Rifater

Sanofi-Aventis U.S. LLC
Sanofi-Aventis U.S. LLC

RIFATER (rifampin, isoniazid and pyrazinamide USP)Tablets

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING
• RIFATER DESCRIPTION
  • Rifampin
  • Isoniazid
  • Pyrazinamide
• CLINICAL PHARMACOLOGY
  • General
  • Microbiology
  • Mechanism of Action
  • Drug Resistance
  • Activity and
  • Susceptibility Testing
• CLINICAL TRIALS
• RIFATER INDICATIONS AND USAGE
• RIFATER CONTRAINDICATIONS
  • Rifampin
  • Isoniazid
• WARNINGS
  • Rifampin
  • Isoniazid
  • Pyrazinamide
• PRECAUTIONS
  • General
  • Information for Patients
  • Laboratory Tests
  • Drug Interactions
  • Drug/Laboratory Test Interactions
  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Nursing Mothers
  • Pediatric Use
  • Geriatric Use
• RIFATER ADVERSE REACTIONS
  • Adverse Experiences During the Clinical Trial
  • Adverse Reactions Reported for Individual Components
• OVERDOSAGE
  • Acute Toxicity
  • Signs and Symptoms
  • Treatment
• RIFATER DOSAGE AND ADMINISTRATION
  • Adults
  • Pediatric Patients
• HOW SUPPLIED
  • Storage
  • Reference
• PRINCIPAL DISPLAY PANEL - 60 Tablet Bottle

FULL PRESCRIBING INFORMATION

RIFATER DESCRIPTION

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, 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

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:

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

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 C₆H₇N₃O.

The chemical name for isoniazid is 4-pyridinecarboxylic acid, hydrazide and its structural formula is:

Pyrazinamide

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:

CLINICAL PHARMACOLOGY

General

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 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 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

Rifampin is readily absorbed from the gastrointestinal tract. Peak serum levels in healthy 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 by about 30% when the drug is ingested with food.

In healthy adults, the biological half-life of rifampin in serum averages 3.35 ± 0.66 hours after a 600 mg oral dose, with increases up to 5.08 ± 2.45 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 mean half-life increased from 3.6 hours in healthy adults 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.

Pediatrics

In one study, pediatric patients 6 to 58 months old were given rifampin suspended in simple syrup or as dry powder mixed with applesauce at a dose of 10 mg/kg body weight. Peak serum concentrations of 10.7 ± 3.7 and 11.5 ± 5.1 mcg/mL were obtained 1 hour after preprandial ingestion of the drug suspension and the applesauce mixture, respectively. After the administration of either preparation, the t_1/2 of rifampin averaged 2.9 hours. It should be noted that in other studies in pediatric populations, at doses of 10 mg/kg body weight, mean peak serum concentrations of 3.5 mcg/mL to 15 mcg/mL have been reported.

Isoniazid

After oral administration, isoniazid is readily absorbed from the GI tract and produces peak blood levels within 1 to 2 hours which decline to 50% or less within 6 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 to 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

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.

Microbiology

Mechanism of Action

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.

Isoniazid

Isoniazid inhibits the biosynthesis of mycolic acids which are major components of the cell wall of Mycobacterium tuberculosis.

Pyrazinamide

The exact mechanism of action by which pyrazinamide inhibits the growth of Mycobacterium tuberculosis organisms is unknown.

Drug Resistance

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.

Activity and

Rifampin, isoniazid, and pyrazinamide at therapeutic levels have demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms (see INDICATIONS AND USAGE).

Pyrazinamide alone is only active at a slightly acidic pH (pH 5.5) in vitro and in vivo. Isoniazid kills actively growing tubercle bacilli.

Susceptibility Testing

Prior to initiation of therapy, appropriate specimens should be collected for identification of the infecting organism and in vitro susceptibility tests.

In vitro testing for Mycobacterium tuberculosis isolates:
Two standardized in vitro susceptibility methods are available for testing isoniazid, rifampin, and pyrazinamide against Mycobacterium tuberculosis organisms. The agar proportion method (CDC or CLSI M24-A) 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.

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 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.

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.

For adverse events, (See ADVERSE REACTIONS).

RIFATER INDICATIONS AND USAGE

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).

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 CONTRAINDICATIONS

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 PRECAUTIONS, Drug Interactions.)

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.

WARNINGS

RIFATER is a combination of the three drugs, rifampin, isoniazid, and pyrazinamide. Each of these individual drugs has been associated with liver dysfunction.

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 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.

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.

PRECAUTIONS

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:

• Patients who are receiving phenytoin (diphenylhydantoin) concurrently. Isoniazid may decrease the excretion of phenytoin or may enhance its effects. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant dose should be made.
• Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis.
• Patients with current chronic liver disease or severe renal dysfunction.

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

Food Interactions

Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Tyramine- and histamine-containing foods should be avoided 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.

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 physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, pain or swelling of the joints.

Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.

