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Drug Interactions between Aftera and IsonaRif

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

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Major

rifAMPin isoniazid

Applies to: IsonaRif (isoniazid / rifampin) and IsonaRif (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 It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement.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. "Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis." Pediatrics 72 (1983): 491-9
  2. Kumar A, Misra PK, Mehotra R, et al. "Hepatotoxicity of rifampin and isoniazid." Am Rev Respir Dis 143 (1991): 1350-2
  3. Abadie-Kemmerly S, Pankey GA, Dalvisio JR "Failure of ketoconazole treatment of blastomyces dermatidis due to interaction of isoniazid and rifampin." Ann Intern Med 109 (1988): 844-5
  4. Acocella G, Bonollo L, Garimoldi M, et al. "Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease." Gut 13 (1972): 47-53
  5. Yamamoto T, Suou T, Hirayama C "Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype." Hepatology 6 (1986): 295-8
  6. Steele MA, Burk RF, Des Prez RM "Toxic hepatitis with isoniazid and rifampin." Chest 99 (1991): 465-71
  7. "Product Information. INH (isoniazid)." Ciba Pharmaceuticals, Summit, NJ.
  8. Sarma G, Immanuel C, Kailasam S, Narayana AS, Venkatesan P "Rifampin-induced release of hydrazine from isoniazid." Am Rev Respir Dis 133 (1986): 1072-5
  9. "Product Information. Mycobutin (rifabutin)." Pharmacia and Upjohn PROD (2001):
  10. "Product Information. Rifadin (rifampin)." Hoechst Marion Roussel PROD (2001):
  11. Askgaard DS, Wilcke T, Dossing M "Hepatotoxicity caused by the combined action of isoniazid and rifampicin." Thorax 50 (1995): 213-4
  12. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  13. Canadian Pharmacists Association "e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink" (2006):
  14. Cerner Multum, Inc. "Australian Product Information." O 0
  15. "Product Information. Isoniazid (isoniazid)." Chartwell RX, LLC. (2023):
  16. "Product Information. Isoniazid (Arrotex) (isoniazid)." Arrotex Pharmaceuticals Pty Ltd (2023):
  17. "Product Information. Isoniazid (isoniazid)." RPH Pharmaceuticals AB (2023):
  18. Sarma GR, Immanual C, Kailasam S, Narayana AS, Venkatesan P "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/" (2024):
  19. Tostmann A, Boeree MJ, Aarnoutse RE, De Lange WCM, Van Der Ven AJAM, Dekhuijzen R "Antituberculosis drug-induced hepatotoxicity: concise up-to-date review https://onlinelibrary.wiley.com/doi/10.1111/j.1440-1746.2007.05207.x" (2024):
  20. "Product Information. Isotamine (isoniazid)." Bausch Health, Canada Inc. (2021):
  21. "Product Information. Rifampin (rifAMPin)." Akorn Inc (2022):
  22. "Product Information. Rifampicin (rifampicin)." Mylan Pharmaceuticals Inc (2022):
  23. "Product Information. Rifadin (rifampicin)." Sanofi (2023):
  24. "Product Information. Rifadin (rifaMPICin)." Sanofi-Aventis Australia Pty Ltd (2024):
  25. "Product Information. Rofact (rifampin)." Bausch Health, Canada Inc. (2019):
View all 25 references

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Major

rifAMPin levonorgestrel

Applies to: IsonaRif (isoniazid / rifampin) and Aftera (levonorgestrel)

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.

