Dolutegravir/lamivudine

Name: Dolutegravir/lamivudine

Dosing & Uses

Dosage Forms & Strengths

dolutegravir/lamivudine

tablet

  • 50mg/300mg

HIV Infection

Indicated as a complete 2-drug regimen for treatment of HIV infection in adults with no antiretroviral (ARV) treatment history and no known substitutions associated with resistance to dolutegravir or lamivudine

1 tablet (ie, dolutegravir 50mg/ lamivudine 300mg) PO qDay

Dosage Modifications

Coadministration with carbamazepine or rifampin

  • Dolutegravir dose (ie, 50mg) contained in the combination is insufficient if coadministered with carbamazepine or rifampin
  • If coadministered, take 1 Dovato tablet qDay, followed by an additional dolutegravir 50-mg tablet at ~12 hr from the Dovato dose

Renal impairment

  • CrCl

Hepatic impairment

  • Mild or moderate (Child-Pugh A or B): No dosage adjustment necessary
  • Severe (Child-Pugh C): Not recommended

Dosing Considerations

Tests before initiating

  • Hepatitis B virus (HBV)
  • Pregnancy in women of childbearing potential

Safety and efficacy not established

Adverse Effects

1-10%

Headache (3%)

Nausea (2%)

Diarrhea (2%)

Insomnia (2%)

Fatigue (2%)

Warnings

Black Box Warnings

All patients with HIV-1 infection should be tested for the presence of hepatitis B virus (HBV) before initiating dolutegravir/lamivudine

Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens reported

Severe acute exacerbations of HBV reported in patients who are coinfected with HIV-1 and HBV and have discontinued lamivudine; closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment

Patients infected with both HIV and HBV should add additional treatment for their hepatitis B or consider a different drug regimen

Formulations of lamivudine used to treat HIV infection contain a higher dose than formulations indicated for chronic HBV infection

Contraindications

Hypersensitivity to dolutegravir or lamivudine

Coadministration with dofetilide

Cautions

Safety and efficacy of lamivudine have not been established for treatment of chronic HBV in patients dually infected with HIV-1 and HBV; emergence of HBV variants associated with resistance to lamivudine reported

Severe acute HBV exacerbations reported in patients coinfected with HIV-1 and HBV who have discontinued lamivudine

Hypersensitivity reactions reported with dolutegravir; reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury

Hepatic adverse events reported with dolutegravir; patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations; in some cases, the elevated transaminases were consistent with immune reconstitution syndrome or HBV reactivation, particularly in the setting where antihepatitis therapy was withdrawn

Preliminary data from an observational study suggest dolutegravir is associated with increased risk of neural tube defects when administered at the time of conception and in early pregnancy

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported with nucleoside analogues, including lamivudine; female sex and obesity may be risk factors

Immune reconstitution syndrome

  • Reported in patients treated with combination ARV therapy
  • During initial phase of combination ARV treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium infection, CMV, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment
  • Autoimmune disorders (eg, Graves disease, polymyositis, and Guillain-Barré syndrome) also reported; however, the time to onset is more variable and can occur many months after initiation of treatment

Drug interaction overview

  • Also see Dosage Modifications
  • Dolutegravir: Uridine diphosphate (UDP)-glucuronosyl-transferase (UGT)1A1 substrate (primary); CYP3A4 substrate (minor); also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro; renal organic cation transporters (OCT)2 inhibitor; multidrug and toxin extrusion transporter (MATE)1 inhibitor
  • Lamivudine: P-gp and BCRP substrate
  • Complete HIV-1 infection treatment regimen; therefore, coadministration with other ARVs not recommended
  • Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (eg, dofetilide [contraindicated], metformin)
  • Drugs that inhibit UGT1A1 and CY3A4 my decrease dolutegravir levels, thereby leading to loss of therapeutic effects and possible development of resistance
  • Coadministration of dolutegravir with polyvalent cation-containing products may decrease dolutegravir absorption
  • Sorbitol decreases lamivudine peak plasma concentration and AUC

Pharmacology

Mechanism of Action

Dolutegravir: Integrase strand transfer inhibitor (INSTI); inhibits catalytic activity of HIV-1 integrase, an HIV-encoded enzyme required for viral replication

Lamivudine: NRTI; following phosphorylation, inhibits HIV reverse transcriptase by viral DNA chain termination; cytosine analog

Absorption

Peak plasma time

  • Dolutegravir: 2.5 hr
  • Lamivudine: 1 hr

Peak plasma concentration

  • Dolutegravir: 3.67 mcg/mL
  • Lamivudine: 2.04 mcg/mL

Trough plasma concentration

  • Dolutegravir: 1.11 mcg/mL
  • Lamivudine: 0.042 mcg/mL

AUC

  • Dolutegravir: 53.6 mcg·hr/mL
  • Lamivudine: 8.87 mcg·hr/mL

Distribution

Protein bound

  • Dolutegravir: ~99%
  • Lamivudine: 36%

Metabolism

Dolutegravir: UGT1A1 (primary); CYP3A (minor)

Lamivudine: Not significantly metabolized

Elimination

Half-life

  • Dolutegravir: ~14 hr
  • Lamivudine: 13-19 hr

Excretion

  • Dolutegravir: 31% urine; 64% feces
  • Lamivudine: ~70% urine

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