dolutegravir/lamivudine (Rx)

1-10%

Headache (3%)

Nausea (2%)

Diarrhea (2%)

Insomnia (2%)

Fatigue (2%)

<2%

• Dizziness
• Blood and lymphatic systems disorders: Anemia, neutropenia, thrombocytopenia
• Gastrointestinal disorders: Abdominal discomfort, abdominal pain, flatulence, upper abdominal pain, vomiting
• General: Fever
• Hepatobiliary disorders: Hepatitis
• Immune system disorders: Hypersensitivity, immune reconstitution syndrome
• Musculoskeletal disorders: Myositis
• Nervous system disorders: Somnolence
• Psychiatric disorders: Anxiety; abnormal dreams; depression; suicidal ideation, attempt, behavior, or completion; these events were observed primarily with preexisting history of depression or other psychiatric illness
• Renal and urinary disorders: Renal impairment
• Skin and subcutaneous tissue disorders: Pruritus, rash

<1%

Hypersensitivity reactions

Postmarketing Reports

Body as a whole: Redistribution/accumulation of body fat

Endocrine and metabolic: Hyperglycemia

General: Weakness

Hemic and lymphatic: Anemia, including pure red blood cell aplasia and severe anemias progressing on therapy

Hepatic and pancreatic: Lactic acidosis and hepatic steatosis pancreatitis, posttreatment exacerbations of HBV

Hepatobiliary disorders: Acute liver failure, hepatotoxicity

Hypersensitivity: Anaphylaxis, urticaria

Investigations: Weight increased

Musculoskeletal: Arthralgia, CPK elevation, muscle weakness, creatinine phosphokinase elevation, myalgia, rhabdomyolysis

Nervous system: Paresthesia, peripheral neuropathy

Skin: Alopecia

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

Pregnancy

Dolutegravir

Based on prospective reports to APR of exposures to dolutegravir during pregnancy resulting in live births (including over 450 exposed in first trimester and over 280 exposed in second/third trimester); avoid use at time of conception through first trimester owing to risk of neural tube defects associated with dolutegravir; advise individuals of childbearing potential to consistently use effective contraception; dolutegravir has been shown to cross the placenta

Lamivudine

Based on prospective Antiretroviral Pregnancy Registry (APR) reports (N >12,000 exposures) resulting in live births (>5,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the US reference population

A pregnancy exposure registry monitors pregnancy outcomes in women during pregnancy; healthcare providers are encouraged to register patients by calling the APR at 1-800-258-4263

Potential risk of neural tube birth defects

• Serious cases of neural tube birth defects involving the brain, spine, and spinal cord reported in babies born to women treated with dolutegravir
• Preliminary results from an ongoing observational study in Botswana found women who had received dolutegravir at the time of becoming pregnant or early in the first trimester appear to be at higher risk for these defects; to date, in this observational study there are no reported cases of babies born with neural tube defects to women starting dolutegravir later in pregnancy

• Recommendations

  • Patients should not discontinue dolutegravir without consulting a healthcare professional because stopping the medicine can cause the HIV infection to worsen
  • Pregnant women stopping dolutegravir-containing regimen without switching to alternative HIV medicines could cause the amount of virus to increase and spread HIV to their baby
  • For patients taking a dolutegravir-containing regimen at the time of becoming pregnant and during the first trimester of pregnancy, there is a potential risk of neural tube defects; neural tube defects happen early in pregnancy, before many women even know they are pregnant
  • Inform women of childbearing age about the potential risk of neural tube defects when a dolutegravir-containing regimen is used at the time of conception and early in pregnancy; women of childbearing age should consult their healthcare providers about other non-dolutegravir-containing ARV medicine
  • Healthcare providers should weigh the benefits and the risks of dolutegravir when prescribing antiretroviral medicines to women of childbearing age; consider alternative antiretroviral medicines; discuss the relative risks and benefits of appropriate alternative antiretroviral therapies
  • Women of childbearing age who decide to take a dolutegravir-containing regimen should consistently use effective birth control (contraception) while on HIV treatment; women should discuss with their healthcare professionals about an effective birth control method to use while taking a dolutegravir-containing regimen
  • Perform pregnancy testing before initiating a dolutegravir-containing regimen in women of childbearing age to exclude pregnancy
  • Initiation of therapy is not recommended in individuals actively trying to become pregnant unless there is no suitable alternative; a benefit-risk assessment should consider factors such as feasibility of switching, tolerability, ability to maintain viral suppression, and risk of transmission to infant against risk of neural tube defects

Lactation

Breastfeeding is not recommended because of potential for HIV-1 transmission from mother to infant

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed infants to avoid risking postnatal transmission of HIV-1 infection; dolutegravir and lamivudine are present in human milk; there is no information on effects of the drug components on breastfed infant or effects on milk production

Because of potential for (1) HIV-1 transmission (in HIV-negative infants) and (2) developing viral resistance (in HIV-positive infants), instruct mothers not to breastfeed if they are receiving drug therapy

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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

Oral Administration

May take with or without food

Missed dose: Instruct patients to take a missed dose as soon as they remember, but do not double their next dose or take more than prescribed

Storage

Store below 30°C (86°F)