Drug Interactions between isoniazid / pyrazinamide / rifampin and Vienva

MONITOR CLOSELY: The risk of hepatotoxicity is greater when rifampin and isoniazid (INH) are given concomitantly, than when either drug is given alone. The proposed mechanism is rifampin's induction of isoniazid hydrolase, an enzyme involved in the conversion of INH to isonicotinic acid and hydrazine. Hydrazine is the proposed toxic metabolite of INH, which has been shown in animal studies to cause steatosis, hepatocyte vacuolation and glutathione depletion. Some studies have also shown that slow acetylators have a two-fold increased risk of developing antituberculosis drug-induced hepatotoxicity (ATDH) as compared with fast acetylators due to more available INH for direct hydrolysis to hydrazine. Theoretically, a similar reaction may occur with rifabutin and isoniazid. Additional risk factors for developing hepatotoxicity include patients with advanced age, malnutrition, existing hepatic impairment, daily alcohol consumption, female gender, HIV infection, extra-pulmonary tuberculosis and/or patients who are taking other potent CYP450-inducing agents.

MANAGEMENT: Caution and close monitoring should be considered if isoniazid (INH) is coadministered with rifampin or rifabutin. In cases where coadministration is required, careful monitoring of liver function, especially ALT and AST, should be done at baseline and then every 2 to 4 weeks during therapy, or in accordance with individual product labeling. Some manufacturers of INH recommend strongly considering its discontinuation if serum aminotransferase concentrations (AST or SGOT, ALT or SGPT) exceed 3 to 5 times the upper limit of normal. Product labeling for rifampin also recommends the immediate discontinuation of therapy if hepatic damage is suspected. INH product labeling suggests alternate drugs be used if hepatitis is attributed to INH in patients with tuberculosis. However, if INH must be used, it should only be resumed after the patient's symptoms and laboratory abnormalities have cleared. It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement. Patients should be counseled to immediately report signs or symptoms consistent with liver damage and notified that prodromal symptoms usually consist of fatigue, weakness, malaise, anorexia, nausea, and/or vomiting.

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GENERALLY AVOID: A two-month regimen consisting of rifampin (RIF) and pyrazinamide (PZA) for the treatment of latent tuberculosis infection (LTBI) has been associated with liver injury resulting in high rates of hospitalization and death. The exact mechanism of interaction is unknown, although both agents are individually hepatotoxic and may have additive effects on the liver during coadministration. In one prospective cohort study of 224 patients in a community setting between 1999 and 2001, investigators found that the risk of hepatotoxicity in patients receiving the RIF-PZA regimen was increased threefold compared to patients receiving six months of isoniazid (INH). When patients were monitored more intensively, severe hepatotoxicity did not develop, but the difference did not reach statistical significance.

MANAGEMENT: The American Thoracic Society and the Centers for Disease Control and Prevention recommend that the two-month RIF-PZA regimen generally not be offered to patients with LTBI (Note: This recommendation does not apply to the appropriate use of RIF and PZA in multidrug regimens for the treatment of persons with active TB disease). A nine-month course of daily INH remains the preferred treatment for LTBI in both HIV-negative and HIV-positive patients. Other acceptable options include nine months of twice-weekly INH, or six months of either daily or twice-weekly INH. Twice-weekly therapy must be administered under direct observed therapy (DOT), and the six-month regimens should generally not be used in HIV-infected individuals, those with fibrotic lesions on chest radiographs, and children. Four months of daily RIF may be considered for persons who are contacts of patients with INH-resistant, RIF-susceptible TB. The RIF-PZA regimen should never be offered to patients who are taking concomitant medications associated with liver injury; patients who drink alcohol excessively (even if alcohol use is discontinued during treatment); patients with underlying liver disease; and patients with a history of INH-associated liver injury. RIF-PZA may be considered in carefully selected patients if there is reason to believe they are not likely to complete the preferred six- or nine-month regimens. If RIF-PZA is prescribed, the PZA dosage should be no more than 20 mg/kg/day (up to a maximum of 2 g/day) or 50 mg/kg twice weekly (up to a maximum of 4 g twice weekly), and no more than a two-week supply of the medications should be dispensed at any given time. Patients should be evaluated in person by a healthcare provider at 2, 4, and 6 weeks of treatment for adherence, tolerance and adverse effects, and at 8 weeks to document treatment completion. Patients should also be instructed to discontinue the drugs promptly and seek medical attention if signs and symptoms of hepatic injury develop, including fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. Serum transaminases and bilirubin should be measured at baseline and at 2, 4, 6, and 8 weeks of treatment in patients taking RIF-PZA. Therapy should be withdrawn and not resumed if transaminase levels exceed five times the upper limit of normal or are anywhere above the normal range when accompanied by symptoms of hepatitis, or if serum bilirubin is greater than the normal range. U.S. healthcare providers should report possible cases of RIF-PZA hepatotoxicity to CDC's Division of Tuberculosis Elimination, telephone 404-639-8442.