References

  1. Venkatesan K "Pharmacokinetic drug interactions with rifampicin." Clin Pharmacokinet 22 (1992): 47-65
  2. Borcherding SM, Baciewicz AM, Self TH "Update on rifampin drug interactions." Arch Intern Med 152 (1992): 711-6
  3. Baciewicz AM "Oral contraceptive drug interactions." Ther Drug Monit 7 (1985): 26-35
  4. Joshi JV, Joshi UM, Sankolli GM, et al. "A study of interaction of a low-dose combination oral contraceptive with anti-tubercular drugs." Contraception 21 (1980): 617-29
  5. Bint AJ, Burtt I "Adverse antibiotic drug interactions." Drugs 20 (1980): 57-68
  6. Skolnick JL, Stoler BS, Katz DB, Anderson WH "Rifampin, oral contraceptives, and pregnancy." JAMA 236 (1976): 1382
  7. Dossetor J "Drug interactions with oral contraceptives." Br Med J 4 (1975): 467-8
  8. "Product Information. Mycobutin (rifabutin)." Pharmacia and Upjohn PROD (2001):
  9. "Product Information. Rifadin (rifampin)." Hoechst Marion Roussel PROD (2001):
  10. Baciewicz AM, Self TH "Rifampin drug interactions." Arch Intern Med 144 (1984): 1667-71
  11. Nocke-finck L "Effects of rifampicin on menstral cycle and on estrogen excretion in patients taking oral contraceptives." JAMA 226 (1973): 378
  12. Bolt HM, Bolt M, Kappus H "Interaction of rifampicin treatment with pharmacokinetics and metabolism of ethinyloestradiol in man." Acta Endocrinol (Copenh) 85 (1977): 189-97
  13. Back DJ, Breckenridge AM, Crawford FE, et al. "The effect of rifampicin on the pharmacokinetics of ethynylestradiol in women." Contraception 21 (1980): 135-43
  14. Back DJ, Breckenridge AM, Crawford F, et al. "The effect of rifampicin on norethisterone pharmacokinetics." Eur J Clin Pharmacol 15 (1979): 193-7
  15. Szoka PR, Edgren RA "Drug interactions with oral contraceptives: compilation and analysis of an adverse experience report database." Fertil Steril 49 (1988): s31-8
  16. Back DJ, Orme ML "Pharmacokinetic drug interactions with oral contraceptives." Clin Pharmacokinet 18 (1990): 472-84
  17. D'Arcy PF "Drug interactions with oral contraceptives." Drug Intell Clin Pharm 20 (1986): 353-62
  18. Strayhorn VA, Baciewicz AM, Self TH "Update on rifampin drug interactions, III." Arch Intern Med 157 (1997): 2453-8
  19. Michalets EL "Update: clinically significant cytochrome P-450 drug interactions." Pharmacotherapy 18 (1998): 84-112
  20. "Product Information. Priftin (rifapentine)." Hoechst Marion Roussel PROD (2001):
  21. Back DJ, Breckenridge AM, Crawford FE, MacIver M, Orne ML, Rowe PH "Interindividual variation and drug interactions with hormonal steroid contraceptives." Drugs 21 (1981): 46-61
  22. LeBel M, Masson E, Guilbert E, Colborn D, Paquet F, Allard S, Vallee F, Narang PK "Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone." J Clin Pharmacol 38 (1998): 1042-50
  23. Barditch-Crovo P, Trapnell CB, Ette E, et al. "The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive." Clin Pharmacol Ther 65 (1999): 428-38
  24. Weisberg E "Interactions between oral contraceptives and antifungals antibacterials - Is contraceptive failure the result?." Clin Pharmacokinet 36 (1999): 309-13
  25. Weaver K, Glasier A "Interaction between broad-spectrum antibiotics and the combined oral contraceptive pill: a literature review." Contraception 59 (1999): 71-8
  26. Zachariassen RD "Loss of oral contraceptive efficacy by concurrent antibiotic administration." Women Health 22 (1994): 17-26
  27. Dickinson BD, Altman RD, Nielsen NH, Sterling ML "Drug interactions between oral contraceptives and antibiotics." Obstet Gynecol 98(5 Pt 1) (2001): 853-60
  28. Archer JS, Archer DF "Oral contraceptive efficacy and antibiotic interaction: A myth debunked." J Am Acad Dermatol 46 (2002): 917-23
  29. DeRossi SS, Hersh EV "Antibiotics and oral contraceptives." Dent Clin North Am 46 (2002): 653-64
  30. "FFPRHC Guidance (April 2005). Drug interactions with hormonal contraception." J Fam Plann Reprod Health Care 31 (2005): 139-51
  31. Bounds W, Guillebaud J "Observational series on women using the contraceptive Mirena concurrently with anti-epileptic and other enzyme-inducing drugs." J Fam Plann Reprod Health Care 28 (2002): 78-80
  32. Faculty of Sexual & Reproductive Healthcare "FSRH Clinical Guidance: Drug Interactions with Hormonal Contraception. file:///C:/Users/df033684/Downloads/ceuguidancedruginteractionshormonal.pdf" (2016):
  33. Curtis KM, Tepper NK, Jatlaoui TC, et al. "U.S. medical eligibility criteria (US MEC) for contraceptive use. https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/index.html" (2023):
  34. Faculty of Sexual & Reproductive Healthcare "FSRH CEU guidance: drug interactions with hormonal contraception (may 2022) https://www.fsrh.org/standards-and-guidance/documents/ceu-clinical-guidance-drug-interactions-with-hormonal/" (2023):
  35. Allen K "Contraception - common issues and practical suggestions." Aust Fam Physician 41 (2012): 770-2
  36. "Product Information. Isoniazid/Rifapentine 300 mg/300 mg (Macleods) (isoniazid-rifapentine)." Imported (India) 2 (2021):
  37. "Product Information. Priftin (rifapentine)." sanofi-aventis (2021):
  38. Macleods Pharmaceuticals Limited "Rifapentine 300 mg tablets (Macleods Pharmaceuticals Ltd), TB398. WHO-PQ recommended summary of product characteristics. https://extranet.who.int/prequal/sites/default/files/whopar_files/TB398part4v1.pdf" (2024):
  39. Wiesinger H, Klein S, Rottmann A, et al. "The effects of weak and strong CYP3A induction by rifampicin on the pharmacokinetics of five progestins and ethinylestradiol compared to midazolam." Clin Pharmacol Ther 108 (2020): 798-807
View all 39 references

