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Drug Interactions between Di-Phen and Valergen

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

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Interactions between your drugs

Moderate

phenytoin estradiol

Applies to: Di-Phen (phenytoin) and Valergen (estradiol)

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of estrogens and progestins. Estrogens have been shown in in vitro and in vivo studies to be partially metabolized by CYP450 3A4, and other steroids including progestins are also believed to undergo metabolism by this isoenzyme. The interaction has been reported primarily with oral contraceptives. There have been case reports of menstrual breakthrough bleeding or unwanted pregnancy in women receiving low-dose oral contraceptives following the addition of known CYP450 3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort. Inadequate response to estrogen replacement therapy has also been reported in a patient treated with phenytoin. Aminoglutethimide, a CYP450 3A4 inducer, has been shown to decrease medroxyprogesterone and megestrol serum levels by 74% in six patients stabilized on their progestin regimen.

MANAGEMENT: Pharmacologic response to estrogens and progestins should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the hormone dosage adjusted as necessary. For patients receiving hormonal contraceptives, additional or alternative non-hormonal birth control may be advisable during concomitant therapy with CYP450 3A4 inducers. Additional or alternative non-hormonal birth control may be recommended beyond discontinuation of the CYP450 3A4 inducer(s). Individual product labeling should be consulted for specific time frames. Intrauterine systems are unlikely to be significantly affected because of their local action. Input from a gynecologist or similar expert on adequate contraception, including emergency contraception, should be sought as needed. Patients should be advised to notify their physician if they experience inadequate control of symptoms associated with estrogen deficiency (e.g., nocturnal sweating, vasomotor disturbances, atrophic vaginitis) or changes in the uterine bleeding profile.

