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Drug Interactions between gepirone and isoniazid / rifampin

This report displays the potential drug interactions for the following 2 drugs:

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Major

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 It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement.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

  1. 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
  2. Kumar A, Misra PK, Mehotra R, et al. (1991) "Hepatotoxicity of rifampin and isoniazid." Am Rev Respir Dis, 143, p. 1350-2
  3. 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
  4. 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
  5. Yamamoto T, Suou T, Hirayama C (1986) "Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype." Hepatology, 6, p. 295-8
  6. Steele MA, Burk RF, Des Prez RM (1991) "Toxic hepatitis with isoniazid and rifampin." Chest, 99, p. 465-71
  7. "Product Information. INH (isoniazid)." Ciba Pharmaceuticals, Summit, NJ.
  8. 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
  9. (2001) "Product Information. Mycobutin (rifabutin)." Pharmacia and Upjohn
  10. (2001) "Product Information. Rifadin (rifampin)." Hoechst Marion Roussel
  11. Askgaard DS, Wilcke T, Dossing M (1995) "Hepatotoxicity caused by the combined action of isoniazid and rifampicin." Thorax, 50, p. 213-4
  12. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  13. Canadian Pharmacists Association (2006) e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink
  14. Cerner Multum, Inc. "Australian Product Information."
  15. (2023) "Product Information. Isoniazid (isoniazid)." Chartwell RX, LLC.
  16. (2023) "Product Information. Isoniazid (Arrotex) (isoniazid)." Arrotex Pharmaceuticals Pty Ltd
  17. (2023) "Product Information. Isoniazid (isoniazid)." RPH Pharmaceuticals AB
  18. 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/
  19. 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
  20. (2021) "Product Information. Isotamine (isoniazid)." Bausch Health, Canada Inc.
  21. (2022) "Product Information. Rifampin (rifAMPin)." Akorn Inc
  22. (2022) "Product Information. Rifampicin (rifampicin)." Mylan Pharmaceuticals Inc
  23. (2023) "Product Information. Rifadin (rifampicin)." Sanofi
  24. (2024) "Product Information. Rifadin (rifaMPICin)." Sanofi-Aventis Australia Pty Ltd
  25. (2019) "Product Information. Rofact (rifampin)." Bausch Health, Canada Inc.
View all 25 references

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Major

rifAMPin gepirone

Applies to: isoniazid / rifampin and gepirone

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentration and effects of gepirone, which is primarily metabolized by the isoenzyme. In 24 study subjects, administration of gepirone (20 mg for 2 days, then 40 mg daily) with the potent CYP450 3A4 inducer rifampin (600 mg daily) decreased the maximum plasma concentration (Cmax) and the systemic exposure (AUC) of gepirone by approximately 20- and 29-fold, respectively. The Cmax and AUC of one of gepirone's active metabolites, 3'-OH gepirone, were decreased by approximately 2.5- and 3-fold, respectively. There was no effect on the pharmacokinetics of the other active metabolite, 1-PP. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, gepirone may potentiate the serotonergic effects of St. John's Wort and increase the risk of serotonin syndrome. Similarly, coadministration of gepirone with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Due to the potential for a significant reduction in the exposure of gepirone, concomitant use with potent CYP450 3A4 inducers is not recommended.

References

  1. (2023) "Product Information. Exxua (gepirone)." Mission Pharmacal Company, 1

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Moderate

isoniazid gepirone

Applies to: isoniazid / rifampin and gepirone

GENERALLY AVOID: Coadministration of isoniazid (INH), with drugs that possess serotonergic activity (e.g., serotonin reuptake inhibitors, 5-HT1 receptor agonists, ergot alkaloids, etc.) may increase the risk of serotonin syndrome, a rare but serious and potentially fatal condition. The proposed mechanism is an increase in serotonin resulting from INH's weak inhibition of monoamine oxidase (the enzyme primarily responsible for breaking down norepinephrine, serotonin, and dopamine) combined with the increase in serotonin from the serotonergic drug(s). In one case report, a patient taking mirtazapine (15 mg nightly) for depression was started on INH (300 mg daily) and pyridoxine (25 mg daily) for tuberculosis prophylaxis following a liver transplant from a donor with latent tuberculosis. Six days following the initiation of INH, the patient developed symptoms consistent with serotonin syndrome (e.g., diarrhea, nausea, tremors, hypertension, and altered mental status) which resolved upon the cessation of INH and mirtazapine. However, consensus on the safety of concomitant use of isoniazid with drugs possessing serotonergic activity is lacking and most of the existing data are limited to case reports.

MANAGEMENT: Until more information is available, coadministration of isoniazid with drugs that possess serotonergic activity (e.g., serotonin reuptake inhibitors, 5-HT1 receptor agonists, ergot alkaloids, etc.) should generally be avoided. If coadministration with a serotonergic drug is required, patients should be advised to promptly seek medical attention if they experience signs and symptoms of serotonin syndrome (including but not limited to confusion, hallucinations, tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, neuromuscular abnormalities and/or unexplained gastrointestinal symptoms).