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MONITOR CLOSELY: Coadministration with rifampin or other rifamycins may reduce the efficacy of estrogen and progestin hormones that are CYP450 3A4 substrates. The interaction stems from accelerated clearance of the hormone(s) as well as decreased plasma concentrations of unbound (active) hormone(s) due to induction of CYP450 enzymatic activity and hormone-binding globulin capacity by rifampin and to a lesser extent with other rifamycins. In a study of 28 healthy premenopausal women on a combination oral contraceptive pill, coadministration with rifampin (300 mg/day for 10 days) reduced ethinyl estradiol peak plasma concentration (Cmax) and systemic exposure (AUC) by 42% and 64%, respectively, while the same dosage of rifabutin reduced ethinyl estradiol Cmax and AUC by 20% and 35%, respectively. Norethindrone AUC was reduced by 60% with rifampin and 20% with rifabutin. In addition, FSH and LH levels increased following rifamycin therapy, and the incidence of spotting was significantly higher after coadministration with rifampin (36.4%) and rifabutin (21.7%) than during the control cycle (3.7%). This interaction is not thought to be clinically relevant for persons using the progestin-only (DMPA) injection (as serum progestin levels are expected to remain adequate), locally acting levonorgestrel-releasing intrauterine systems (as the local effect on the endometrium is unaffected by enzyme induction), and the non-hormonal copper intrauterine device for contraception. Similarly, this interaction may not be as significant for each hormone. A pharmacokinetic study (n=65) in postmenopausal women examined the effects of rifampin (600 mg/day) on the exposure of levonorgestrel (0.03 mg, n=13), norethindrone (0.35 mg, n=14), desogestrel (0.075 mg, n=12), dienogest (2 mg, n=12), and a combination of drospirenone and ethinyl estradiol (3 mg/0.03 mg, n=14). Bound and unbound hormone levels were reviewed. The largest decreases in AUC were observed for etonogestrel (desogestrel's active metabolite), dienogest, and drospirenone at >80%. Levonorgestrel, norethindrone, and ethinyl estradiol had reductions in AUC between 50% and less than 80%.

MANAGEMENT: Caution and close clinical monitoring for reduced efficacy are advised for people using an estrogen and/or progestin-containing product for purposes other than contraception. These patients should be counseled to report any changes in efficacy of the hormonal product to their healthcare provider. Women using estrogens and/or progestins for contraception should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant rifamycin therapy, even when given in short doses. Long-acting progestin-only injections and levonorgestrel-releasing intrauterine systems may be considered as alternative contraceptive agents. For the most current guidance, local relevant guidelines should be consulted. In general, alternative or additional methods of non-hormonal birth control should be used during and for at least 28 days after rifamycin therapy.

The following apply only to the specific medications (combined oral contraception) or situations (emergency contraception) specified:

-If a combination oral contraceptive pill is chosen despite the risks, a regimen containing at least 30 mcg of ethinyl estradiol per day or equivalent should be selected. Some authorities have suggested increasing to 50 mcg of ethinyl estradiol or equivalent; however, they recommend advising the patient that contraceptive effectiveness, even at this dose, may be reduced and that there could be an increased risk of thrombosis if exposure to ethinyl estradiol is increased.

-For emergency contraception in patients who have used a hepatic enzyme inducer in the past 4 weeks, a non-hormonal emergency contraceptive (e.g., copper intrauterine device) is considered preferable. If this is not possible, some authorities recommend that the usual dose of levonorgestrel (1.5 mg) be doubled to 3 mg and taken as a single dose as soon as possible (typically within 72 hours, though some guidelines suggest up to 96 hours, of unprotected sexual intercourse). However, the efficacy of this regimen is unknown.