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Drug and food interactions

Moderate

rifAMPin food

Applies to: IsonaRif (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. "Product Information. Rifampin (rifAMPin)." Akorn Inc (2022):
  2. "Product Information. Rifampicin (rifampicin)." Mylan Pharmaceuticals Inc (2022):
  3. "Product Information. Rifadin (rifampicin)." Sanofi (2023):
  4. "Product Information. Rifadin (rifaMPICin)." Sanofi-Aventis Australia Pty Ltd (2024):
  5. Peloquin CA, Namdar R, Singleton MD, Nix DE "Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids https://pubmed.ncbi.nlm.nih.gov/9925057/" (2024):
  6. "Product Information. Rofact (rifampin)." Bausch Health, Canada Inc. (2019):
View all 6 references

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Moderate

isoniazid food

Applies to: IsonaRif (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 "Isoniazid and reaction to cheese." Ann Intern Med 88 (1978): 520-1
  2. Dimartini A "Isoniazid, tricyclics and the ''cheese reaction''." Int Clin Psychopharmacol 10 (1995): 197-8
  3. Uragoda CG, Kottegoda SR "Adverse reactions to isoniazid on ingestion of fish with a high histamine content." Tubercle 58 (1977): 83-9
  4. Self TH, Chrisman CR, Baciewicz AM, Bronze MS "Isoniazid drug and food interactions." Am J Med Sci 317 (1999): 304-11
  5. "Product Information. Isoniazid/Rifapentine 300 mg/300 mg (Macleods) (isoniazid-rifapentine)." Imported (India) 2 (2021):
  6. "Product Information. Isoniazid (isoniazid)." Chartwell RX, LLC. (2023):
  7. "Product Information. Isoniazid (Arrotex) (isoniazid)." Arrotex Pharmaceuticals Pty Ltd (2023):
  8. "Product Information. Isoniazid (isoniazid)." RPH Pharmaceuticals AB (2023):
  9. Saukkonen JJ, Cohn DL, Jasmer RM, et al. "An official ATS statement: hepatotoxicity of antituberculosis therapy." Am J Respir Crit Care Med 174 (2006): 935-52
  10. Bouazzi OE, Hammi S, Bourkadi JE, et al. "First line anti-tuberculosis induced hepatotoxicity: incidence and risk factors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326068/" (2024):
  11. Wang P, Pradhan K, Zhong XB, Ma X "Isoniazid metabolism and hepatoxicity." Acta Pharm Sin B 6 (2016): 384-92
  12. Saktiawati AM, Sturkenboom MG, Stienstra Y, et al. "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 (2016): 703-10
  13. Hahn JA, Ngabirano C, Fatch R, et al. "Safety and tolerability of isoniazid preventive therapy for tuberculosis for persons with HIV with and without alcohol use." AIDS 37 (2023): 1535-43
  14. Huang YS, Chern HD, Su WJ, et al. "Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis." Hepatology 37 (2003): 924-30
  15. Sousou JM, Griffith EM, Marsalisi C, Reddy P "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#!/" (2024):
  16. Miki M, Ishikawa T, Okayama H "An outbreak of histamine poisoning after ingestion of the ground saury paste in eight patients taking isoniazid in tuberculous ward." Intern Med 44 (2005): 1133-6
  17. "Product Information. Isotamine (isoniazid)." Bausch Health, Canada Inc. (2021):
View all 17 references

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Moderate

levonorgestrel food

Applies to: Aftera (levonorgestrel)

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.

