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Drug Interactions between atazanavir / cobicistat and Necon 0.5/35

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

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Interactions between your drugs

Moderate

ethinyl estradiol atazanavir

Applies to: Necon 0.5 / 35 (ethinyl estradiol / norethindrone) and atazanavir / cobicistat

GENERALLY AVOID: Coadministration with atazanavir may increase the plasma concentrations of ethinyl estradiol and norethindrone and possibly other contraceptive hormones. The mechanism is atazanavir inhibition of CYP450 3A4 and UGT1A1, the enzymes responsible for the metabolic clearance of contraceptive hormones. In 19 study subjects, atazanavir (400 mg once a day for 14 days) increased the mean steady-state peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of ethinyl estradiol (Ortho-Novum 7/7/7) by 15%, 48% and 91%, respectively, compared to administration of the oral contraceptive alone. The Cmax, AUC and Cmin of norethindrone were increased by 67%, 110% and 262%, respectively. Decreased HDL or increased insulin resistance may be associated with elevated plasma concentrations of norethindrone.

MANAGEMENT: The manufacturer recommends alternate methods of nonhormonal contraception during atazanavir or atazanavir-ritonavir therapy.

References

  1. "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb (2003):

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Moderate

norethindrone atazanavir

Applies to: Necon 0.5 / 35 (ethinyl estradiol / norethindrone) and atazanavir / cobicistat

GENERALLY AVOID: Coadministration with atazanavir may increase the plasma concentrations of ethinyl estradiol and norethindrone and possibly other contraceptive hormones. The mechanism is atazanavir inhibition of CYP450 3A4 and UGT1A1, the enzymes responsible for the metabolic clearance of contraceptive hormones. In 19 study subjects, atazanavir (400 mg once a day for 14 days) increased the mean steady-state peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of ethinyl estradiol (Ortho-Novum 7/7/7) by 15%, 48% and 91%, respectively, compared to administration of the oral contraceptive alone. The Cmax, AUC and Cmin of norethindrone were increased by 67%, 110% and 262%, respectively. Decreased HDL or increased insulin resistance may be associated with elevated plasma concentrations of norethindrone.

MANAGEMENT: The manufacturer recommends alternate methods of nonhormonal contraception during atazanavir or atazanavir-ritonavir therapy.

References

  1. "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb (2003):

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Moderate

ethinyl estradiol cobicistat

Applies to: Necon 0.5 / 35 (ethinyl estradiol / norethindrone) and atazanavir / cobicistat

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with cobicistat and elvitegravir may alter the plasma concentrations of contraceptive hormones. The exact mechanism of interaction has not been described. In 13 study subjects, administration of ethinyl estradiol 0.025 mg and norgestimate 0.18 to 0.25 mg once daily in combination with elvitegravir 150 mg plus cobicistat 150 mg once daily decreased the mean ethinyl estradiol peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 6%, 25% and 44%, respectively. In contrast, norgestimate Cmax, AUC and Cmin increased by 2.08-, 2.26- and 2.67-fold, respectively. Clinical effects of increased progestogen levels are not fully known, but may include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis.

MANAGEMENT: The potential risks and benefits of using norgestimate-containing contraceptives in combination with cobicistat and elvitegravir should be considered, particularly in women who have risk factors for insulin resistance, dyslipidemia, acne, and venous thrombosis. Coadministration of cobicistat and elvitegravir with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives), oral contraceptives containing progestogens other than norgestimate, or less than 25 mcg of ethinyl estradiol has not been studied and is not recommended. Some authorities recommend that hormonal contraceptives containing at least 30 mcg of ethinyl estradiol with norgestimate should be used in combination with the multi-ingredient antiretroviral formulations containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. However, the long term effects of increased progesterone exposure are not known. Alternative, nonhormonal methods of contraception may be considered.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. Cerner Multum, Inc. "Australian Product Information." O 0
  3. "Product Information. Stribild (cobicistat/elvitegravir/emtricitabine/tenofov)." Gilead Sciences (2012):

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Moderate

norethindrone cobicistat

Applies to: Necon 0.5 / 35 (ethinyl estradiol / norethindrone) and atazanavir / cobicistat

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with cobicistat and elvitegravir may alter the plasma concentrations of contraceptive hormones. The exact mechanism of interaction has not been described. In 13 study subjects, administration of ethinyl estradiol 0.025 mg and norgestimate 0.18 to 0.25 mg once daily in combination with elvitegravir 150 mg plus cobicistat 150 mg once daily decreased the mean ethinyl estradiol peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 6%, 25% and 44%, respectively. In contrast, norgestimate Cmax, AUC and Cmin increased by 2.08-, 2.26- and 2.67-fold, respectively. Clinical effects of increased progestogen levels are not fully known, but may include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis.

MANAGEMENT: The potential risks and benefits of using norgestimate-containing contraceptives in combination with cobicistat and elvitegravir should be considered, particularly in women who have risk factors for insulin resistance, dyslipidemia, acne, and venous thrombosis. Coadministration of cobicistat and elvitegravir with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives), oral contraceptives containing progestogens other than norgestimate, or less than 25 mcg of ethinyl estradiol has not been studied and is not recommended. Some authorities recommend that hormonal contraceptives containing at least 30 mcg of ethinyl estradiol with norgestimate should be used in combination with the multi-ingredient antiretroviral formulations containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. However, the long term effects of increased progesterone exposure are not known. Alternative, nonhormonal methods of contraception may be considered.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. Cerner Multum, Inc. "Australian Product Information." O 0
  3. "Product Information. Stribild (cobicistat/elvitegravir/emtricitabine/tenofov)." Gilead Sciences (2012):

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Drug and food interactions

Moderate

norethindrone food

Applies to: Necon 0.5 / 35 (ethinyl estradiol / norethindrone)

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

atazanavir food

Applies to: atazanavir / cobicistat

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.

References

  1. "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb (2003):

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Minor

ethinyl estradiol food

Applies to: Necon 0.5 / 35 (ethinyl estradiol / norethindrone)

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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Minor

ethinyl estradiol food

Applies to: Necon 0.5 / 35 (ethinyl estradiol / norethindrone)

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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Minor

norethindrone food

Applies to: Necon 0.5 / 35 (ethinyl estradiol / norethindrone)

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.

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