Rifater Information
Rifater (Rifampin,isoniazid,pyrazinamide) 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 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 The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent liver involvement.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) Description
Rifater (Rifampin,isoniazid,pyrazinamide) (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 (Rifampin,isoniazid,pyrazinamide) 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 hydrazide 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:
Rifater (Rifampin,isoniazid,pyrazinamide) Clinical Pharmacology
In a single-dose bioavailability study of five Rifater (Rifampin,isoniazid,pyrazinamide) tablets (Treatment A, n=23) versus RIFADIN 600 mg, isoniazid 250 mg, and pyrazinamide 1500 mg (Treatment B, n=24) administered concurrently in healthy 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 (Rifampin,isoniazid,pyrazinamide) 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 (Rifampin,isoniazid,pyrazinamide) tablets was not studied.
Organisms resistant to rifampin are likely to be resistant to other rifamycins. β-lactamase production should have no effect on rifampin activity.
In the treatment of tuberculosis, the small number of resistant cells present within large populations of susceptible cells can rapidly become predominant. In addition, resistance to rifampin has been determined to occur as single-step mutations of the DNA-dependent RNA polymerase. Since resistance can emerge rapidly, appropriate susceptibility tests should be performed in the event of persistent positive cultures.
Rifampin, isoniazid, and pyrazinamide at therapeutic levels have demonstrated bactericidal activity against both intracellular and extracellular organisms (see section).
Pyrazinamide alone is only active at a slightly acidic pH (pH 5.5) and . Isoniazid kills actively growing tubercle bacilli.
Prior to initiation of therapy, appropriate specimens should be collected for identification of the infecting organism and susceptibility tests.
99
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 H37Rv, ATCC 27294, as a control organism.
The clinical relevance of susceptibility test results for mycobacterial species other than using either the radiometric broth method or the proportion method has not been determined.
Rifater (Rifampin,isoniazid,pyrazinamide) Clinical Trials
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 (Rifampin,isoniazid,pyrazinamide) tablets based on body weight for 56 days. Rifater (Rifampin,isoniazid,pyrazinamide) 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.
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
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.
For adverse events, (See )
Rifater (Rifampin,isoniazid,pyrazinamide) Indications And Usage
Rifater (Rifampin,isoniazid,pyrazinamide) is indicated in the initial phase of the short-course treatment of pulmonary tuberculosis. During this phase, which should last 2 months, Rifater (Rifampin,isoniazid,pyrazinamide) should be administered on a daily, continuous basis (See ).
Following the initial phase and treatment with Rifater (Rifampin,isoniazid,pyrazinamide) , 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 (Rifampin,isoniazid,pyrazinamide) and the patient is not responding to therapy, the drug regimen should be modified.
Rifater (Rifampin,isoniazid,pyrazinamide) Contraindications
Rifater (Rifampin,isoniazid,pyrazinamide) 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 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.
Rifater (Rifampin,isoniazid,pyrazinamide) Warnings
Rifater (Rifampin,isoniazid,pyrazinamide) 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 (Rifampin,isoniazid,pyrazinamide) 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 (Rifampin,isoniazid,pyrazinamide) 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 .)
Since Rifater (Rifampin,isoniazid,pyrazinamide) contains isoniazid, ophthalmologic examinations (including ophthalmoscopy) should be done before treatment is started and periodically thereafter, even without occurrence of visual symptoms.
Since Rifater (Rifampin,isoniazid,pyrazinamide) contains pyrazinamide, patients started on Rifater (Rifampin,isoniazid,pyrazinamide) 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 (Rifampin,isoniazid,pyrazinamide) 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 (Rifampin,isoniazid,pyrazinamide) Precautions
Adults treated for tuberculosis with Rifater (Rifampin,isoniazid,pyrazinamide) 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.
Rifater (Rifampin,isoniazid,pyrazinamide) Adverse Reactions
Adverse event data reported for the Rifater (Rifampin,isoniazid,pyrazinamide) 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 (Rifampin,isoniazid,pyrazinamide) 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 (Rifampin,isoniazid,pyrazinamide) are consistent with those described below for the individual components.
Rifater (Rifampin,isoniazid,pyrazinamide) Overdosage
There is no human experience with Rifater (Rifampin,isoniazid,pyrazinamide) overdosage.
The airway should be secured and adequate respiratory exchange should be established in cases of overdosage with Rifater (Rifampin,isoniazid,pyrazinamide) . Only then should gastric emptying (lavage-aspiration) be attempted; this may be difficult because of seizures.
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.
Bile drainage may be indicated in presence of serious impairment of hepatic function lasting more than 24–48 hours. Under these circumstances and for severe cases, extracorporeal hemodialysis may be required; 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.
Untreated or inadequately treated cases of gross isoniazid overdosage can terminate fatally, but good response has been reported in most patients brought under adequate treatment within the first few hours after drug ingestion.
Rifater (Rifampin,isoniazid,pyrazinamide) Dosage And Administration
Rifater (Rifampin,isoniazid,pyrazinamide) 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 , for dosing information in patients with renal failure.
Rifater (Rifampin,isoniazid,pyrazinamide) How Supplied
Rifater (Rifampin,isoniazid,pyrazinamide) tablets are light beige, smooth, round, and shiny sugar-coated tablets imprinted with "Rifater (Rifampin,isoniazid,pyrazinamide) " 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 (Rifampin,isoniazid,pyrazinamide)
Rifater (Rifampin,isoniazid,pyrazinamide) Principal Display Panel - Tablet Bottle