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MONITOR CLOSELY: Coadministration with rifampin or other rifamycins may reduce the efficacy of estrogen and progestin hormones that are CYP450 3A4 substrates. The interaction stems from accelerated clearance of the hormone(s) as well as decreased plasma concentrations of unbound (active) hormone(s) due to induction of CYP450 enzymatic activity and hormone-binding globulin capacity by rifampin and to a lesser extent with other rifamycins. In a study of 28 healthy premenopausal women on a combination oral contraceptive pill, coadministration with rifampin (300 mg/day for 10 days) reduced ethinyl estradiol peak plasma concentration (Cmax) and systemic exposure (AUC) by 42% and 64%, respectively, while the same dosage of rifabutin reduced ethinyl estradiol Cmax and AUC by 20% and 35%, respectively. Norethindrone AUC was reduced by 60% with rifampin and 20% with rifabutin. In addition, FSH and LH levels increased following rifamycin therapy, and the incidence of spotting was significantly higher after coadministration with rifampin (36.4%) and rifabutin (21.7%) than during the control cycle (3.7%). This interaction is not thought to be clinically relevant for persons using the progestin-only (DMPA) injection (as serum progestin levels are expected to remain adequate), locally acting levonorgestrel-releasing intrauterine systems (as the local effect on the endometrium is unaffected by enzyme induction), and the non-hormonal copper intrauterine device for contraception. Similarly, this interaction may not be as significant for each hormone. A pharmacokinetic study (n=65) in postmenopausal women examined the effects of rifampin (600 mg/day) on the exposure of levonorgestrel (0.03 mg, n=13), norethindrone (0.35 mg, n=14), desogestrel (0.075 mg, n=12), dienogest (2 mg, n=12), and a combination of drospirenone and ethinyl estradiol (3 mg/0.03 mg, n=14). Bound and unbound hormone levels were reviewed. The largest decreases in AUC were observed for etonogestrel (desogestrel's active metabolite), dienogest, and drospirenone at >80%. Levonorgestrel, norethindrone, and ethinyl estradiol had reductions in AUC between 50% and less than 80%.

MANAGEMENT: Caution and close clinical monitoring for reduced efficacy are advised for people using an estrogen and/or progestin-containing product for purposes other than contraception. These patients should be counseled to report any changes in efficacy of the hormonal product to their healthcare provider. Women using estrogens and/or progestins for contraception should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant rifamycin therapy, even when given in short doses. Long-acting progestin-only injections and levonorgestrel-releasing intrauterine systems may be considered as alternative contraceptive agents. For the most current guidance, local relevant guidelines should be consulted. In general, alternative or additional methods of non-hormonal birth control should be used during and for at least 28 days after rifamycin therapy.

The following apply only to the specific medications (combined oral contraception) or situations (emergency contraception) specified:

-If a combination oral contraceptive pill is chosen despite the risks, a regimen containing at least 30 mcg of ethinyl estradiol per day or equivalent should be selected. Some authorities have suggested increasing to 50 mcg of ethinyl estradiol or equivalent; however, they recommend advising the patient that contraceptive effectiveness, even at this dose, may be reduced and that there could be an increased risk of thrombosis if exposure to ethinyl estradiol is increased.

-For emergency contraception in patients who have used a hepatic enzyme inducer in the past 4 weeks, a non-hormonal emergency contraceptive (e.g., copper intrauterine device) is considered preferable. If this is not possible, some authorities recommend that the usual dose of levonorgestrel (1.5 mg) be doubled to 3 mg and taken as a single dose as soon as possible (typically within 72 hours, though some guidelines suggest up to 96 hours, of unprotected sexual intercourse). However, the efficacy of this regimen is unknown.

