Drug Interactions between atrasentan and isoniazid / pyrazinamide / rifampin

Using isoniazid together with rifAMPin can cause serious side effects that may affect your liver. You should avoid or limit the use of alcohol while being treated with these medications. Your doctor may already be aware of the risks but has determined that this is the best course of treatment for you, has taken appropriate precautions, and is monitoring you closely for any potential complications. If you develop severe liver problems, you may need a dose adjustment or an interruption in therapy. Call your doctor immediately if you have fever, chills, joint pain or swelling, unusual bleeding or bruising, skin rash, itching, loss of appetite, fatigue, nausea, vomiting, abdominal pain, dark colored urine, light colored stools, and/or yellowing of the skin or eyes, as these may be signs and symptoms of liver damage. Talk to your healthcare provider if you have any questions or concerns. 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.

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.

Consumer information for this interaction is not currently available.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of atrasentan, which is primarily metabolized by the isoenzyme. In drug interaction studies, coadministration with the potent CYP450 3A4 inducer rifampin reduced atrasentan (single dose, 10 mg) trough plasma concentration (Ctrough) by 90%. Rifampin is also an inhibitor of the hepatic influx transporters organic anion transporting polypeptides (OATP) 1B1 and 1B3, of which atrasentan is a substrate. No data are available about potent or moderate CYP450 3A4 inducers that do not inhibit OATP1B1 and/or 1B3, but greater decreases in atrasentan exposure may occur.

MANAGEMENT: Concomitant use of atrasentan with potent or moderate CYP450 3A4 inducers should generally be avoided.

Isoniazid may cause liver problems and using it with other medications that can also affect the liver, such as pyrazinamide, may increase that risk. You should avoid or limit the use of alcohol while being treated with these medications. Your doctor may already be aware of the risks but has determined that this is the best course of treatment for you, has taken appropriate precautions, and is monitoring you closely for any potential complications. If you develop severe liver problems, you may need a dose adjustment or an interruption in therapy. Call your doctor immediately if you have fever, chills, joint pain or swelling, unusual bleeding or bruising, skin rash, itching, loss of appetite, fatigue, nausea, vomiting, abdominal pain, dark colored urine, light colored stools, and/or yellowing of the skin or eyes, as these may be signs and symptoms of liver damage. Talk to your healthcare provider if you have any questions or concerns. 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.

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.