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Drug Interactions between dyphylline / ephedrine / guaifenesin / phenobarbital and Nexplanon

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

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Major

PHENobarbital etonogestrel

Applies to: dyphylline / ephedrine / guaifenesin / phenobarbital and Nexplanon (etonogestrel)

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with certain anticonvulsants such as carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, and primidone may reduce the efficacy of contraceptive hormones. There have been numerous case reports of menstrual abnormalities (e.g., breakthrough bleeding, amenorrhea, irregular menses) and unintended pregnancy occurring in women who received oral contraceptives with anticonvulsants. The incidence of menstrual irregularities associated with this combination has been reported to be as high as 65% in some studies. The interaction stems from accelerated clearance of contraceptive hormones as well as decreased plasma concentrations of unbound (active) hormones due to induction of hepatic CYP450 enzymatic activity and hormone-binding globulin capacity by some anticonvulsants. Pharmacokinetic studies have found that normally recommended dosages of carbamazepine, oxcarbazepine, phenobarbital, and phenytoin can individually reduce ethinyl estradiol and levonorgestrel systemic exposure (AUC) by a third or more. Eslicarbazepine acetate 1200 mg once daily for 2 weeks decreased the mean AUC of single-dose ethinyl estradiol (30 mcg) and levonorgestrel (150 mcg) by 32% and 24%, respectively, while eslicarbazepine 800 mg once daily decreased the mean AUCs by 25% and 11%, respectively.

MANAGEMENT: Women using hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant therapy with enzyme-inducing anticonvulsants. Alternative or additional methods of birth control should be used during and for at least two weeks after short-term and 4 weeks after long-term (greater than 4 weeks) anticonvulsant therapy. If a combination oral contraceptive pill is used, a regimen containing at least 50 mcg of ethinyl estradiol per day or equivalent should be considered. Although breakthrough bleeding is not necessarily indicative of low ethinyl estradiol serum levels or increased risk of ovulation, some clinicians suggest that women who experience breakthrough bleeding during enzyme-inducing therapy may be prescribed an increased dose of ethinyl estradiol above 50 mcg daily by combining more than one formulation of contraceptive pill if necessary. For emergency contraception in patients who have used an 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) should be doubled to 3 mg and taken as a single dose as soon as possible (within 72 hours of unprotected sexual intercourse). However, there are no data on efficacy, compliance, or side effects of this regimen. For women with the etonogestrel subdermal implant, the addition of a barrier method is recommended during concomitant use and for 28 days after discontinuation of hepatic enzyme inducing drugs. It is recommended to remove the implant and to prescribe a nonhormonal method in women who require long-term treatment with hepatic enzyme inducing drugs. No precautions or recommendations are available for women using hormone-releasing intrauterine systems, but a significant interaction with these systems is thought to be unlikely due to their local action. Injectable progestin-only contraceptives are also thought to be unaffected by enzyme-inducing drugs.

