Rifater

Name: Rifater

Manufacturer

  • Remedyrepack Inc.

  • Sanofi-Aventis U.S. LLC

What should I discuss with my healthcare provider before taking this medicine?

You should not use this medication if you are allergic to isoniazid, pyrazinamide, or rifampin, or if you have:

  • severe liver disease;

  • an attack of gout;

  • a history of fever, chills, and joint pain or stiffness caused by taking isoniazid; or

  • if you also take certain antiviral medicines--atazanavir, darunavir, fosamprenavir, tipranavir, or saquinavir.

To make sure isoniazid, pyrazinamide, and rifampin is safe for you, tell your doctor if you have:

  • liver disease, cirrhosis, a history of alcoholism, or if you drink more than 3 alcoholic beverages per day;

  • gout;

  • diabetes;

  • kidney disease;

  • if you take phenytoin (Dilantin); or

  • if you take antiviral medication to treat HIV or hepatitis.

FDA pregnancy category C. In animal studies, this medicine caused birth defects. However, it is not known whether these effects would occur in people. Taking this medicine during the last few weeks of pregnancy may increase your risk of bleeding during delivery. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

This medicine can make birth control pills less effective. Ask your doctor about using non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking this medicine.

Isoniazid, pyrazinamide, and rifampin can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of lupus like a rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs.
  • Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
  • Signs of too much acid in the blood (acidosis) like confusion; fast breathing; fast heartbeat; a heartbeat the does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; or feeling very tired or weak.
  • Chest pain or pressure.
  • Coughing up blood.
  • Fever or chills.
  • Sore throat.
  • Flu-like signs.
  • A heartbeat that does not feel normal.
  • Swollen gland.
  • Joint pain or swelling.
  • Period (menstrual) changes.
  • Ringing in ears.
  • Muscle pain or weakness.
  • Shortness of breath.
  • Swelling in the arms or legs.
  • Any unexplained bruising or bleeding.
  • Purple spots or redness of the skin.
  • Feeling very tired or weak.
  • Very bad dizziness or passing out.
  • A burning, numbness, or tingling feeling that is not normal.
  • Seizures.
  • Feeling confused.
  • Memory problems or loss.
  • Change in eyesight.
  • Mood changes.
  • Change in balance.
  • Not able to focus.
  • Change in how you act.

Rifater - 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.

Parameter Cmax
(mcg/mL)
Half-life
(hr)
Apparent Oral
Clearance
(L/hr)
Bioavailability
(%)
Treatment A B A B A B A
Isoniazid 3.09
± 0.88
3.14
± 0.92
2.80
± 1.02
2.80
± 1.11
24.02
±15.29
25.72
±18.38
100.6
±16.6
Rifampin 11.04
± 3.08
13.61
± 3.96
3.19
± 0.63
3.41
± 0.86
9.62
± 3.00
8.30
± 2.50
88.8
±16.5
Pyrazinamide 28.02
± 4.52
29.21
± 4.35
10.04
± 1.54
10.08
± 1.29
3.82
± 0.65
3.70
± 0.59
96.8
± 7.6

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 t1/2 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 in vitro and in vivo

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.

Dose of Isoniazid, Rifampin and Pyrazinamide Administered as Separate Drugs
Patient Weight Isoniazid
(mg)
Rifampin
(mg)
Pyrazinamide
(mg)
<50 kg 300 450 1500
≥50 kg 300 600 2000
Dose of Isoniazid, Rifampin and Pyrazinamide Administered as Rifater
Patient
Weight
Number of
Tablets
Isoniazid
(mg)
Rifampin
(mg)
Pyrazinamide
(mg)
≤44 kg 4 200 480 1200
45 to 54 kg 5 250 600 1500
≥55 kg 6 300 720 1800

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.

Negative Sputums/No. of Patients (Percent Negative)
Treatment 2 Months 6 Months Follow-up Period*
* The median follow-up time for all the Rifater patients was 756 days with a range of 42 to 1325 days and 745 days with a range of 50 to 1427 days for the patients dosed with separate tablets and capsules. † Isoniazid, rifampin, and pyrazinamide dosed as separate tablets and capsules.
Rifater 91/96 (95%) 100/104 (96%) 99/101 (98%)
Separate† 99/108 (92%) 95/96 (99%) 105/106 (99%)

For adverse events, (See ADVERSE REACTIONS).

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:

  1. 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.
  2. Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis.
  3. 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 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 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 coadministered 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 defluorination 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)

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.

