Dolutegravir and Lamivudine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Dovato: Dolutegravir sodium 50 mg and lamivudine 300 mg

Pharmacology

Mechanism of Action

Dolutegravir, an integrase inhibitor, inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration. Lamivudine is a cytosine analog. In vitro, lamivudine is triphosphorylated, the principle mode of action is inhibition of HIV reverse transcription via viral DNA chain termination; inhibits RNA- and DNA-dependent DNA polymerase activities of reverse transcriptase.

Use: Labeled Indications

HIV-1 infection: Treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults with no antiretroviral treatment history and with no known substitutions associated with resistance to dolutegravir or lamivudine.

Contraindications

Hypersensitivity to dolutegravir, lamivudine, or any component of the formulation; concurrent use with dofetilide

Dosage and Administration

Dosing: Adult

HIV-1 infection, treatment: Oral: One tablet (dolutegravir 50 mg/lamivudine 300 mg) once daily.

Dosage adjustment for concomitant therapy with carbamazepine or rifampin: One tablet (dolutegravir 50 mg/lamivudine 300 mg) once daily, with an additional dolutegravir 50 mg tablet once daily, administered 12 hours after the fixed-dose combination product.

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer with or without food. Administer 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, dolutegravir/lamivudine and supplements containing calcium or iron can be taken together with food.

Dietary Considerations

Take with or without food and 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, dolutegravir/lamivudine and supplements containing calcium or iron can be taken together with food.

Storage

Store below 30°C (86°F).

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral aluminum hydroxide. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral aluminum hydroxide. Consider therapy modification

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

Calcium Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral calcium. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral calcium salts. Alternatively, dolutegravir and oral calcium can be taken together with food. Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily when used together with carbamazepine. Patients with known or suspected integrase strand inhibitor resistance should use an alternative to carbamazepine when possible. Consider therapy modification

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

Dofetilide: Dolutegravir may increase the serum concentration of Dofetilide. Avoid combination

Efavirenz: May decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily in adults or children. Consider alternatives to efavirenz for INSTI experienced patients with clinically suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Emtricitabine: LamiVUDine may enhance the adverse/toxic effect of Emtricitabine. Avoid combination

Etravirine: May decrease the serum concentration of Dolutegravir. Management: Avoid etravirine with dolutegravir unless with atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir; avoid use with Dovato brand combination. Canada recommends using dolutegravir 50 mg twice daily when with etravirine without a boosted PI. Consider therapy modification

Fosamprenavir: May decrease the serum concentration of Dolutegravir. Specifically, Fosamprenavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Fosamprenavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir to 50 mg twice daily in adults and pediatric patients (12 yrs or older and at least 40 kg). Seek alternatives to fosamprenavir/ritonavir in INSTI-experienced patients with suspected or certain INSTI resistance. Consider therapy modification

Fosphenytoin-Phenytoin: May decrease the serum concentration of Dolutegravir. Avoid combination

Iron Preparations: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral iron. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral iron. Alternatively, dolutegravir and oral iron can be taken together with food. Exceptions: Ferric Carboxymaltose; Ferric Derisomaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Magnesium Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral magnesium salts. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral magnesium salts. Consider therapy modification

MetFORMIN: Dolutegravir may increase the serum concentration of MetFORMIN. Management: Consider the risks and benefits of this combination. If combined, limit the daily metformin dose to 1,000 mg when used with dolutegravir. Monitor for increased metformin effects/toxicities (including lactic acidosis) during concomitant use. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after multivitamins. Administer the dolutegravir/rilpivirine product at least 4 hours before or 6 hours multivitamins. Alternatively, dolutegravir and multivitamins can be taken together with food Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after multivitamins. Administer the dolutegravir/rilpivirine product at least 4 hours before or 6 hours multivitamins. Alternatively, dolutegravir and multivitamins can be taken together with food Consider therapy modification

Nevirapine: May decrease the serum concentration of Dolutegravir. Avoid combination

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Dolutegravir. Avoid combination