References

  1. Crawford P, Chadwick DJ, Martin C, et al. "The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids." Br J Clin Pharmacol 30 (1990): 892-6
  2. Venkatesan K "Pharmacokinetic drug interactions with rifampicin." Clin Pharmacokinet 22 (1992): 47-65
  3. Borcherding SM, Baciewicz AM, Self TH "Update on rifampin drug interactions." Arch Intern Med 152 (1992): 711-6
  4. Weber JC "Interaction between oral contraceptives and griseofulvin." Br Med J 288 (1984): 1125-6
  5. McDaniel PA, Caldroney RD "Oral contraceptives and griseofulvin interaction." Drug Intell Clin Pharm 20 (1986): 384
  6. Cote J "Interaction of griseofulvin and oral contraceptives." J Am Acad Dermatol 22 (1990): 124-5
  7. Baciewicz AM "Oral contraceptive drug interactions." Ther Drug Monit 7 (1985): 26-35
  8. Skolnick JL, Stoler BS, Katz DB, Anderson WH "Rifampin, oral contraceptives, and pregnancy." JAMA 236 (1976): 1382
  9. Lundgren S, Lonning PE, Aakvaag A, Kvinnsland S, Lnning PE "Influence of aminoglutethimide on the metabolism of medroxyprogesterone acetate and megestrol acetate in postmenopausal patients with advanced breast cancer." Cancer Chemother Pharmacol 27 (1990): 101-5
  10. Halpenny O, Bye A, Cranny A, Feely J, Daly PA "Influence of aminoglutethimide on plasma levels of medroxyprogesterone acetate." Med Oncol Tumor Pharmacother 7 (1990): 241-7
  11. Mumford JP "Letter: Drugs affecting oral contraceptives." Br Med J 2 (1974): 333-4
  12. Back DJ, Bates M, Bowden A, et al. "The interaction of phenobarbital and other anticonvulsants with oral contraceptive steroid therapy." Contraception 22 (1980): 495-503
  13. Dossetor J "Drug interactions with oral contraceptives." Br Med J 4 (1975): 467-8
  14. Baciewicz AM, Self TH "Rifampin drug interactions." Arch Intern Med 144 (1984): 1667-71
  15. Nocke-finck L "Effects of rifampicin on menstral cycle and on estrogen excretion in patients taking oral contraceptives." JAMA 226 (1973): 378
  16. 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
  17. Back DJ, Breckenridge AM, Crawford FE, et al. "The effect of rifampicin on the pharmacokinetics of ethynylestradiol in women." Contraception 21 (1980): 135-43
  18. Furlan AJ, Rothner AD "Anti-epileptic drugs and failure of oral contraceptives." Lancet 1 (1974): 1113
  19. Coulam CB, Annegers JF "Do anticonvulsants reduce the efficacy of oral contraceptives?" Epilepsia 20 (1979): 519-26
  20. Szoka PR, Edgren RA "Drug interactions with oral contraceptives: compilation and analysis of an adverse experience report database." Fertil Steril 49 (1988): s31-8
  21. Mattson RH, Cramer JA, Darney PD, Naftolin F "Use of oral contraceptives by women with epilepsy." JAMA 256 (1986): 238-40
  22. van Dijke CP, Weber JC "Interaction between oral contraceptives and griseofulvin." Br Med J (Clin Res Ed) 288 (1984): 1125-6
  23. Laengner H, Detering K "Letter: Anti-epileptic drugs and failure of oral contraceptives." Lancet 2 (1974): 600
  24. Janz D, Schmidt D "Letter: Anti-epileptic drugs and failure of oral contraceptives." Lancet 1 (1974): 1113
  25. Curran MA "Drug interactions with the pill." Med J Aust 144 (1986): 670-1
  26. Back DJ, Orme ML "Pharmacokinetic drug interactions with oral contraceptives." Clin Pharmacokinet 18 (1990): 472-84
  27. D'Arcy PF "Drug interactions with oral contraceptives." Drug Intell Clin Pharm 20 (1986): 353-62
  28. Notelovitz M, Tjapkes J, Ware M "Interaction between estrogen and dilantin in a menopausal woman." N Engl J Med 304 (1981): 788-9
  29. "Product Information. Premarin (conjugated estrogens)." Wyeth-Ayerst Laboratories PROD (2001):
  30. Strayhorn VA, Baciewicz AM, Self TH "Update on rifampin drug interactions, III." Arch Intern Med 157 (1997): 2453-8
  31. Michalets EL "Update: clinically significant cytochrome P-450 drug interactions." Pharmacotherapy 18 (1998): 84-112
  32. 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
  33. 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
  34. 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
  35. Weisberg E "Interactions between oral contraceptives and antifungals antibacterials - Is contraceptive failure the result?." Clin Pharmacokinet 36 (1999): 309-13
  36. Klosterskov Jensen P, Saano V, Haring P, Svenstrup B, Menge GP "Possible interaction between oxcarbazepine and an oral contraceptive." Epilepsia 33 (1992): 1149-52
  37. Wilbur K, Ensom MHH "Pharmacokinetic drug interactions between oral contraceptives and second-generation anticonvulsants." Clin Pharmacokinet 38 (2000): 355-65
  38. Durr D, Stieger B, KullakUblick GA, Rentsch KM, Steinert HC, Meier PJ, Fattinger K "St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4." Clin Pharmacol Ther 68 (2000): 598-604
  39. Weaver K, Glasier A "Interaction between broad-spectrum antibiotics and the combined oral contraceptive pill: a literature review." Contraception 59 (1999): 71-8
  40. Zachariassen RD "Loss of oral contraceptive efficacy by concurrent antibiotic administration." Women Health 22 (1994): 17-26
  41. Dickinson BD, Altman RD, Nielsen NH, Sterling ML "Drug interactions between oral contraceptives and antibiotics." Obstet Gynecol 98(5 Pt 1) (2001): 853-60
  42. "Unwanted pregnancy on self-medication with St John's wort despite hormonal contraception." Br J Clin Pharmacol 55 (2003): 112-113
  43. Pfrunder A, Schiesser M, Gerber S, Haschke M, Bitzer J, Drewe J "Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial." Br J Clin Pharmacol 56 (2003): 683-90
  44. Hall SD, Wang Z, Huang SM, et al. "The interaction between St John's wort and an oral contraceptive." Clin Pharmacol Ther 74 (2003): 525-35
  45. Gorski JC, Hamman MA, Wang Z, Vasvada N, Huang S, Hall SD "The effect of St. John's wort on the efficacy of oral contraception." Clin Pharmacol Ther 71 (2002): P25
  46. Schwarz UI, Buschel B, Kirch W "Failure of oral contraceptives because of St. John's wort." Eur J Clin Pharmacol 57 (2001): A25
  47. Faculty of Sexual & Reproductive Healthcare "FSRH Clinical Guidance: Drug Interactions with Hormonal Contraception. file:///C:/Users/df033684/Downloads/ceuguidancedruginteractionshormonal.pdf" (2016):
View all 47 references

