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Drug Interactions between dasabuvir / ombitasvir / paritaprevir / ritonavir and Phenytoin Sodium

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

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Interactions between your drugs

Major

phenytoin ombitasvir

Applies to: Phenytoin Sodium (phenytoin) and dasabuvir / ombitasvir / paritaprevir / ritonavir

CONTRAINDICATED: Coadministration with potent inducers of CYP450 isoenzymes may significantly decrease the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir. In 12 study subjects, administration of single-dose ombitasvir, paritaprevir, ritonavir, and dasabuvir with the potent CYP450 inducer carbamazepine (200 mg once daily followed by 200 mg twice daily) decreased ombitasvir peak plasma concentration (Cmax) by 31% and systemic exposure (AUC) by 31%; paritaprevir Cmax by 66% and AUC by 70%; ritonavir Cmax by 83% and AUC by 87%; and dasabuvir Cmax by 55% and AUC by 70%. Loss of therapeutic effects and development of resistance may occur.

MANAGEMENT: Concomitant use of ombitasvir/paritaprevir/ritonavir plus dasabuvir with potent CYP450 inducers such as carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort is considered contraindicated.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh J, Gelderblom H "Mitotane has a strong and a durable inducing effect on CYP3A4 activity." Eur J Endocrinol 164 (2011): 621-6
  3. "Product Information. Xtandi (enzalutamide)." Astellas Pharma US, Inc (2012):
  4. "Product Information. Viekira Pak (dasabuvir/ombitasvir/paritaprev/ritonav)." AbbVie US LLC (2022):
View all 4 references

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Major

phenytoin dasabuvir

Applies to: Phenytoin Sodium (phenytoin) and dasabuvir / ombitasvir / paritaprevir / ritonavir

CONTRAINDICATED: Coadministration with potent inducers of CYP450 isoenzymes may significantly decrease the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir. In 12 study subjects, administration of single-dose ombitasvir, paritaprevir, ritonavir, and dasabuvir with the potent CYP450 inducer carbamazepine (200 mg once daily followed by 200 mg twice daily) decreased ombitasvir peak plasma concentration (Cmax) by 31% and systemic exposure (AUC) by 31%; paritaprevir Cmax by 66% and AUC by 70%; ritonavir Cmax by 83% and AUC by 87%; and dasabuvir Cmax by 55% and AUC by 70%. Loss of therapeutic effects and development of resistance may occur.

MANAGEMENT: Concomitant use of ombitasvir/paritaprevir/ritonavir plus dasabuvir with potent CYP450 inducers such as carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort is considered contraindicated.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh J, Gelderblom H "Mitotane has a strong and a durable inducing effect on CYP3A4 activity." Eur J Endocrinol 164 (2011): 621-6
  3. "Product Information. Xtandi (enzalutamide)." Astellas Pharma US, Inc (2012):
  4. "Product Information. Viekira Pak (dasabuvir/ombitasvir/paritaprev/ritonav)." AbbVie US LLC (2022):
View all 4 references

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Moderate

phenytoin ritonavir

Applies to: Phenytoin Sodium (phenytoin) and dasabuvir / ombitasvir / paritaprevir / ritonavir

MONITOR: Coadministration of ritonavir and phenytoin may result in decreased plasma concentrations of both drugs. The proposed mechanism involves ritonavir induction of phenytoin metabolism via CYP450 2C9 and, conversely, phenytoin induction of ritonavir metabolism via CYP450 3A4. Data are limited. In one case report, serum phenytoin levels in a patient receiving carbamazepine (1200 mg/day), phenytoin (500 mg/day), and phenobarbital (250 mg/day) declined 30% following initiation of antiretroviral therapy containing ritonavir (300 mg twice a day). In another case, a patient receiving carbamazepine (600 mg/day) and phenytoin (400 mg/day) was started on ritonavir (600 mg twice daily) with no apparent change in serum phenytoin levels. In a pharmacokinetic study of 8 healthy volunteers, administration of phenytoin (300 mg once daily for 22 days) in combination with lopinavir-ritonavir (400 mg-100 mg twice a day on days 12 thru 22) decreased phenytoin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 28%, 31% and 34%, respectively, compared to administration of phenytoin alone. In a different arm of the same study, Cmax, AUC and Cmin of lopinavir decreased by 24%, 33% and 46%, respectively, when lopinavir-ritonavir (400 mg-100 mg twice a day for 22 days) was coadministered with phenytoin (300 mg once daily on days 11 through 22) in 12 healthy subjects. Ritonavir Cmax, AUC and Cmin were also reduced by 20%, 28% and 47%, respectively, although only the change in Cmin was statistically significant.

MANAGEMENT: The potential for reduced therapeutic effects of phenytoin should be considered during coadministration with ritonavir. Phenytoin serum levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of ritonavir in patients who are stabilized on their anticonvulsant regimen. In addition, it may be necessary to monitor patients for potentially reduced antiretroviral response due to decreased plasma levels of ritonavir and other antiretroviral agents induced by phenytoin.

References

  1. "Product Information. Dilantin (phenytoin)." Parke-Davis PROD (2001):
  2. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):
  3. Brooks J, Daily J, Schwamm L "Protease inhibitors and anticonvulsants." AIDS Clin Care 9 (1997): 87,90
  4. Barry M, Gibbons S, Back D, Mulcahy F "Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations." Clin Pharmacokinet 32 (1997): 194-209
  5. Sommadossi JP "HIV protease inhibitors: pharmacologic and metabolic distinctions." AIDS 13 (1999): s29-40
  6. Durant J, Clevenbergh P, Garraffo R, Halfon P, Icard S, DelGiudice P, Montagne N, Schapiro JM, Dellamonica P "Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study." Aids 14 (2000): 1333-9
  7. Liedtke MD, Lockhart SM, Rathbun RC "Anticonvulsant and antiretroviral interactions." Ann Pharmacother 38 (2004): 482-9
  8. Lim ML, Min SS, Eron JJ, et al. "Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction." J Acquir Immune Defic Syndr 36 (2004): 1034-40
View all 8 references

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Drug and food interactions

Moderate

phenytoin food

Applies to: Phenytoin Sodium (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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Moderate

ritonavir food

Applies to: dasabuvir / ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

References

  1. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):

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Moderate

paritaprevir food

Applies to: dasabuvir / ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of ombitasvir, paritaprevir, ritonavir, and dasabuvir. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a moderate-fat meal (approximately 600 Kcal; 20% to 30% calories from fat) increased the mean systemic exposure (AUC) by 82%, 211%, 49%, and 30%, respectively. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a high-fat meal (approximately 900 Kcal; with 60% calories from fat) increased the mean AUC by 76%, 180%, 44%, and 22%, respectively.

MANAGEMENT: Ombitasvir/paritaprevir/ritonavir plus dasabuvir should always be administered with a meal. The fat or calorie content does not matter.

References

  1. "Product Information. Viekira Pak (dasabuvir/ombitasvir/paritaprev/ritonav)." AbbVie US LLC (2022):

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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

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