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Drug Interactions between Di-Phen and dolutegravir

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

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Interactions between your drugs

Major

phenytoin dolutegravir

Applies to: Di-Phen (phenytoin) and dolutegravir

GENERALLY AVOID: Coadministration with potent inducers of UGT1A1 and CYP450 3A4 isoenzymes may significantly decrease the plasma concentrations of dolutegravir, which is primarily metabolized by UGT1A1 with some contribution from CYP450 3A4. Dolutegravir is also a substrate of UGT1A3, UGT1A9, and P-glycoprotein in vitro. In 16 study subjects, administration of dolutegravir 50 mg once daily with the potent CYP450 3A4 inducer carbamazepine at a dose of 300 mg twice daily decreased dolutegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin; 24 hours post-dose) by 33%, 49%, and 73%, respectively, compared to administration without carbamazepine. Data are not available for other potent CYP450 3A4 inducers phenytoin, phenobarbital (phenobarbitone), and St. John's wort.

MANAGEMENT: In patients with HIV-1 without integrase inhibitor (INI) resistance, some authorities recommend a dolutegravir dose of 50 mg twice daily for both adults and pediatric patients 12 years of age and older who weigh at least 40 kg when coadministered with potent UGT1A1 and CYP450 3A4 inducers including carbamazepine, phenytoin, phenobarbital, and St. John's Wort. However, other authorities advise that coadministration of dolutegravir with these inducers should be avoided. The safety and efficacy of dosages above 50 mg twice daily have not been evaluated. Alternative treatment combinations that do not include metabolic inducers should be considered whenever possible for INI-experienced patients with certain INI-associated resistance substitutions or clinically suspected INI resistance. In addition, concomitant use of potent UGT1A1 and CYP450 3A4 inducers with fixed-dose combination products containing dolutegravir is not recommended; however, when used in combination with carbamazepine, some authorities advise administration of an additional 50 mg daily dose of dolutegravir approximately 12 hours from the combination product. Local antiretroviral treatment experts should be consulted for current practice.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2013) "Product Information. Tivicay (dolutegravir)." ViiV Healthcare
  4. (2014) "Product Information. Triumeq (abacavir/dolutegravir/lamivudine)." ViiV Healthcare
  5. (2019) "Product Information. Dovato (dolutegravir-lamivudine)." ViiV Healthcare
View all 5 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 (1981) "Effect of short- and long-term alcohol use on phenytoin kinetics in chronic alcoholics." Clin Pharmacol Ther, 30, p. 390-7
  2. Holtz L, Milton J, Sturek JK (1987) "Compatibility of medications with enteral feedings." JPEN J Parenter Enteral Nutr, 11, p. 183-6
  3. Sellers EM, Holloway MR (1978) "Drug kinetics and alcohol ingestion." Clin Pharmacokinet, 3, p. 440-52
  4. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  5. Doak KK, Haas CE, Dunnigan KJ, et al. (1998) "Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings." Pharmacotherapy, 18, p. 637-45
  6. Rodman DP, Stevenson TL, Ray TR (1995) "Phenytoin malabsorption after jejunostomy tube delivery." Pharmacotherapy, 15, p. 801-5
  7. Au Yeung SC, Ensom MH (2000) "Phenytoin and enteral feedings: does evidence support an interaction?" Ann Pharmacother, 34, p. 896-905
  8. Ozuna J, Friel P (1984) "Effect of enteral tube feeding on serum phenytoin levels." J Neurosurg Nurs, 16, p. 289-91
  9. Faraji B, Yu PP (1998) "Serum phenytoin levels of patients on gastrostomy tube feeding." J Neurosci Nurs, 30, p. 55-9
  10. Marvel ME, Bertino JS (1991) "Comparative effects of an elemental and a complex enteral feeding formulation on the absorption of phenytoin suspension." JPEN J Parenter Enteral Nutr, 15, p. 316-8
  11. Fleisher D, Sheth N, Kou JH (1990) "Phenytoin interaction with enteral feedings administered through nasogastric tubes." JPEN J Parenter Enteral Nutr, 14, p. 513-6
  12. Haley CJ, Nelson J (1989) "Phenytoin-enteral feeding interaction." DICP, 23, p. 796-8
  13. Guidry JR, Eastwood TF, Curry SC (1989) "Phenytoin absorption in volunteers receiving selected enteral feedings." West J Med, 150, p. 659-61
  14. Krueger KA, Garnett WR, Comstock TJ, Fitzsimmons WE, Karnes HT, Pellock JM (1987) "Effect of two administration schedules of an enteral nutrient formula on phenytoin bioavailability." Epilepsia, 28, p. 706-12
  15. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  16. Cerner Multum, Inc. "Australian Product Information."
View all 16 references

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Minor

dolutegravir food

Applies to: dolutegravir

Food increases the extent of absorption and slows the rate of absorption of dolutegravir. When administered with a low-, moderate- or high-fat meal, dolutegravir peak plasma concentration (Cmax) increased by 46%, 52% and 67%, systemic exposure (AUC) increased by 33%, 41% and 66%, and time to reach Cmax (Tmax) increased from 2 hours to 3, 4 and 5 hours, respectively, compared to administration under fasted conditions. Dolutegravir may be taken with or without food.

References

  1. (2013) "Product Information. Tivicay (dolutegravir)." ViiV Healthcare

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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.

See also

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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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