Laboratory Tests

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 CONTRAINDICATIONS.)

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 substantially decrease the plasma concentrations of the following antiviral drugs: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. These antiviral drugs must not be co-administered with rifampin. (See CONTRAINDICATIONS.)

Rifampin has been reported to accelerate the metabolism of the following drugs: anticonvulsants (e.g., phenytoin), digitoxin, antiarrhythmics (e.g., disopyramide, mexiletine, quinidine, tocainide), oral anticoagulants, antifungals (e.g., fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (e.g., diltiazem, nifedipine, verapamil), chloramphenicol, clarithromycin, fluoroquinolones (e.g., ciprofloxacin), corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral or other systemic hormonal contraceptives, dapsone, diazepam, doxycycline, haloperidol, oral hypoglycemic agents (sulfonylureas), levothyroxine, methadone, narcotic analgesics, progestins, quinine, tacrolimus, theophylline, tricyclic antidepressants (e.g., amitriptyline, nortriptyline), and zidovudine. It may be necessary to adjust dosages of these drugs if they are given concurrently with RIFATER since it contains rifampin.

Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during rifampin therapy.

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.

When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampin were observed.

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.

Other Interactions

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.

Isoniazid

Enzyme Inhibition: Isoniazid is known to inhibit certain cytochrome P-450 enzymes. Coadministration of isoniazid with drugs that undergo biotransformation through these metabolic pathways may decrease elimination. 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 (e.g., carbamazepine, phenytoin, primidone, valproic acid), benzodiazepines (e.g., diazepam), haloperidol, ketoconazole, theophylline, and warfarin. It may be necessary to adjust the dosages of these drugs if they are given 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.

Other Interactions

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 (e.g., prednisolone) may decrease the serum concentration of isoniazid by increasing acetylation rate and/or renal clearance. Para-aminosalicylic acid may increase the plasma concentration and elimination half-life of isoniazid by competition of acetylating enzymes.

Pharmacodynamic Interactions

Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis. Isoniazid, when given concomitantly with rifampin, has been reported to increase the hepatotoxicity of both drugs. Patients receiving both rifampin and isoniazid as in RIFATER should be monitored closely for hepatotoxicity.

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.

Food Interactions

Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Tyramine- and histamine-containing foods should be avoided by patients receiving RIFATER.

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 B₁₂. 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 vitro 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 (Salmonella typhi, Escherichia coli) and eukaryotic (Saccharomyces cerevisiae) bacteria, Drosophila melanogaster, 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 vitro in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide.

Isoniazid

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

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.

Pregnancy – Teratogenic Effects

Category C. Although animal reproduction studies have not been conducted with RIFATER teratogenic effects (including cleft palate and spina bifida) have been observed in rodents treated with rifampin at doses 0.2 to 2 times the maximum recommended human dose, based on body surface area comparisons. There are no adequate and well-controlled studies of RIFATER in pregnant women. RIFATER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Rifampin

Congenital malformations, primarily spina bifida were increased in the offspring of pregnant rats given rifampin during organogenesis at oral doses of 150 to 250 mg/kg/day (about 1 to 2 times the maximum recommended human dose based on body surface area comparisons). Cleft palate was increased in a dose-dependent fashion in fetuses of pregnant mice treated at oral doses of 50 to 200 mg/kg (about 0.2 to 0.8 times the maximum recommended human dose based on body surface area comparisons). Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given rifampin at oral doses up to 200 mg/kg/day (about 3 times the maximum recommended daily human dose based on body surface area comparisons). Although there are no adequate and well-controlled studies in pregnant women, rifampin has been reported to cross the placental barrier and appear in cord blood.

Isoniazid

It has been reported that in both rats and rabbits, isoniazid may exert an embryocidal effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, and rabbits).

Pyrazinamide

Animal reproductive studies have not been conducted with pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm when administered to a pregnant woman.

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.

Rifampin

When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant. In this case, treatment with vitamin K may be indicated for postnatal hemorrhage.

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 CLINICAL PHARMACOLOGY, General; See also DOSAGE AND ADMINISTRATION)

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 WARNINGS)

RIFATER ADVERSE REACTIONS

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.

Adverse Events Reported During the Clinical Study

	Number of Patients With Adverse EventsA given patient may have experienced ≥1 adverse event.
Adverse Events by Body Systems During First 2 Months of Trial	RIFATER n = 122A total of 250 patients (124 RIFATER; 126 separate) were originally enrolled in the study. Five patients (2 RIFATER; 3 separate) were excluded due to admission errors.	SeparateIsoniazid, rifampin and pyrazinamide dosed as separate tablets and capsules. n = 123A total of 250 patients (124 RIFATER; 126 separate) were originally enrolled in the study. Five patients (2 RIFATER; 3 separate) were excluded due to admission errors.
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.

Side Effects Reported for Individual Components

Rifampin

Gastrointestinal

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.

Hepatic

Transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, alkaline phosphatase, serum transaminases) have been observed. Rarely, hepatitis or a shocklike syndrome with hepatic involvement and abnormal liver function tests has been reported.

