rifampin/isoniazid/pyrazinamide (Rx)

Brand and Other Names:Rifater
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

rifampin/isoniazid/pyrazinamide

tablet

  • 120mg/50mg/300mg

Tuberculosis

Indicated in the initial phase of the short-course treatment (ie, 2 months) of pulmonary tuberculosis

<44 kg: 4 tablets PO qDay

44-54 kg: 5 tablets PO qDay

>55 kg: 6 tablets PO qDay

Following initial phase dosing with rifampin/isoniazide for at least 4 months; continue longer if patient is still sputum or culture positive, if resistant organisms present, or if patient is positive for HIV infection

<15 years: Safety and efficacy not established

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Interactions

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            Warnings

            Black Box Warnings

            Severe and sometimes fatal hepatitis may occur within the first 3 months of treatment and many months after treatment

            Risk is related to age and increased with daily alcohol consumption

            Patients should be instructed about signs and symptoms of hepatitis

            Contraindications

            Hypersensitivity to isoniazid, pyrazinamide, rifamycins

            Acute liver disease, severe hepatic damage, acute gout

            Rifampin contraindicated in patients receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity

            Many CYP substrates are contraindicated with rifampin owing to risk for decreased systemic exposure

            Rifampin is contraindicated with atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir because of the potential to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy for HIV infection and/or development of viral resistance

            Cautions

            Systemic hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, may occur; signs and symptoms may include fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations;. reactions may be severe and fatal; monitor for signs and/or symptoms of hypersensitivity reactions; discontinue therapy and administer supportive measures if symptoms occur

            Rifampin is not recommended for intermittent therapy; caution patient against intentional or accidental interruption of 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

            Patient should be told that rifampin may produce a discoloration (yellow, orange, red, brown) of teeth, urine, sweat, sputum, and tears, and should be forewarned of this; soft contact lenses may be permanently stained

            Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea reported; although Clostridium difficile shown in vitro to be sensitive to rifampin, pseudomembranous colitis reported with use of rifampin (and other broad spectrum antibiotics); consider this diagnosis in patients who develop diarrhea in association with antibiotic use

            Isoniazid has some monoamine oxidase inhibiting activity; 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 therapy

            The reliability of oral or other systemic hormonal contraceptives may be affected by rifampin; consideration should be given to using alternative contraceptive measures

            Patients should abstain from alcohol, hepatotoxic medications or herbal products while receiving therapy

            Emphasize compliance with full course of therapy, and stress importance of not missing any doses

            Monitor for symptoms and clinical/laboratory signs of liver injury, especially if treatment is prolonged or given with other hepatotoxic drugs; patients with impaired liver function should be given rifampin only in cases of necessity and then under strict medical supervision; carefully monitor liver function in these patients prior to therapy and then every 2- 4 weeks during therapy; if signs of hepatic damage occur or worsen, discontinue rifampin

            Cases of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), reported; if symptoms or signs of severe cutaneous adverse reactions develop, discontinue immediately and institute appropriate therapy

            Rifampin may cause vitamin K–dependent coagulation disorders and bleeding; monitor coagulation tests during rifampin treatment (prothrombin time and other coagulation tests) in patients at risk of vitamin K deficiency (such as those with chronic liver disease, poor nutritional status, on prolonged antibacterial drugs or anticoagulants); consider discontinuation of therapy if abnormal coagulation tests and/or bleeding occur; supplemental vitamin K administration should be considered when appropriate

            Postmarketing reports suggest that concomitant administration of high doses of cefazolin and rifampin may prolong prothrombin time, leading to severe vitamin K–dependent coagulation disorders that may be life-threatening or fatal; avoid concomitant use of cefazolin and rifampin in patients at increased risk for bleeding; if no alternative treatment options are available, closely monitor prothrombin time and other coagulation tests, and administer vitamin K as indicated

            Drug interaction overview

            • Isoniazid is known to inhibit certain cytochrome P-450 enzymes (eg, CYP1A2, CYP2C9, CYP2C19, CYP3A4); concomitant use may decrease elimination of drugs metabolized by these enzymes which may increase the risk of toxicities of these drugs; adjust dosages of drugs metabolized by these enzymes based on approved drug labeling and if applicable, therapeutic drug monitoring;
            • isoniazid has been reported to inhibit the metabolism of the following drugs: anticonvulsants (eg, carbamazepine, phenytoin, primidone, valproic acid), benzodiazepines (eg, diazepam), haloperidol, ketoconazole, theophylline, and warfarin; therefore, isoniazid may increase risk of toxicities of these drugs
            • As the drug combination contains both isoniazid (inhibitor) and rifampin (inducer), the effect on metabolism of above listed drugs when used concomitantly with drug combination is unknown; a potential for increased toxicity cannot be excluded; monitor closely for adverse reactions
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            Pregnancy & Lactation

            Pregnancy

            Isoniazid: Embryocidal effects reported in both rats and rabbits, although no congenital abnormalities observed in mammalian offspring when given during pregnancy

            Pyrazinamide: Animal reproductive studies have not been conducted

            Rifampin

            • No adequate and well-controlled studies have been performed in pregnant women; has been shown to be teratogenic in rodents
            • Rifampin has been reported to cross the placental barrier and appear in cord blood
            • When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated
            • Use during pregnancy only if the potential benefit justifies the potential risk to the fetus
            • Animal studies
              • Congenital malformations, primarily spina bifida, were increased in offspring of pregnant rats given rifampin during organogenesis at oral doses of 150-250 mg/kg/day (~1-2 times the maximum recommended human dose [MRHD] 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 50-200 mg/kg (~0.2-0.8 times MRHD)
              • Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given rifampin at oral doses up to 200 mg/kg/day (~3 times MRHD)

            Lactation

            Isoniazid is known to be secreted into breast milk

            Because of potential for tumorigenicity shown for rifampin in animal studies, a decision should be made whether to discontinue nursing or discontinue drug, taking into account importance of drug to mother

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            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: Inhibits 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

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            Administration

            Oral Administration

            Take on empty stomach 1 hr ac or 2 hr pc with full glass of water

            Storage

            Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

            Protect from excessive humidity

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            Formulary

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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.