Drug Interactions between isoniazid / rifampin and mefloquine
This report displays the potential drug interactions for the following 2 drugs:
- isoniazid/rifampin
- mefloquine
Interactions between your drugs
rifAMPin isoniazid
Applies to: isoniazid / rifampin and isoniazid / rifampin
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 It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement.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.
References
- O'Brien RJ, Long MW, Cross FS, et al. (1983) "Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis." Pediatrics, 72, p. 491-9
- Kumar A, Misra PK, Mehotra R, et al. (1991) "Hepatotoxicity of rifampin and isoniazid." Am Rev Respir Dis, 143, p. 1350-2
- Abadie-Kemmerly S, Pankey GA, Dalvisio JR (1988) "Failure of ketoconazole treatment of blastomyces dermatidis due to interaction of isoniazid and rifampin." Ann Intern Med, 109, p. 844-5
- Acocella G, Bonollo L, Garimoldi M, et al. (1972) "Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease." Gut, 13, p. 47-53
- Yamamoto T, Suou T, Hirayama C (1986) "Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype." Hepatology, 6, p. 295-8
- Steele MA, Burk RF, Des Prez RM (1991) "Toxic hepatitis with isoniazid and rifampin." Chest, 99, p. 465-71
- "Product Information. INH (isoniazid)." Ciba Pharmaceuticals, Summit, NJ.
- Sarma G, Immanuel C, Kailasam S, Narayana AS, Venkatesan P (1986) "Rifampin-induced release of hydrazine from isoniazid." Am Rev Respir Dis, 133, p. 1072-5
- (2001) "Product Information. Mycobutin (rifabutin)." Pharmacia and Upjohn
- (2001) "Product Information. Rifadin (rifampin)." Hoechst Marion Roussel
- Askgaard DS, Wilcke T, Dossing M (1995) "Hepatotoxicity caused by the combined action of isoniazid and rifampicin." Thorax, 50, p. 213-4
- Cerner Multum, Inc. "UK Summary of Product Characteristics."
- Canadian Pharmacists Association (2006) e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink
- Cerner Multum, Inc. "Australian Product Information."
- (2023) "Product Information. Isoniazid (isoniazid)." Chartwell RX, LLC.
- (2023) "Product Information. Isoniazid (Arrotex) (isoniazid)." Arrotex Pharmaceuticals Pty Ltd
- (2023) "Product Information. Isoniazid (isoniazid)." RPH Pharmaceuticals AB
- Sarma GR, Immanual C, Kailasam S, Narayana AS, Venkatesan P (2024) Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin https://pubmed.ncbi.nlm.nih.gov/3717759/
- Tostmann A, Boeree MJ, Aarnoutse RE, De Lange WCM, Van Der Ven AJAM, Dekhuijzen R (2024) Antituberculosis drug-induced hepatotoxicity: concise up-to-date review https://onlinelibrary.wiley.com/doi/10.1111/j.1440-1746.2007.05207.x
- (2021) "Product Information. Isotamine (isoniazid)." Bausch Health, Canada Inc.
- (2022) "Product Information. Rifampin (rifAMPin)." Akorn Inc
- (2022) "Product Information. Rifampicin (rifampicin)." Mylan Pharmaceuticals Inc
- (2023) "Product Information. Rifadin (rifampicin)." Sanofi
- (2024) "Product Information. Rifadin (rifaMPICin)." Sanofi-Aventis Australia Pty Ltd
- (2019) "Product Information. Rofact (rifampin)." Bausch Health, Canada Inc.
rifAMPin mefloquine
Applies to: isoniazid / rifampin and mefloquine
MONITOR CLOSELY: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of mefloquine, which is primarily metabolized by the isoenzyme. In seven healthy, nonsmoking male volunteers, administration of a single 500 mg oral dose of mefloquine on day 7 of treatment with the potent CYP450 3A4 inducer rifampin (600 mg orally once daily on days 1 through 7, followed by 600 mg twice weekly on days 8 through 56) decreased mean mefloquine peak plasma concentration (Cmax) and systemic exposure (AUC) by 19% and 68%, respectively, compared to mefloquine administered alone. The mean elimination half-life of mefloquine was also decreased by 63% (from 305 to 113 hours) in the presence of rifampin, while mean apparent oral clearance increased by 281%.
MANAGEMENT: The possibility of diminished antimalarial efficacy should be considered when mefloquine is used in combination with potent CYP450 3A4 inducers. Alternative agents with minimal or less enzyme induction potential are recommended when possible to avoid the risk of therapeutic failure, particularly in the treatment of acute malaria infections.