Hematologic

Thrombocytopenia has occurred primarily with high dose intermittent therapy, but has also been noted after resumption of interrupted treatment. It rarely occurs during well-supervised daily therapy. This effect is reversible if the drug is discontinued as soon as purpura occurs. Cerebral hemorrhage and fatalities have been reported when rifampin administration has been continued or resumed after the appearance of purpura.

Rare reports of disseminated intravascular coagulation have been observed.

Leukopenia, hemolytic anemia, and decreased hemoglobin have been observed.

Agranulocytosis has been reported rarely.

Central Nervous System

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

Psychoses have been rarely reported.

Rare reports of myopathy have also been observed.

Ocular

Visual disturbances have been observed.

Endocrine

Menstrual disturbances have been observed.

Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.

Renal

Elevations in BUN and serum uric acid have been reported. Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal insufficiency, and acute renal failure have been noted. These are generally considered to be hypersensitivity reactions. They usually occur during intermittent therapy or when treatment is resumed following intentional or accidental interruption of a daily dosage regimen, and are reversible when rifampin is discontinued and appropriate therapy instituted.

Dermatologic

Cutaneous reactions are mild and self-limiting and do not appear to be hypersensitivity reactions. Typically, they consist of flushing and itching with or without a rash. More serious cutaneous reactions which may be due to hypersensitivity occur but are uncommon.

Hypersensitivity Reactions

Occasionally pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis, vasculitis, eosinophilia, sore mouth, sore tongue and conjunctivitis have been observed.

Anaphylaxis has been reported rarely.

Miscellaneous

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.

Isoniazid

The most frequent reactions are those affecting the nervous system and the liver. (See the boxed WARNING)

Nervous System

Peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics), and is usually preceded by 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.

Gastrointestinal

Pancreatitis, nausea, vomiting, and epigastric distress.

Hepatic

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.

Hematologic

Agranulocytosis; hemolytic, sideroblastic, or aplastic anemia; thrombocytopenia; and eosinophilia.

Hypersensitivity Reactions

Fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, anaphylactic reactions, Stevens-Johnson syndrome, and vasculitis.

Metabolic and Endocrine

Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and gynecomastia.

Miscellaneous

Rheumatic syndrome and systemic lupus erythematosus-like syndrome.

Pyrazinamide

The principal adverse effect is a hepatic reaction (See WARNINGS). Hepatotoxicity appears to be dose related and may appear at any time during therapy. Pyrazinamide can cause hyperuricemia and gout (See PRECAUTIONS).

Gastrointestinal

GI disturbances including nausea, vomiting, and anorexia have also been reported.

Hematologic and Lymphatic

Thrombocytopenia and sideroblastic anemia with erythroid hyperplasia, vacuolation of erythrocytes and increased serum concentration have occurred rarely with this drug. Adverse effects on blood clotting mechanisms have also been rarely reported.

Other

Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including rashes, urticaria, pruritus, and erythema have been reported. Angioedema has been reported rarely. Fever, acne, photosensitivity, porphyria, dysuria, and interstitial nephritis have been reported rarely.

OVERDOSAGE

There is no human experience with RIFATER overdosage.

Acute Toxicity

Rifampin

The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 gm rifampin. Fatal acute overdoses in adults have been reported with doses ranging from 14 to 60 gm. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in pediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses has been reported.

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.

Pyrazinamide

Overdosage experience with pyrazinamide is limited.

Signs and Symptoms

The following signs and symptoms have been seen with each individual component in an overdosage situation.

Rifampin

Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after rifampin overdosage; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. 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.

Facial or periorbital edema has also been reported in pediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

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.

Pyrazinamide

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

Treatment

The airway should be secured and adequate respiratory exchange should be established in cases of overdosage with RIFATER. 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 (e.g., serum sodium, pH, etc).

Forced osmotic diuresis must be started early and should be continued for some hours after clinical improvement to hasten renal clearance of drug and help prevent relapse; monitor fluid intake and output.

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 DOSAGE AND ADMINISTRATION

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

See CLINICAL PHARMACOLOGY, General, for dosing information in patients with renal failure.

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

Pediatric Patients

The ratio of the drugs in RIFATER may not be appropriate in pediatric patients under the age of 15 (e.g., higher mg/kg doses of isoniazid are usually given in pediatric patients than adults).

HOW SUPPLIED

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).

Storage

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from excessive humidity.

Reference

• Clinical Laboratory Standards Institute. 2003. Susceptibility Testing of Mycobacteria, Nocardiae,and Other Aerobic Actinomycetes; Approved Document M24-A.

sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY

Revised February 2013

©2013 sanofi-aventis U.S. LLC

PRINCIPAL DISPLAY PANEL - 60 Tablet Bottle

NDC 0088-0576-41

Rifater^®
rifampin, isoniazid
and pyrazinamide

60 Tablets

sanofi aventis