Interactions for Rifater

Induces certain CYP enzymes.161

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs metabolized by CYP enzymes; increased metabolism of these drugs.161

Specific Drugs and Tests

Drug or Test

Interaction

Comments

β-Adrenergic blocking agents

Potential increased metabolism of the β-adrenergic blocking agent161

Dosage adjustment of the β-adrenergic blocking agent may be needed161

Aminosalicylic acid

Decreased rifampin serum concentrations reported with certain aminosalicylic acid preparations;aa not reported with commercially available aminosalicylic acid delayed-release granules (Paser)aa

May be caused by an excipient not included in commercially available aminosalicylic acid delayed-release granules (Paser)aa

Antacids

Possible decreased absorption of rifampin161

Administer rifampin at least 1 hour before antacids161

Antiarrhythmic agents (disopyramide, mexiletine, quinidine, tocainide)

Potential increased metabolism of the antiarrhythmic agent110 111 161

Dosage adjustment of the antiarrhythmic agent may be needed161

Anticoagulants, oral

Potential increased metabolism of warfarin and decreased anticoagulant effect161

Monitor PT daily or as frequently as necessary to establish and maintain required anticoagulant dosage161

Anticonvulsants (phenytoin)

Potential increased phenytoin metabolism161

Dosage adjustment of phenytoin may be needed161

Antifungals, azole (fluconazole, itraconazole, ketoconazole, voriconazole)

Decreased plasma concentrations of fluconazole, itraconazole, ketoconazole, or voriconazole;131 132 161 242 262 264 265 o altered rifampin concentrations161 264 265

Antifungal efficacy may be decreased263 264

Itraconazole or ketoconazole: Concomitant use not recommended131 132 242 264 265

Fluconazole: If used with rifampin, fluconazole dosage may needed to be increased161 262

Voriconazole: Concomitant use contraindicatedo

Antifungals, echinocandins (anidulafungin, caspofungin, micafungin)

Caspofungin: Decreased caspofungin trough concentrations; no effect on rifampin concentrationsm q

Anidulafungin or micafungin: No evidence of pharmacokinetic interactionn p

Caspofungin: Increase caspofungin dosage to 70 mg dailym q

Anidulafungin or micafungin: Dosage adjustment not necessaryn p

Antiretrovirals, entry inhibitors

Decreased AUC and concentrations of maraviroc101 ee

Dosage adjustment necessary;101 ee if used with rifampin, use maraviroc dosage of 600 mg twice daily101 ee

Some experts state concomitant use with rifampin not recommended and suggest use of rifabutin as an alternative101

Antiretrovirals, HIV fusion inhibitors

Enfuvirtide: Pharmacokinetic interaction unlikely272

Antiretrovirals, HIV integrase inhibitors

Decreased raltegravir concentrations101

Clinical importance unclear; use with caution or consider alternative101

Antiretrovirals, HIV protease inhibitors (PIs)

Decreased concentrations of atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir101 124 126 152 175 177 192 256 260 j

Possible decreased darunavir concentrations; possible decreased antiretroviral activity101

Possible decreased tipranavir concentrations; possible decreased antiretroviral activity and increased risk of tipranavir resistancec

Concomitant use with atazanavir, ritonavir-boosted darunavir, fosamprenavir, indinavir, ritonavir-boosted indinavir, fixed combination of lopinavir and ritonavir, nelfinavir, ritonavir, ritonavir-boosted saquinavir, or ritonavir-boosted tipranavir not recommended101 126 260 c j

Antiretrovirals, nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Delavirdine, efavirenz, or nevirapine: Decreased plasma concentrations of the NNRTI101 217 218

Nevirapine: Potential for additive hepatotoxicity; virologic consequences uncertain101

Delavirdine: Concomitant use contraindicated101

Efavirenz: If used with rifampin, use efavirenz 600 mg once daily in patients weighing <50 kg or consider using efavirenz 800 mg once daily101

Nevirapine: Concomitant use not recommended; if used concomitantly, monitor carefully101

Antiretrovirals, nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)

Zidovudine: Decreased plasma concentrations of the NRTI251

Tenofovir: Pharmacokinetic interaction unlikely271

Tenofovir: Dosage adjustments not necessary271

Atovaquone

Decreased atovaquone concentrations and half-life;161 261 gg increased rifampin concentrations161

Concomitant use not recommended261 gg

Barbiturates

Potential increased metabolism of the barbiturate161

Dosage adjustment of the barbiturate may be needed161

Benzodiazepines (diazepam)

Potential increased metabolism of diazepam161

Dosage adjustment of diazepam may be needed161

Calcium-channel blocking agents (diltiazem, nifedipine, verapamil)

Potential increased metabolism of the calcium-channel blocking agent161

Decreased plasma verapamil concentrations; loss of therapeutic effect of oral verapamil reported157 158 159 160