PHENobarbital: May decrease the serum concentration of Dolutegravir. Avoid combination

Primidone: May decrease the serum concentration of Dolutegravir. Specifically, the Primidone metabolite phenobarbital may decrease Dolutegravir serum concentrations. Avoid combination

RifAMPin: May decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily in adults or children. Consider alternatives to rifampin for INSTI experienced patients with clinically suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Selenium: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral selenium. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral selenium. Consider therapy modification

Sorbitol: May decrease the serum concentration of LamiVUDine. Management: When possible, avoid chronic coadministration of sorbitol-containing solutions with lamivudine, but if this combination cannot be avoided, monitor patients more closely for possible therapeutic failure associated with decreased lamivudine exposure. Consider therapy modification

St John's Wort: May decrease the serum concentration of Dolutegravir. Avoid combination

Sucralfate: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after sucralfate. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after sucralfate. Consider therapy modification

Tipranavir: May decrease the serum concentration of Dolutegravir. Specifically, Tipranavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Tipranavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir dose to 50 mg twice daily in patients receiving tipranavir/ritonavir. Seek alternatives to tipranavir/ritonavir in INSTI experienced patients with suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Trimethoprim: May increase the serum concentration of LamiVUDine. Monitor therapy

Zinc Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral zinc salts. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral zinc salts. Consider therapy modification

Adverse Reactions

See individual agents.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: Hepatic adverse events, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have been reported with dolutegravir; these events have occurred in patients without underlying hepatic disease or other risk factors. Patients with hepatitis B or C may be at increased risk for worsening or development of increased transaminases; sometimes these increases were consistent with immune reconstitution syndrome or hepatitis B reactivation (particularly when anti-hepatitis therapy was withdrawn). Drug-induced liver injury requiring liver transplantation has been reported with dolutegravir in combination with abacavir and lamivudine. Monitor patients for signs/symptoms of hepatotoxicity.
• Hypersensitivity reactions: Rash, constitutional findings, and organ dysfunction (eg, liver injury) have been reported with dolutegravir. Discontinue immediately if signs of hypersensitivity (eg, severe rash, rash with fever, malaise, fatigue, muscle/joint aches, blistering or peeling of skin, oral blisters/lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing) occur. Monitor clinical status and liver function tests and initiate supportive therapy as appropriate. If hypersensitivity occurs, do not reinitiate therapy.
• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.
• Lactic acidosis/hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis have been reported with nucleoside analogues, including fatal cases. Use with caution and closely monitor patients with risk factors for liver disease (risk may be increased with female gender or obesity); suspend use in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis).

Disease-related concerns:

• Chronic hepatitis B: [US Boxed Warning]: Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment.
• Hepatic impairment: Not recommended for use in patients with severe hepatic impairment (Child-Pugh class C) (has not been studied).
• HBV resistance [US Boxed Warning]: All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating dolutegravir/lamivudine. Emergence of lamivudine-resistant HBV variants in patients receiving lamivudine-containing antiretroviral regimens has been reported. If dolutegravir/lamivudine is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.
• Renal impairment: Use is not recommended in patients with CrCl <50 mL/minute.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Hepatitis B virus testing prior to initiation; viral load, CD4 count; renal and hepatic function (baseline and during therapy); signs/symptoms of hypersensitivity reactions, lactic acidosis

Pregnancy

Pregnancy Considerations

The Health and Human Services perinatal HIV guidelines do not recommend use of this fixed-dose 2-drug combination in pregnant females living with HIV who are antiretroviral naive, who have had antiretroviral therapy (ART) in the past but are restarting, who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen), and who are not yet pregnant but are trying to conceive. For females who become pregnant while taking this combination as a complete regimen, the regimen should be changed, or additional agents added (2-drug regimens are not recommended during pregnancy) (HHS [perinatal] 2019).

Refer to individual monographs for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience headache, diarrhea, nausea, or trouble sleeping. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of lactic acidosis (fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), muscle pain, joint pain, mouth sores, eye irritation, shortness of breath, severe loss of strength and energy, or signs of infection (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.