Dovato (dolutegravir and lamivudine)

WARNING

PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HUMAN IMMUNODEFICIENCY VIRUS (HIV-1): EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND 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 variants associated with lamivudine-containing antiretroviral regimens has been reported. If Dovato 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.

Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of Dovato. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment.

Dovato can cause serious side effects, including:

• Allergic reactions. Call your healthcare provider right away if you develop a rash with Dovato. Stop taking Dovato and get medical help right away if you develop a rash with any of the following signs or symptoms:
  • fever
  • generally ill feeling
  • tiredness
  • muscle or joint aches
  • blisters or sores in mouth
  • blisters or peeling of the skin
  • redness or swelling of the eyes
  • swelling of the mouth, face, lips, or tongue
  • problems breathing
• Liver problems. People with a history of hepatitis B or C virus may have an increased risk of developing new or worsening changes in certain liver tests during treatment with Dovato. Liver problems, including liver failure, have also happened in people without a history of liver disease or other risk factors. Your healthcare provider may do blood tests to check your liver.

Tell your healthcare provider right away if you get any of the following signs or symptoms of liver problems:

• • your skin or the white part of your eyes turns yellow (jaundice)
  • dark or “tea-colored” urine
  • light-colored stools (bowel movements)
  • nausea or vomiting
  • loss of appetite
  • pain, aching, or tenderness on the right side of your stomach area
• Too much lactic acid in your blood (lactic acidosis). Lactic acidosis is a serious medical emergency that can lead to death.
  Tell your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:
  • feel very weak or tired
  • unusual (not normal) muscle pain
  • trouble breathing
  • stomach pain with nausea and vomiting
  • feel cold, especially in your arms and legs
  • feel dizzy or light-headed
  • have a fast or irregular heartbeat
• Lactic acidosis can also lead to severe liver problems, which can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Tell your healthcare provider right away if you get any of the signs or symptoms of liver problems which are listed above under “Liver problems”. You may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).
• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking Dovato.
• The most common side effects of Dovato include:
  • headache
  • diarrhea
  • nausea
  • trouble sleeping
  • tiredness

These are not all the possible side effects of Dovato. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Testing Prior To Or When Initiating Treatment With Dovato

• Prior to or when initiating Dovato, test patients for HBV infection.
• Perform pregnancy testing before initiation of Dovato in individuals of childbearing potential.

Recommended Dosage

• Dovato is a fixed-dose combination product containing 50 mg of dolutegravir and 300 mg of lamivudine. The recommended dosage regimen of Dovato in adults is one tablet taken orally once daily with or without food.

Recommended Dosage With Certain Coadministered Drugs

• The dolutegravir dose (50 mg) in Dovato is insufficient when coadministered with drugs listed in Table 1 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended.

Table 1. Dosing Recommendations for Dovato with Coadministered Drugs

Not Recommended In Patients With Renal Impairment

• Because Dovato is a fixed-dose tablet and cannot be dose adjusted, Dovato is not recommended in patients with creatinine clearance less than 30 mL per minute.

Not Recommended In Patients With Severe Hepatic Impairment

• Dovato is not recommended in patients with severe hepatic impairment (Child-Pugh Score C).

Coadministration With Other Antiretroviral Drugs

• Dovato is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral drugs for the treatment of HIV-1 infection is not recommended. Information regarding potential drug-drug interactions with other antiretroviral drugs is not provided.

Potential For Dovato To Affect Other Drugs

• Dolutegravir, a component of Dovato, inhibits the renal organic cation transporters (OCT)2 and multidrug and toxin extrusion transporter (MATE)1; thus, it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin.

Potential For Other Drugs To Affect The Components Of Dovato

• Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 with some contribution from cytochrome P450 (CYP)3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of Dovato.
• Coadministration of Dovato and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.
• Coadministration of dolutegravir with polyvalent cation-containing products may lead to decreased absorption of dolutegravir.

Established And Other Potentially Significant Drug Interactions

• No drug interaction studies were conducted with Dovato. The drug interactions described are based on studies conducted with dolutegravir or lamivudine when administered alone. Information regarding potential drug interactions with Dovato are provided in Table 5.
• 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.

Table 5. Established and Other Potentially Significant Drug Interactions for Dovato: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions

• There are insufficient human data on the use of Dovato during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage.
• Data from a birth outcome surveillance study have identified an increased risk of neural tube defects when dolutegravir, a component of Dovato, is administered at the time of conception compared with non-dolutegravir-containing antiretroviral regimens.
  • As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk.
  • In addition, 2 of the 5 birth defects (encephalocele and iniencephaly) that have been observed with dolutegravir use, although often termed neural tube defects, may occur post-neural tube closure, the time period of which may be later than 6 weeks of gestation, but within the first trimester.
  • Due to the limited understanding of the types of reported neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, an alternative treatment to Dovato should be considered at the time of conception through the first trimester of pregnancy.
• Initiation of Dovato is not recommended in individuals actively trying to become pregnant unless there is no suitable alternative The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
• Lamivudine, a component of Dovato, is present in human milk. It is not known whether dolutegravir, a component of Dovato, is present in human milk.