Dosage adjustment of the calcium-channel blocking agent may be needed161

Cardiac glycosides

Potential increased metabolism of the cardiac glycoside161

Dosage adjustment of the cardiac glycoside may be needed161

Chloramphenicol

Potential increased metabolism of chloramphenicol121 161

Dosage adjustment of chloramphenicol may be needed161

Clofazimine

Clinically important interaction unlikely in leprosy patients142 143

Clofibrate

Potential increased metabolism of clofibrate161

Dosage adjustment of clofibrate may be needed161

Co-trimoxazole

Increased rifampin concentrations161

Corticosteroids

Potential increased metabolism of the corticosteroid 109 161

Dosage adjustment of the corticosteroid may be needed161

Dapsone

Potential increased metabolism and decreased plasma concentrations of dapsone 161 gg

Dosage adjustment of dapsone may be needed161

Dosage of dapsone used in multiple-drug regimens (rifampin with or without clofazimine) for treatment of leprosy is well established;198 200 204 206 207 change in dapsone dosage in these regimens not requiredgg

Doxycycline

Potential increased metabolism of doxycycline 161

Dosage adjustment of doxycycline may be needed161

Enalapril

Decreased concentrations of enalaprilat, the active metabolite161

Adjust enalapril dosage as required161

Erlotinib

Possible decreased erlotinib AUCf

Avoid concomitant use if possiblef

If alternative to rifampin cannot be used, consider increasing erlotinib dosage (as tolerated at 2-week intervals) during rifampin therapy and decreasing erlotinib dosage to usual dosage when rifampin is discontinued; closely monitor patientf

Fluoroquinolones (ciprofloxacin)

Potential increased metabolism of ciprofloxacin;161 possible increased rifampin concentrations193

Lupus-like syndrome reported in a few patients receiving rifampin and ciprofloxacin193

Dosage adjustment of ciprofloxacin may be required161

Halothane

Increased risk of hepatotoxicity161

Concomitant use not recommended161

Hormonal contraceptives

Potential increased metabolism of the estrogen and/or progestin161

Use nonhormonal methods of contraception161

Immunosuppressive agents (cyclosporine, tacrolimus)

Decreased concentrations of the immunosuppressive agent161 243 244 245 246 246

Monitor concentrations of the immunosuppressive agent; adjust dosage of the immunosuppressive agent accordingly243 244 245 246

Isoniazid

Increased risk of hepatotoxicity161

Monitor closely for signs and symptoms of hepatotoxicity161

Levothyroxine

Potential increased levothyroxine metabolism161

Dosage adjustment of levothyroxine may be needed161

Macrolides (clarithromycin)

Potential increased metabolism of clarithromycin;161 possible increased rifampin concentrations193

Lupus-like syndrome reported in a few patients receiving rifampin and clarithromycin193

Dosage adjustment of clarithromycin may be needed161

Opiate agonists (methadone)

Potential increased metabolism of the opiate agonist161

Dosage adjustment of the opiate agonist may be needed161

Probenecid

Increased rifampin concentrations161

Psychotherapeutic agents (amitriptyline, haloperidol, nortriptyline)

Potential increased metabolism of the psychotherapeutic agent161

Dosage adjustment of the psychotherapeutic agent may be needed161

Pyrazinamide

Severe liver injuries, including some fatalities, reported in patients receiving a 2-month daily regimen of rifampin and pyrazinamide for treatment of LTBI222 225

Use of rifampin and pyrazinamide for treatment of LTBI should be considered only in carefully selected patients with close monitoring and only if potential benefits outweigh the risk of hepatotoxicity and death257

Quinine

Possible decreased plasma concentrations of quinine161

Dosage adjustment of quinine may be needed161

Rosiglitazone

Decreased rosiglitazone AUCi

Dosage adjustment of rosiglitazone may be neededi

Sulfasalazine

Possible decreased plasma concentrations of sulfapyridine161

Sulfonylurea antidiabetic agents

Potential increased metabolism of the sulfonylurea agent; diabetes may be more difficult to control161

Dosage adjustment of the antidiabetic agent may be needed161

Telithromycin

Decreased telithromycin concentrations and AUCh

Avoid concomitant useh

Tests for opiates

Possible cross-reactivity and false-positive results in opiate urine screening tests that use kinetic interaction of microparticles in solution (KIMS) method161 or opiate immunoassaysii

Perform confirmatory tests (e.g., gas chromatography/mass spectrometry)161 ii

Tests for serum folate and vitamin B12

Standard microbiologic assays for serum folate and vitamin B12 are inhibited by therapeutic rifampin concentrations161

Consider using alternative assays to determine serum folate and vitamin B12161

Theophylline

Potential increased metabolism of theophylline161

Dosage adjustment of theophylline may be needed161

Tinidazole

Possible decreased tinidazole concentrationsg

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