Drug Interactions between Estratab and isoniazid / pyrazinamide / rifampin

Using isoniazid together with rifAMPin can cause serious side effects that may affect your liver. Call your doctor immediately if you experience a fever, chills, joint pain or swelling, excessive tiredness or weakness, unusual bleeding or bruising, skin rash or itching, loss of appetite, nausea, vomiting, or yellowing of the skin or the whites of your eyes. If your doctor does prescribe these medications together, you may need a dose adjustment or special tests to safely take both medications. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

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Ask your doctor before using rifAMPin together with pyrazinamide. This can cause damage to the liver. Liver function and drug levels in the blood may be monitored with blood tests during treatment. Call your doctor if you experience fever, rash, loss of appetite, nausea, vomiting, fatigue, right upper abdominal pain, dark urine, and jaundice. You may need a dose adjustment or special tests to safely take both medications. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

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Consumer information for this interaction is not currently available.

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.

Consumer information for this interaction is not currently available.

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.