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MONITOR: Coadministration of isoniazid (INH) with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. INH-associated hepatotoxicity is believed to be due to an accumulation of toxic metabolites and may also be partly immune mediated, though the exact mechanisms are not universally agreed upon. INH is metabolized by N-acetyltransferase and CYP450 2E1. The rate of INH's acetylation is genetically determined and generally classified as slow or rapid, with slow acetylators characterized by a relative lack of N-acetyltransferase. While the rate of acetylation does not significantly alter INH's effectiveness, it can lead to higher blood levels of INH and an increase of adverse reactions. In addition, INH is an in vitro inhibitor of several CYP450 isoenzymes (2C9, 2C19, 2E1, and 3A4). Coadministration of hepatotoxic drugs eliminated by one or more of these pathways may lead to elevated concentrations of the concomitant drug and increase the risk of hepatotoxicity. Most of the INH-associated hepatitis cases occur during the first 3 months of treatment, but may occur at any time and have been reported to be severe or even fatal. INH is reported in medical literature to cause clinically apparent acute liver injury with jaundice in 0.5% to 1% and fatality in 0.05% to 0.1% of recipients. A United States Public Health Service Surveillance Study of 13,838 people taking INH reported 8 deaths among 174 cases of hepatitis. Risk factors for INH related liver injury may include: age > 35 years, female gender, postpartum period, daily consumption of alcohol, injection drug user, slow acetylator phenotype, malnutrition, HIV infection, pre-existing liver disease, extra-pulmonary tuberculosis, and concomitant use of hepatotoxic medications. Clinical data have been reported with concurrent use of acetaminophen, alcohol, carbamazepine, phenobarbital, phenytoin, and rifampin.

MANAGEMENT: Coadministration of isoniazid (INH) with other hepatotoxic medications should be done with caution and close clinical monitoring. Some authorities recommend avoiding concurrent use when possible. If coadministration is needed, baseline and monthly liver function testing as well as monthly interviewing of the patient to check for signs and symptoms of adverse effects is recommended. More frequent testing may be advisable in patients at increased risk of INH-associated liver injury. Some manufacturers of INH recommend strongly considering its discontinuation if serum aminotransferase concentrations (AST or SGOT, ALT or SGPT) exceed 3 to 5 times the upper limit of normal. Patients should be counseled to immediately report signs or symptoms consistent with liver damage and notified that prodromal symptoms usually consist of fatigue, weakness, malaise, anorexia, nausea, and/or vomiting. If hepatic damage is suspected, INH should be immediately discontinued as continuation may lead to more severe damage. If hepatitis is attributed to INH in patients with tuberculosis, alternative drugs should be used. However, if INH must be used, it should only be resumed after the patient's symptoms and laboratory abnormalities have cleared. It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement. Consultation with product labeling and relevant guidelines is advisable.

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MONITOR: The effectiveness of estrogen-containing medications may be impaired by concomitant treatment with antimicrobial agents. During metabolism, the estrogen component is conjugated, resulting in sulfation or glucuronidation of the original estrogenic steroid. The conjugates reach the intestine by way of the bile duct where hydrolytic enzymes of intestinal bacteria break down the conjugates into free, active estrogenic hormone. The active hormone is then available for enterohepatic cycling, which helps to maintain estrogen levels. It is important to note that the progestin component of a combined hormonal product does not undergo this process. It has been suggested that broad-spectrum antibiotics may reduce the effectiveness of estrogen-containing contraceptives because of their potential to reduce the number of intestinal bacteria and thus interfere with enterohepatic cycling of estrogen. Most of the research regarding this possible interaction has been done with oral contraceptives, but all estrogens appear to undergo enterohepatic recirculation so theoretically this interaction is a possibility with estrogen containing medications that are being used for alternative purposes. However, the risk appears to be small, and supportive data are primarily limited to anecdotal evidence from case reports and findings from uncontrolled or poorly controlled studies. Most antimicrobials, with the exception of enzyme inducing medications like the rifamycins and possibly griseofulvin, have not been shown to significantly increase the clearance of oral contraceptive estrogens. It is possible that a small number of women may be more sensitive to the effects of antimicrobials on estrogen disposition in vivo, but risk factors or genetic predispositions have yet to be identified.

MANAGEMENT: If a person is using estrogen for a purpose other than contraception, it is important to note that there is a theoretical possibility of lower levels of systemic estrogen available during treatment with an antibiotic due to interference with enterohepatic cycling. These patients should be counseled to report any changes in efficacy of the hormonal product to their healthcare provider. In the case of contraception specifically, the Centers for Disease Control and Prevention do not consider most broad-spectrum antibiotics to significantly interfere with the effectiveness of combined hormonal contraception. However, the manufacturers of certain combined hormonal contraceptives and/or certain antibiotics do recommend using a back-up method of birth control for varying amounts of time; therefore, consulting the product labeling of each medication involved is advised. Some illnesses, as well as some antibiotics, may cause nausea, vomiting, and/or diarrhea. If the patient vomits within a few hours of taking an oral contraceptive pill, consult the product labeling for instructions on what to do in the event of a missed pill. Some authorities recommend a back-up method of birth control if an individual has persistent vomiting or diarrhea.

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