References
- (2021) "Product Information. Mefloquine Hydrochloride (mefloquine)." Hikma USA (formerly West-Ward Pharmaceutical Corporation)
- Ridtitid W, Wongnawa M, Mahatthanatrakul W, Chaipol P, Sunbhanich M (2000) "Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers." J Pharm Pharmacol, 52, p. 1265-9
- (2022) "Product Information. Lariam (mefloquine)." Pharmaco Australia Ltd
- (2017) "Product Information. Mefloquine (mefloquine)." AA Pharma Inc
- (2022) "Product Information. Lariam (mefloquine)." Neon Healthcare Ltd
Drug and food interactions
rifAMPin food
Applies to: isoniazid / rifampin
GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.
ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.
MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.
References
- (2022) "Product Information. Rifampin (rifAMPin)." Akorn Inc
- (2022) "Product Information. Rifampicin (rifampicin)." Mylan Pharmaceuticals Inc
- (2023) "Product Information. Rifadin (rifampicin)." Sanofi
- (2024) "Product Information. Rifadin (rifaMPICin)." Sanofi-Aventis Australia Pty Ltd
- Peloquin CA, Namdar R, Singleton MD, Nix DE (2024) Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids https://pubmed.ncbi.nlm.nih.gov/9925057/
- (2019) "Product Information. Rofact (rifampin)." Bausch Health, Canada Inc.
isoniazid food
Applies to: isoniazid / rifampin
GENERALLY AVOID: Concurrent use of isoniazid (INH) in patients who ingest alcohol daily may result in an increased incidence of both hepatotoxicity and peripheral neuropathy. The increase in hepatotoxicity may be due to an additive risk as both alcohol and INH are individually associated with this adverse reaction. 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 acetylation is genetically determined and generally classified as slow or rapid. Slow acetylators have been identified by some studies as having a higher risk of hepatotoxicity; therefore, this interaction may be more significant for patients who fall into this category. Other studies have postulated that alcohol-mediated CYP450 2E1 induction may play a role, as this isoenzyme is involved in INH metabolism and may be responsible for producing hepatotoxic metabolites. However, available literature is conflicting. The labeling for some INH products lists daily alcohol use or chronic alcoholism as a risk factor for hepatitis, but not all studies have found a significant association between alcohol use and INH-induced hepatotoxicity. Additionally, INH and alcohol are both associated with pyridoxine (B6) deficiency, which may increase the risk of peripheral neuropathy.
GENERALLY AVOID: Concomitant administration of isoniazid (INH) with foods containing tyramine and/or histamine may increase the risk of symptoms relating to tyramine- and/or histamine toxicity (e.g., headache, diaphoresis, flushing, palpitations, and hypotension). The proposed mechanism is INH-mediated inhibition of monoamine oxidase (MAO) and diamine oxidase (DAO), enzymes responsible for the metabolism of tyramine and histamine, respectively. Some authors have suggested that the reactions observed are mainly due to INH's effects on DAO instead of MAO or the amounts of histamine instead of tyramine present in the food. A Japanese case report recorded an example in 8 out of 25 patients on the tuberculosis ward who developed an accidental histamine poisoning after ingesting a fish paste (saury). Patients developed allergy-like symptoms, which started between 20 minutes and 2 hours after ingesting the food. A high-level of histamine (32 mg/100 g of fish) was confirmed in the saury paste and all 8 patients were both on INH and had reduced MAO concentrations. The 17 remaining patients were not on INH (n=5) or reported not eating the saury paste (n=12).
ADJUST DOSING INTERVAL: Administration with food significantly reduces oral isoniazid (INH) absorption, increasing the risk of therapeutic failure or resistance. The mechanism is unknown. Pharmacokinetic studies completed in both healthy volunteers (n=14) and tuberculosis patients (n=20 treatment-naive patients during days 1 to 3 of treatment) have resulted in almost doubling the time to reach INH's maximum concentration (tmax) and a reduction in isoniazid's maximum concentration (Cmax) of 42%-51% in patients who consumed high-fat or high-carbohydrate meals prior to INH treatment.
MANAGEMENT: The manufacturer of oral forms of isoniazid (INH) recommends administration on an empty stomach (i.e., 30 minutes before or 2 hours after meals). Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and INH concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with INH. Concomitant pyridoxine (B6) administration is also recommended to reduce the risk of peripheral neuropathy, with some authorities suggesting a dose of at least 10 mg/day. Patients should be advised to avoid foods containing tyramine (e.g., aged cheese, cured meats such as sausages and salami, fava beans, sauerkraut, soy sauce, beer, or red wine) or histamine (e.g., skipjack, tuna, mackerel, salmon) during treatment with isoniazid. Consultation of product labeling for combination products containing isoniazid and/or relevant guidelines may be helpful for more specific recommendations.