References

  1. (2021) "Product Information. Isoniazid/Rifapentine 300 mg/300 mg (Macleods) (isoniazid-rifapentine)." Imported (India), 2
  2. (2023) "Product Information. Isoniazid (isoniazid)." Chartwell RX, LLC.
  3. (2023) "Product Information. Isoniazid (Arrotex) (isoniazid)." Arrotex Pharmaceuticals Pty Ltd
  4. Stockley IH (2024) Lack of clinical evidence for potential interaction between isoniazid and selective serotonin reuptake inhibitors https://academic.oup.com/ajhp/article-abstract/53/18/2217/5094445?redirectedFrom=fulltext
  5. Evans ME, kortas kj (2024) Potential interaction between isoniazid and selective serotonin reuptake inhibitors https://academic.oup.com/ajhp/article-abstract/52/19/2135/5094220?redirectedFrom=fulltext&login=false
  6. (2023) "Product Information. Isoniazid (isoniazid)." RPH Pharmaceuticals AB
  7. OBrien M, Gandhi RG, Kotton CN, Adamsick ML (2024) Risk of serotonin syndrome with Isoniazid https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927797/
  8. (2021) "Product Information. Isotamine (isoniazid)." Bausch Health, Canada Inc.
View all 8 references

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Drug and food interactions

Moderate

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

  1. (2022) "Product Information. Rifampin (rifAMPin)." Akorn Inc
  2. (2022) "Product Information. Rifampicin (rifampicin)." Mylan Pharmaceuticals Inc
  3. (2023) "Product Information. Rifadin (rifampicin)." Sanofi
  4. (2024) "Product Information. Rifadin (rifaMPICin)." Sanofi-Aventis Australia Pty Ltd
  5. 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/
  6. (2019) "Product Information. Rofact (rifampin)." Bausch Health, Canada Inc.
View all 6 references

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Moderate

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

  1. Smith CK, Durack DT (1978) "Isoniazid and reaction to cheese." Ann Intern Med, 88, p. 520-1
  2. Dimartini A (1995) "Isoniazid, tricyclics and the ''cheese reaction''." Int Clin Psychopharmacol, 10, p. 197-8
  3. Uragoda CG, Kottegoda SR (1977) "Adverse reactions to isoniazid on ingestion of fish with a high histamine content." Tubercle, 58, p. 83-9
  4. Self TH, Chrisman CR, Baciewicz AM, Bronze MS (1999) "Isoniazid drug and food interactions." Am J Med Sci, 317, p. 304-11
  5. (2021) "Product Information. Isoniazid/Rifapentine 300 mg/300 mg (Macleods) (isoniazid-rifapentine)." Imported (India), 2
  6. (2023) "Product Information. Isoniazid (isoniazid)." Chartwell RX, LLC.
  7. (2023) "Product Information. Isoniazid (Arrotex) (isoniazid)." Arrotex Pharmaceuticals Pty Ltd
  8. (2023) "Product Information. Isoniazid (isoniazid)." RPH Pharmaceuticals AB
  9. 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
  10. 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/
  11. Wang P, Pradhan K, Zhong XB, Ma X (2016) "Isoniazid metabolism and hepatoxicity." Acta Pharm Sin B, 6, p. 384-92
  12. 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
  13. 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
  14. 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
  15. 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#!/
  16. 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
  17. (2021) "Product Information. Isotamine (isoniazid)." Bausch Health, Canada Inc.
View all 17 references

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Moderate

gepirone food

Applies to: gepirone

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the plasma concentrations and effects of gepirone. The proposed mechanism is inhibition of CYP450 3A4 mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. For example, when subjects who were at steady state on the strong CYP450 3A4 inhibitor ketoconazole (200 mg twice daily) received a single dose of gepirone (36.3 mg), the maximum plasma concentration (Cmax) and systemic exposure (AUC) of gepirone increased by approximately 5-fold. Similarly, when subjects who were at steady state on the moderate CYP450 3A4 inhibitor verapamil (80 mg three times daily) received a single dose of gepirone (18.2 mg), the maximum plasma concentration (Cmax) and systemic exposure (AUC) of gepirone increased by approximately 2.6-fold. In general, the effects of grapefruit products are concentration-, dose-, and preparation-dependent and can vary widely among both brands and individual patients. Some preparations have demonstrated strong CYP450 3A4 inhibition, while others have demonstrated moderate inhibition.

ADJUST DOSING INTERVAL: Food enhances the bioavailability of gepirone and its major active metabolites (3'-OH-gepirone and 1-PP). The magnitude of the effect is dependent on the fat content of the meal, but the systemic exposure of gepirone and its major metabolites was consistently higher under fed conditions as compared to the fasted state. The peak plasma concentration (Cmax) of gepirone after intake of a low-fat (about 200 calorie) breakfast was 27% higher, after a medium-fat (about 500 calorie) breakfast was 55% higher, and after a high-fat (about 850 calorie) breakfast was 62% higher than the Cmax achieved in the fasted state. Likewise, the systemic exposure (AUC) of gepirone was about 14% higher after a low-fat breakfast, 22% higher after a medium-fat breakfast, and 32% to 37% higher after a high-fat breakfast when compared to the AUC achieved in the fasted state. The effect of varying amounts of fat on the AUC and Cmax of 3'-OH-gepirone and 1-PP were similar to that of gepirone.

MANAGEMENT: Coadministration of gepirone with grapefruit products should be avoided. If grapefruit juice is consumed, monitoring for adverse effects (e.g., QT prolongation, serotonin syndrome, dizziness, nausea, insomnia, abdominal pain, and/or dyspepsia) should be considered. Gepirone should be taken orally with food at the approximately the same time each day. Tablets should be swallowed whole.

References

  1. (2023) "Product Information. Exxua (gepirone)." Mission Pharmacal Company, 1
  2. FDA. U.S. Food and Drug Administration (2024) Grapefruit juice and some drugs don't mix. https://www.fda.gov/consumers/consumer-updates/grapefruit-juice-and-some-drugs-dont-mix
  3. Chen M, Zhou S, Fabriaga E, Zhang P, Zhou Q (2024) Food-drug interactions precipitated by fruit juices other than grapefruit juice: an update review. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326888/
  4. Kiani J, Imam SZ (2024) Medicinal importance of grapefruit juice and its interaction with various drugs. https://nutritionj.biomedcentral.com/articles/10.1186/1475-2891-6-33
View all 4 references

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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.


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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor 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.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.