References

  1. Edgar B, Bailey D, Bergstrand R, et al. "Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics on felodipine and its potential clinical relevance." Eur J Clin Pharmacol 42 (1992): 313-7
  2. Jonkman JH, Sollie FA, Sauter R, Steinijans VW "The influence of caffeine on the steady-state pharmacokinetics of theophylline." Clin Pharmacol Ther 49 (1991): 248-55
  3. Bailey DG, Arnold JM, Munoz C, Spence JD "Grapefruit juice--felodipine interaction: mechanism, predictability, and effect of naringin." Clin Pharmacol Ther 53 (1993): 637-42
  4. Bailey DG, Arnold JMO, Spence JD "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet 26 (1994): 91-8
  5. Sigusch H, Hippius M, Henschel L, Kaufmann K, Hoffmann A "Influence of grapefruit juice on the pharmacokinetics of a slow release nifedipine formulation." Pharmazie 49 (1994): 522-4
  6. Bailey DG, Arnold JM, Strong HA, Munoz C, Spence JD "Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics." Clin Pharmacol Ther 54 (1993): 589-94
  7. Yamreudeewong W, Henann NE, Fazio A, Lower DL, Cassidy TG "Drug-food interactions in clinical practice." J Fam Pract 40 (1995): 376-84
  8. "Grapefruit juice interactions with drugs." Med Lett Drugs Ther 37 (1995): 73-4
  9. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ "Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice." Clin Pharmacol Ther 58 (1995): 127-31
  10. Min DI, Ku YM, Geraets DR, Lee HC "Effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of quinidine in healthy volunteers." J Clin Pharmacol 36 (1996): 469-76
  11. Majeed A, Kareem A "Effect of grapefruit juice on cyclosporine pharmacokinetics." Pediatr Nephrol 10 (1996): 395
  12. Clifford CP, Adams DA, Murray S, Taylor GW, Wilkins MR, Boobis AR, Davies DS "Pharmacokinetic and cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice." Br J Clin Pharmacol 42 (1996): p662
  13. Josefsson M, Zackrisson AL, Ahlner J "Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers." Eur J Clin Pharmacol 51 (1996): 189-93
  14. Kantola T, Kivisto KT, Neuvonen PJ "Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid." Clin Pharmacol Ther 63 (1998): 397-402
  15. Ozdemir M, Aktan Y, Boydag BS, Cingi MI, Musmul A "Interaction between grapefruit juice and diazepam in humans." Eur J Drug Metab Pharmacokinet 23 (1998): 55-9
  16. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  17. Bailey DG, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit juice felodipine interaction: Effect of naringin and 6',7'-dihydroxybergamottin in humans." Clin Pharmacol Ther 64 (1998): 248-56
  18. Garg SK, Kumar N, Bhargava VK, Prabhakar SK "Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy." Clin Pharmacol Ther 64 (1998): 286-8
  19. Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors." Clin Pharmacol Ther 64 (1998): 477-83
  20. Fuhr U, Maier-Bruggemann A, Blume H, et al. "Grapefruit juice increases oral nimodipine bioavailability." Int J Clin Pharmacol Ther 36 (1998): 126-32
  21. Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin." Clin Pharmacol Ther 66 (1999): 118-27
  22. Eagling VA, Profit L, Back DJ "Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components." Br J Clin Pharmacol 48 (1999): 543-52
  23. Damkier P, Hansen LL, Brosen K "Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine." Br J Clin Pharmacol 48 (1999): 829-38
  24. Lee AJ, Chan WK, Harralson AF, Buffum J, Bui BCC "The effects of grapefruit juice on sertraline metabolism: An in vitro and in vivo study." Clin Ther 21 (1999): 1890-9
  25. Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57
  26. Gunston GD, Mehta U "Potentially serious drug interactions with grapefruit juice." S Afr Med J 90 (2000): 41
  27. Takanaga H, Ohnishi A, Maatsuo H, et al. "Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model." Br J Clin Pharmacol 49 (2000): 49-58
  28. Libersa CC, Brique SA, Motte KB, et al. "Dramatic inhibition of amiodarone metabolism induced by grapefruit juice." Br J Clin Pharmacol 49 (2000): 373-8
  29. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther 68 (2000): 468-77
  30. Zaidenstein R, Soback S, Gips M, Avni B, Dishi V, Weissgarten Y, Golik A, Scapa E "Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers." Ther Drug Monit 23 (2001): 369-73
  31. Sato J, Nakata H, Owada E, Kikuta T, Umetsu M, Ito K "Influence of usual intake of dietary caffeine on single-dose kinetics of theophylline in healthy human subjects." Eur J Clin Pharmacol 44 (1993): 295-8
  32. Flanagan D "Understanding the grapefruit-drug interaction." Gen Dent 53 (2005): 282-5; quiz 286
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Minor

levonorgestrel food

Applies to: Aftera (levonorgestrel)

The central nervous system effects and blood levels of ethanol may be increased in patients taking oral contraceptives, although data are lacking and reports are contradictory. The mechanism may be due to enzyme inhibition. Consider counseling women about this interaction which is unpredictable.

References

  1. Hobbes J, Boutagy J, Shenfield GM "Interactions between ethanol and oral contraceptive steroids." Clin Pharmacol Ther 38 (1985): 371-80

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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.

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