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. Odlind V, Olsson SE "Enhanced metabolism of levonorgestrel during phenytoin treatment in a woman with norplant implants." Contraception 33 (1986): 257-61
  3. Baciewicz AM "Oral contraceptive drug interactions." Ther Drug Monit 7 (1985): 26-35
  4. 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
  5. Dossetor J "Drug interactions with oral contraceptives." Br Med J 4 (1975): 467-8
  6. Furlan AJ, Rothner AD "Anti-epileptic drugs and failure of oral contraceptives." Lancet 1 (1974): 1113
  7. Coulam CB, Annegers JF "Do anticonvulsants reduce the efficacy of oral contraceptives?" Epilepsia 20 (1979): 519-26
  8. Szoka PR, Edgren RA "Drug interactions with oral contraceptives: compilation and analysis of an adverse experience report database." Fertil Steril 49 (1988): s31-8
  9. Mattson RH, Cramer JA, Darney PD, Naftolin F "Use of oral contraceptives by women with epilepsy." JAMA 256 (1986): 238-40
  10. Laengner H, Detering K "Letter: Anti-epileptic drugs and failure of oral contraceptives." Lancet 2 (1974): 600
  11. Janz D, Schmidt D "Letter: Anti-epileptic drugs and failure of oral contraceptives." Lancet 1 (1974): 1113
  12. Back DJ, Orme ML "Pharmacokinetic drug interactions with oral contraceptives." Clin Pharmacokinet 18 (1990): 472-84
  13. Diamond MP, Greene JW, Thompson JM, VanHooydonk JE, Wentz AC "Interaction of anticonvulsants and oral contraceptives in epileptic adolescents." Contraception 31 (1985): 623-32
  14. D'Arcy PF "Drug interactions with oral contraceptives." Drug Intell Clin Pharm 20 (1986): 353-62
  15. Rapport DJ, Calabrese JR "Interactions between carbamazepine and birth control pills." Psychosomatics 30 (1989): 462-4
  16. Notelovitz M, Tjapkes J, Ware M "Interaction between estrogen and dilantin in a menopausal woman." N Engl J Med 304 (1981): 788-9
  17. Saano V, Glue P, Banfield CR "Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive." Clin Pharmacol Ther 58 (1995): 523-31
  18. 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
  19. Shane-McWorter L, Cerveny JD, MacFarlane LL, Osborn C "Enhanced metabolism of levonorgestrel during phenobarbital treatment and resultant pregnancy." Pharmacotherapy 18 (1998): 1360-4
  20. Haukkamaa M "Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment." Contraception 33 (1986): 559-65
  21. Fattore C, Cipolla G, Gatti G, Limido GL, Sturm Y, Bernasconi C, Perucca E "Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women." Epilepsia 40 (1999): 783-7
  22. Klosterskov Jensen P, Saano V, Haring P, Svenstrup B, Menge GP "Possible interaction between oxcarbazepine and an oral contraceptive." Epilepsia 33 (1992): 1149-52
  23. "Product Information. Trileptal (oxcarbazepine)." Novartis Pharmaceuticals PROD (2001):
  24. "Product Information. Norplant System (levonorgestrel)." Wyeth-Ayerst Laboratories PROD (2001):
  25. Wilbur K, Ensom MHH "Pharmacokinetic drug interactions between oral contraceptives and second-generation anticonvulsants." Clin Pharmacokinet 38 (2000): 355-65
  26. Kenyon IE "Unplanned pregnancy in an epileptic. (Letter to the editor)." Br Med J 1 (1972): 686
  27. "FFPRHC Guidance (April 2005). Drug interactions with hormonal contraception." J Fam Plann Reprod Health Care 31 (2005): 139-51
  28. Back DJ, Grimmer SF, Orme ML, Proudlove D, Mann RD, Breckenridge AM "Evaluation of Committee on Safety of Medicines yellow card reports on oral contraceptive-drug interactions with anticonvulsants and antibiotics." Br J Clin Pharmacol 25 (1988): 527-32
  29. Schindlbeck C, Janni W, Friese K "Failure of Implanon contraception in a patient taking carbamazepin for epilepsia." Arch Gynecol Obstet 273 (2006): 255-6
  30. O'Brien MD, Guillebaud J "Contraception for women with epilepsy." Epilepsia 47 (2006): 1419-22
  31. "Product Information. Fycompa (perampanel)." Eisai Inc (2012):
  32. "Product Information. Aptiom (eslicarbazepine)." Sunovion Pharmaceuticals Inc (2013):
  33. Faculty of Sexual & Reproductive Healthcare "FSRH Clinical Guidance: Drug Interactions with Hormonal Contraception. file:///C:/Users/df033684/Downloads/ceuguidancedruginteractionshormonal.pdf" (2016):
View all 33 references

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Minor

ePHEDrine dyphylline

Applies to: dyphylline / ephedrine / guaifenesin / phenobarbital and dyphylline / ephedrine / guaifenesin / phenobarbital

Ephedrine-methylxanthine combinations are used for the treatment of asthma but the efficacy of the combination has been questioned. This combination may lead to increased xanthine side effects. The mechanism is unknown, but may be related to synergistic pharmacologic effects. Patients using this combination should be closely monitored for side effects such as nausea, vomiting, tachycardia, nervousness, or insomnia. If side effects are noted, the dosage of the xanthine may need to be decreased.

