopoietic reactions (leukopenia, thrombocytopenia, or acute hemolytic anemia); cutaneous, gastrointestinal, and hepatic reactions; shortness of breath; shock, anaphylaxis, and renal failure. Recent studies indicate that regimens using twice-weekly doses of rifampin 600 mg plus isoniazid 15 mg/kg are much better tolerated.
Rifampin is not recommended for intermittent therapy; the patient should be cautioned against intentional or accidental interruption of the daily dosage regimen since rare renal hypersensitivity reactions have been reported when therapy was resumed in such cases.
Rifampin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D.
Isoniazid
All drugs should be stopped and an evaluation of the patient should be made at the first sign of a hypersensitivity reaction.
Use of RIFATER, because it contains isoniazid, should be carefully monitored in the following:
Pyrazinamide
Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia which is usually asymptomatic. If hyperuricemia is accompanied by acute gouty arthritis, RIFATER, because it contains pyrazinamide, should be discontinued.
Information for Patients
Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Tyramine and histamine-containing foods should be avoided in patients receiving RIFATER.
RIFATER, because it contains rifampin, may produce a discoloration (yellow, orange, red, brown) of the teeth, urine, sweat, sputum, and tears, and the patient should be forewarned of this.
The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures.
Patients should be instructed to take RIFATER either 1 hour before or 2 hours after a meal with a full glass of water.
Patients should be instructed to notify their physician immediately if they experience any of the following: rash with fever or blisters, with or without peeling skin, fever or swollen lymph nodes, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, cough, shortness of breath, wheezing, pain or swelling of the joints.
Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.
Laboratory Tests
Adults treated for tuberculosis with RIFATER should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count (CBC) and platelet count (or estimate), and blood uric acid.
Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not necessary.
Drug Interactions
Rifampin
Healthy subjects who received rifampin 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity. Therefore, concomitant use of these medications is contraindicated. (See .)
Isoniazid
Drug/Laboratory Test Interactions
Rifampin
Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving rifampin when using the KIMS (Kinetic Interaction of Microparticles in Solution) method (e.g., Abuscreen OnLine opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish rifampin from opiates.
Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B. Therefore, alternative assay methods should be considered. Transient abnormalities in liver function tests (e.g., elevation in serum bilirubin, alkaline phosphatase and serum transaminases), and reduced biliary excretion of contrast media used for visualization of the gallbladder have also been observed. Therefore, these tests should be performed before the morning dose of RIFATER.
Rifampin and isoniazid have been reported to alter vitamin D metabolism. In some cases, reduced levels of circulating 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D have been accompanied by reduced serum calcium and phosphate, and elevated parathyroid hormone.
Pyrazinamide
Pyrazinamide has been reported to interfere with ACETEST and KETOSTIX urine tests to produce a pink-brown color.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Increased frequency of chromosomal aberrations was observed in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide.
Rifampin
A few cases of accelerated growth of lung carcinoma have been reported in man, but a causal relationship with the drug has not been established. Hepatomas were increased in female (C3Hf/DP) mice dosed for 60 weeks with rifampicin followed by an observation period of 46 weeks, at 20 to 120 mg/kg (equivalent to 0.1 to 0.5 times the maximum dosage used clinically, based on body surface area comparisons). There was no evidence of tumorigenicity in male C3Hf/DP mice or, in similar studies in BALB/c mice, or in two year studies in Wistar rats.
There was no evidence of mutagenicity in both prokaryotic () and eukaryotic () bacteria, , or ICR/Ha Swiss mice. An increase in chromatid breaks was noted when whole blood cell cultures were treated with rifampin. Increased frequency of chromosomal aberrations was observed in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide.
Isoniazid
Isoniazid has been reported to induce pulmonary tumors in a number of strains of mice.
Pyrazinamide
Pyrazinamide was not carcinogenic in lifetime bioassays in rats (at doses up to 500 mg/kg, about three times the recommended human dose, based on body surface area comparisons) or mice (at doses up to 2000 mg/kg, about five times the recommended human dose, based on body surface area comparisons).
Pyrazinamide was not mutagenic in the Ames bacterial test, but induced chromosomal aberrations in human lymphocyte cell cultures.
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Pregnancy – Teratogenic Effects
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Pregnancy – Non-Teratogenic Effects
When administered during the last few weeks of pregnancy, rifampin can cause post-natal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.
Nursing Mothers
Since rifampin, isoniazid, and pyrazinamide are known to pass into maternal breast milk, a decision should be made whether to discontinue nursing or to discontinue RIFATER, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients under the age of 15 have not been established. (See ; See also .)
Geriatric Use
Clinical studies of RIFATER did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using rifampin and isoniazid in elderly patients. (See .)
What are the side effects of Rifater?
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.
| Number of Patientswith Adverse Events | |||
|---|---|---|---|
| Adverse Events by Body SystemsDuring First 2 Months of Trial | RIFATERn=122 | Separate n=123 | |
| Cutaneous | 8 (7%) | 21 (17%) | |
| Gastrointestinal | 8 (7%) | 14 (11%) | |
| Musculoskeletal | 5 (4%) | 8 (7%) | |
| Hearing and Vestibular | 3 (2%) | 6 (5%) | |
| Liver and Biliary | 0 (0%) | 2 (2%) | |
| Central and Peripheral Nervous System | 5 (4%) | 4 (3%) | |
| Total Body | 2 (2%) | 4 (3%) | |
| Cardiorespiratory | 8 (7%) | 3 (2%) | |
| Total number of patients with one or more adverse events | 29 | 43 |
Adverse Reactions Reported for Individual Components
Rifampin
Isoniazid
The most frequent reactions are those affecting the nervous system and the liver. (See the boxed .)
Pyrazinamide
The principal adverse effect is a hepatic reaction (see ). Hepatotoxicity appears to be dose related and may appear at any time during therapy. Pyrazinamide can cause hyperuricemia and gout (see ).
What should I look out for while using Rifater?
RIFATER is contraindicated in patients with a history of hypersensitivity to rifampin, isoniazid, pyrazinamide or any of the components, or to any of the rifamycins.
RIFATER is a combination of the three drugs, rifampin, isoniazid, and pyrazinamide. Each of these individual drugs has been associated with liver dysfunction.
Systemic hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, may occur in patients receiving RIFATER (see ). Signs and symptoms of hypersensitivity reactions may include fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). These reactions may be severe and DRESS may be fatal. Manifestations of hypersensitivity, such as fever, lymphadenopathy or laboratory abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. Monitor patients receiving RIFATER for signs and/or symptoms of hypersensitivity reactions. If these signs or symptoms occur, discontinue RIFATER and administer supportive measures.
What might happen if I take too much Rifater?
There is no human experience with RIFATER overdosage.
How should I store and handle Rifater?
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from excessive humidity.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).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).
