DOLUTEGRAVIR Drug Interactions: What You Need to Know

INTERACTIONS

• Refer to the full prescribing information for important drug interactions with TIVICAY or TIVICAY PD. ( 4 , 7 )
• Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir. ( 7.2 , 7.3 )
• TIVICAY or TIVICAY PD should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. When taken with food, TIVICAY and supplements containing calcium or iron can be taken at the same time. ( 7.3 )

7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC 50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE) 1 (IC 50 = 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 ) <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Drug Interactions ( 7.3 )]</span> . In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC 50 = 2.12 microM) and OAT3 (IC 50 = 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 (IC 50 greater than 50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyltransferase (UGT)1A1, 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 ) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )]</span> . 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 )] INSTI = integrase strand transfer inhibitor. 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: Etravirine a ↓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: Efavirenz a ↓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/ritonavir a Tipranavir/ritonavir a ↓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 )] . Carbamazepine a ↓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 antacids a 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. Rifampin a ↓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

7.4 Drugs without Clinically Significant Interactions with Dolutegravir Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, darunavir/ritonavir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, sofosbuvir/velpatasvir, and tenofovir <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

JULUCA is contraindicated in patients:

• with previous hypersensitivity reaction to dolutegravir or rilpivirine [see Warnings and Precautions ( 5.1 )] .
• receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events [see Drug Interactions ( 7 )] .
• receiving other coadministered drugs in Table 1 that significantly decrease rilpivirine plasma concentrations [see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] .

Table

1.

Drugs That Are

Contraindicated with JULUCA Drug Class Contraindicated Drugs in Class Clinical Comment Antiarrhythmic Dofetilide Potential for serious and/or life-threatening events due to the potential for increased dofetilide plasma concentrations.

Anticonvulsants Carbamazepine Oxcarbazepine Phenobarbital Phenytoin

Potential for significant decreases in rilpivirine plasma concentrations due to cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response.

Antimycobacterials Rifampin Rifapentine

Glucocorticoid (systemic) Dexamethasone (more than a single-dose treatment)

Herbal Products St

John’s wort ( Hypericum perforatum )

Proton Pump

Inhibitors e.g., Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response.

• Previous hypersensitivity reaction to dolutegravir or rilpivirine. ( 4 )
• Coadministration with dofetilide. ( 4 )
• Coadministration with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response. ( 4 )

AND PRECAUTIONS

• Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported with dolutegravir. Discontinue DOVATO immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. ( 5.2 )
• Hepatotoxicity has been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with DOVATO. Monitoring for hepatotoxicity is recommended. ( 5.3 )
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. ( 5.4 )
• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. ( 5.6 )

5.1 Patients Co-infected with HIV-1 and HBV: Emergence of Lamivudine-Resistant HBV and the Risk of Posttreatment Exacerbations of HBV All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of Lamivudine-Resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic HBV in subjects dually infected with HIV-1 and HBV. Emergence of HBV variants associated with resistance to lamivudine has been reported in HIV‑1–infected subjects who have received lamivudine‑containing antiretroviral regimens in the presence of concurrent infection with HBV. If a decision is made to administer DOVATO to patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.

Severe Acute

Exacerbations of HBV in Patients Co-infected with HIV-1 and HBV Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing lamivudine, and may occur with discontinuation of DOVATO. Patients who are co-infected with HIV-1 and HBV who discontinue DOVATO should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with DOVATO. If appropriate, initiation of anti-HBV therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Hypersensitivity Reactions Hypersensitivity reactions have been reported with the use of dolutegravir, a component of DOVATO, and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in &lt;1% of subjects receiving dolutegravir in Phase 3 clinical trials. Discontinue DOVATO immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with DOVATO or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

5.3 Hepatotoxicity Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of DOVATO <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or HBV reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have also been reported in patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended.

5.4 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine (a component of DOVATO). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Monitor closely when administering DOVATO to any patient with known risk factors for liver disease. Treatment with DOVATO should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

5.5 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The coadministration of DOVATO and other drugs may result in known or potentially significant drug interactions, some of which may lead to <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Drug Interactions ( 7.4 )]</span> :

• Loss of therapeutic effect of DOVATO and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of coadministered drugs.

See Table

5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with DOVATO, review coadministered drugs during therapy with DOVATO, and monitor for the adverse reactions associated with the coadministered drugs.

5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including DOVATO. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.