References
- Smith CK, Durack DT (1978) "Isoniazid and reaction to cheese." Ann Intern Med, 88, p. 520-1
- Dimartini A (1995) "Isoniazid, tricyclics and the ''cheese reaction''." Int Clin Psychopharmacol, 10, p. 197-8
- Uragoda CG, Kottegoda SR (1977) "Adverse reactions to isoniazid on ingestion of fish with a high histamine content." Tubercle, 58, p. 83-9
- Self TH, Chrisman CR, Baciewicz AM, Bronze MS (1999) "Isoniazid drug and food interactions." Am J Med Sci, 317, p. 304-11
- (2021) "Product Information. Isoniazid/Rifapentine 300 mg/300 mg (Macleods) (isoniazid-rifapentine)." Imported (India), 2
- (2023) "Product Information. Isoniazid (isoniazid)." Chartwell RX, LLC.
- (2023) "Product Information. Isoniazid (Arrotex) (isoniazid)." Arrotex Pharmaceuticals Pty Ltd
- (2023) "Product Information. Isoniazid (isoniazid)." RPH Pharmaceuticals AB
- Saukkonen JJ, Cohn DL, Jasmer RM, et al. (2006) "An official ATS statement: hepatotoxicity of antituberculosis therapy." Am J Respir Crit Care Med, 174, p. 935-52
- Bouazzi OE, Hammi S, Bourkadi JE, et al. (2024) First line anti-tuberculosis induced hepatotoxicity: incidence and risk factors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326068/
- Wang P, Pradhan K, Zhong XB, Ma X (2016) "Isoniazid metabolism and hepatoxicity." Acta Pharm Sin B, 6, p. 384-92
- Saktiawati AM, Sturkenboom MG, Stienstra Y, et al. (2016) "Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment naive TB patients: a randomized cross-over trial." J Antimicrob Chemother, 71, p. 703-10
- Hahn JA, Ngabirano C, Fatch R, et al. (2023) "Safety and tolerability of isoniazid preventive therapy for tuberculosis for persons with HIV with and without alcohol use." AIDS, 37, p. 1535-43
- Huang YS, Chern HD, Su WJ, et al. (2003) "Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis." Hepatology, 37, p. 924-30
- Sousou JM, Griffith EM, Marsalisi C, Reddy P (2024) Pyridoxine deficiency and neurologic dysfunction: an unlikely association. https://www.cureus.com/articles/188310-pyridoxine-deficiency-and-neurologic-dysfunction-an-unlikely-association?score_article=true#!/
- Miki M, Ishikawa T, Okayama H (2005) "An outbreak of histamine poisoning after ingestion of the ground saury paste in eight patients taking isoniazid in tuberculous ward." Intern Med, 44, p. 1133-6
- (2021) "Product Information. Isotamine (isoniazid)." Bausch Health, Canada Inc.
mefloquine food
Applies to: mefloquine
ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of mefloquine. The proposed mechanism is increased drug solubility in the presence of food. In 20 healthy volunteers, administration of a single 750 mg oral dose of mefloquine 30 minutes following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of mefloquine by 73% and 40%, respectively, compared to administration in the fasting state. The Cmax and AUC of the carboxylic acid metabolite were also increased by 35% and 33%, respectively, compared to fasting. In addition, the time to reach peak plasma concentration (Tmax) of mefloquine was significantly shorter after food intake (17 hours) than in the fasting state (36 hours). There was no difference in the elimination half-life of mefloquine and metabolite, or the Tmax for the metabolite.
MANAGEMENT: To ensure maximal oral absorption, mefloquine should be administered immediately after a meal with at least 8 ounces of water.
References
- (2021) "Product Information. Mefloquine Hydrochloride (mefloquine)." Hikma USA (formerly West-Ward Pharmaceutical Corporation)
- Schmidt LE, Dalhoff K (2002) "Food-drug interactions." Drugs, 62, p. 1481-502
Therapeutic duplication warnings
No warnings were found for your selected drugs.
Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.
See also
Drug Interaction Classification
Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit. | |
Moderately clinically significant. Usually avoid combinations; use it only under special circumstances. | |
Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan. | |
No interaction information available. |
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