References

  1. Weinberger M, Bronsky E, Bensch GW, Bock GN, Yecies JJ "Interaction of ephedrine and theophylline." Clin Pharmacol Ther 17 (1975): 585-92
  2. Sims JA, doPico GA, Reed CE "Bronchodilating effect of oral theophylline-ephedrine combination." J Allergy Clin Immunol 62 (1978): 15-21
  3. Tinkelman DG, Avner SE "Ephedrine therapy in asthmatic children. Clinical tolerance and absence of side effects." JAMA 237 (1977): 553-7
  4. Weinberger MM, Brousky EA "Evaluation of oral bronchodilator therapy in asthmatic children: bronchodilators in asthmatic children." J Pediatr 84 (1974): 421-7
  5. Badiei B, Faciane J, Sly M "Effect of throphylline, ephedrine and theri combination upon exercise-induced airway obstruction." Ann Allergy 35 (1975): 32-6
View all 5 references

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Drug and food interactions

Major

PHENobarbital food

Applies to: dyphylline / ephedrine / guaifenesin / phenobarbital

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

References

  1. Gupta RC, Kofoed J "Toxological statistics for barbiturates, other sedatives, and tranquilizers in Ontario: a 10-year survey." Can Med Assoc J 94 (1966): 863-5
  2. Misra PS, Lefevre A, Ishii H, Rubin E, Lieber CS "Increase of ethanol, meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats." Am J Med 51 (1971): 346-51
  3. Saario I, Linnoila M "Effect of subacute treatment with hypnotics, alone or in combination with alcohol, on psychomotor skills related to driving." Acta Pharmacol Toxicol (Copenh) 38 (1976): 382-92
  4. Stead AH, Moffat AC "Quantification of the interaction between barbiturates and alcohol and interpretation of fatal blood concentrations." Hum Toxicol 2 (1983): 5-14
  5. Seixas FA "Drug/alcohol interactions: avert potential dangers." Geriatrics 34 (1979): 89-102
View all 5 references

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Moderate

etonogestrel food

Applies to: Nexplanon (etonogestrel)

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
View all 32 references

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Moderate

ePHEDrine food

Applies to: dyphylline / ephedrine / guaifenesin / phenobarbital

MONITOR: Coadministration of two or more sympathomimetic agents may increase the risk of adverse effects such as nervousness, irritability, and increased heart rate. Central nervous system (CNS) stimulants, particularly amphetamines, can potentiate the adrenergic response to vasopressors and other sympathomimetic agents. Additive increases in blood pressure and heart rate may occur due to enhanced peripheral sympathetic activity.

MANAGEMENT: Caution is advised if two or more sympathomimetic agents are coadministered. Pulse and blood pressure should be closely monitored.

References

  1. Rosenblatt JE, Lake CR, van Kammen DP, Ziegler MG, Bunney WE Jr "Interactions of amphetamine, pimozide, and lithium on plasma norepineophrine and dopamine-beta-hydroxylase in schizophrenic patients." Psychiatry Res 1 (1979): 45-52
  2. Cavanaugh JH, Griffith JD, Oates JA "Effect of amphetamine on the pressor response to tyramine: formation of p-hydroxynorephedrine from amphetamine in man." Clin Pharmacol Ther 11 (1970): 656
  3. "Product Information. Adderall (amphetamine-dextroamphetamine)." Shire Richwood Pharmaceutical Company Inc PROD (2001):
  4. "Product Information. Tenuate (diethylpropion)." Aventis Pharmaceuticals PROD (2001):
  5. "Product Information. Sanorex (mazindol)." Novartis Pharmaceuticals PROD (2001):
  6. "Product Information. Focalin (dexmethylphenidate)." Mikart Inc (2001):
  7. "Product Information. Strattera (atomoxetine)." Lilly, Eli and Company (2002):
View all 7 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.

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