Tivicay PD (Page 4 of 9)

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary Disorders

Acute liver failure, hepatotoxicity.

Investigations

Weight increased.

Musculoskeletal

Arthralgia, myalgia.

Psychiatric

Anxiety.

7 DRUG INTERACTIONS

7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents

In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide, dalfampridine, and metformin, Table 8) [see Contraindications (4), Drug Interactions (7.3)].

In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.

In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.

7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir

Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir.

Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration.

Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir (Table 8) [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].

In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.

7.3 Established and Other Potentially Significant Drug Interactions

Table 8 provides clinical recommendations as a result of drug interactions with TIVICAY or TIVICAY PD. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy [ s ee Dosage and Administration (2), Clinical Pharmacology (12.3).]

Table 8. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see Dosage and Administration (2)]
a See Clinical Pharmacology (12.3) Table 11 or Table 12 for magnitude of interaction.b The lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology (12.4)]) upon coadministration with certain inducers may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents.

Concomitant Drug Class: Drug Name

Effect on Concentration of Dolutegravir and/or Concomitant Drug

Clinical Comment

HIV-1 Antiviral Agents

Non-nucleoside reverse transcriptase inhibitor:

Etravirinea

↓Dolutegravir

Use of TIVICAY or TIVICAY PD with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.

Non-nucleoside reverse transcriptase inhibitor:

Efavirenza

↓Dolutegravir

Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4).

Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b

Non-nucleoside reverse transcriptase inhibitor:

Nevirapine

↓Dolutegravir

Avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations.

Protease inhibitors:

Fosamprenavir/ritonavira

Tipranavir/ritonavira

↓Dolutegravir

Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4).

Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b

Other Agents

Dofetilide

↑Dofetilide

Coadministration is contraindicated with TIVICAY or TIVICAY PD [see Contraindications (4)].

Carbamazepinea

↓Dolutegravir

Adjust dose of TIVICAY to twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4).

Use alternative treatment that does not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b

Oxcarbazepine Phenytoin Phenobarbital St. John’s wort (Hypericum perforatum)

↓Dolutegravir

Avoid coadministration with TIVICAY or TIVICAY PD because there are insufficient data to make dosing recommendations.

Medications containing polyvalent cations (e.g., Mg or Al):

Cation-containing antacidsa or laxatives Sucralfate Buffered medications

↓Dolutegravir

Administer TIVICAY or TIVICAY PD 2 hours before or 6 hours after taking medications containing polyvalent cations.

Oral calcium or iron supplements, including multivitamins containing calcium or iron a

↓Dolutegravir

When taken with food, TIVICAY and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, TIVICAY or TIVICAY PD should be taken 2 hours before or 6 hours after taking supplements containing calcium or iron.

Potassium channel blocker:

Dalfampridine

↑Dalfampridine

Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with TIVICAY or TIVICAY PD should be considered against the risk of seizures in these patients.

Metformin

↑Metformin

Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of TIVICAY or TIVICAY PD and metformin.

Rifampina

↓Dolutegravir

Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4).

Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.