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Drug and food interactions

Moderate

phenytoin food

Applies to: Di-Phen (phenytoin)

ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

References

  1. Sandor P, Sellers EM, Dumbrell M, Khouw V "Effect of short- and long-term alcohol use on phenytoin kinetics in chronic alcoholics." Clin Pharmacol Ther 30 (1981): 390-7
  2. Holtz L, Milton J, Sturek JK "Compatibility of medications with enteral feedings." JPEN J Parenter Enteral Nutr 11 (1987): 183-6
  3. Sellers EM, Holloway MR "Drug kinetics and alcohol ingestion." Clin Pharmacokinet 3 (1978): 440-52
  4. "Product Information. Dilantin (phenytoin)." Parke-Davis PROD (2001):
  5. Doak KK, Haas CE, Dunnigan KJ, et al. "Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings." Pharmacotherapy 18 (1998): 637-45
  6. Rodman DP, Stevenson TL, Ray TR "Phenytoin malabsorption after jejunostomy tube delivery." Pharmacotherapy 15 (1995): 801-5
  7. Au Yeung SC, Ensom MH "Phenytoin and enteral feedings: does evidence support an interaction?" Ann Pharmacother 34 (2000): 896-905
  8. Ozuna J, Friel P "Effect of enteral tube feeding on serum phenytoin levels." J Neurosurg Nurs 16 (1984): 289-91
  9. Faraji B, Yu PP "Serum phenytoin levels of patients on gastrostomy tube feeding." J Neurosci Nurs 30 (1998): 55-9
  10. Marvel ME, Bertino JS "Comparative effects of an elemental and a complex enteral feeding formulation on the absorption of phenytoin suspension." JPEN J Parenter Enteral Nutr 15 (1991): 316-8
  11. Fleisher D, Sheth N, Kou JH "Phenytoin interaction with enteral feedings administered through nasogastric tubes." JPEN J Parenter Enteral Nutr 14 (1990): 513-6
  12. Haley CJ, Nelson J "Phenytoin-enteral feeding interaction." DICP 23 (1989): 796-8
  13. Guidry JR, Eastwood TF, Curry SC "Phenytoin absorption in volunteers receiving selected enteral feedings." West J Med 150 (1989): 659-61
  14. Krueger KA, Garnett WR, Comstock TJ, Fitzsimmons WE, Karnes HT, Pellock JM "Effect of two administration schedules of an enteral nutrient formula on phenytoin bioavailability." Epilepsia 28 (1987): 706-12
  15. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  16. Cerner Multum, Inc. "Australian Product Information." O 0
View all 16 references

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Minor

estradiol food

Applies to: Valergen (estradiol)

Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.

References

  1. Weber A, Jager R, Borner A, et al. "Can grapefruit juice influence ethinyl estradiol bioavailability?" Contraception 53 (1996): 41-7
  2. Schubert W, Eriksson U, Edgar B, Cullberg G, Hedner T "Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17B-estradiol." Eur J Drug Metab Pharmacokinet 20 (1995): 219-24

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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.

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