DOSAGE FORMS & STRENGTHS SECTION.


3DOSAGE FORMS AND STRENGTHS. DOVATO tablets are oval, biconvex, white, film-coated tablets, debossed with SV 137 on one face. Each tablet contains 50 mg of dolutegravir and 300 mg of lamivudine.. Tablets: 50 mg of dolutegravir and 300 mg of lamivudine. (3).

DRUG INTERACTIONS SECTION.


7DRUG INTERACTIONS. oDOVATO is 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. (7.1)oRefer to the full prescribing information for important drug interactions with DOVATO. (4, 5.6, 7). oDOVATO is 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. (7.1). oRefer to the full prescribing information for important drug interactions with DOVATO. (4, 5.6, 7). 7.1Coadministration with Other Antiretroviral Drugs. DOVATO is 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 [see Indications and Usage (1)]. Information regarding potential drug-drug interactions with other antiretroviral drugs is not provided [see Contraindications (4), Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. 7.2Potential for DOVATO to Affect Other Drugs. Dolutegravir, 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 [see Contraindications (4), Drug Interactions (7.4), Clinical Pharmacology (12.3)]. 7.3Potential 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 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 [see Drug Interactions (7.4), Clinical Pharmacology (12.3)]. 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 [see Drug Interactions (7.4), Clinical Pharmacology (12.3)].. 7.4Established 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 [see Clinical Pharmacology (12.3)]. 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 [see Contraindications (4), Clinical Pharmacology (12.3)]. 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 Increase, Decrease. See Clinical Pharmacology (12.3) Table or Table for magnitude of interaction. Coadministered Drug Class:Drug NameEffect on ConcentrationClinical CommentAntiarrhythmic: DofetilideDofetilideCoadministration is contraindicated with DOVATO [see Contraindications (4)]. Anticonvulsant:Carbamazepinea DolutegravirAn additional dolutegravir 50-mg dose should be taken, separated by 12 hours from DOVATO [see Dosage and Administration (2.3)]. Anticonvulsants:OxcarbazepinePhenytoinPhenobarbitalDolutegravirAvoid coadministration with DOVATO because there are insufficient data to make dosing recommendations. Antidiabetic:Metformina MetforminRefer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of DOVATO and metformin. Antimycobacterial:Rifampina DolutegravirAn additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from DOVATO [see Dosage and Administration (2.3)]. Herbal product:St. Johns wort (Hypericum perforatum)DolutegravirAvoid coadministration with DOVATO because there are insufficient data to make dosing recommendations. Medications containing polyvalent cations(e.g., Mg or Al):Cation-containing antacidsa or laxatives SucralfateBuffered medicationsDolutegravirAdminister DOVATO hours before or hours after taking medications containing polyvalent cations. Oral calcium and iron supplements, including multivitamins containing calcium or ironaDolutegravirWhen taken with food, DOVATO and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, DOVATO should be taken hours before or hours after taking supplements containing calcium or iron. Potassium channel blocker:DalfampridineDalfampridineElevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with DOVATO should be considered against the risk of seizures in these patients.SorbitolaLamivudineWhen possible, avoid use of sorbitol-containing medicines with DOVATO.

GERIATRIC USE SECTION.


8.5Geriatric Use. Clinical trials of DOVATO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of DOVATO in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. Each DOVATO tablet contains 50 mg of dolutegravir as dolutegravir sodium and 300 mg lamivudine and is an oval, biconvex, white, film-coated tablet, debossed with SV 137 on one face. Bottle of 30 tablets with child-resistant closure NDC 49702-246-13.Store below 30C (86F).

SPL PATIENT PACKAGE INSERT SECTION.


PATIENT INFORMATIONDOVATO (doe VAH toe)(dolutegravir and lamivudine) tabletsWhat is the most important information should know about DOVATOIf you have both human immunodeficiency virus-1 (HIV-1) infection and Hepatitis virus (HBV) infection, DOVATO can cause serious side effects, including:oResistant HBV. Your healthcare provider will test you for HBV infection before you start treatment with DOVATO. If you have HIV-1 and hepatitis B, the HBV can change (mutate) during your treatment with DOVATO and become harder to treat (resistant). It is not known if DOVATO is safe and effective in people who have HIV-1 and HBV infection.oWorsening of HBV infection. If you have HBV infection and take DOVATO, your HBV may get worse (flare-up) if you stop taking DOVATO. flare-up is when your HBV infection suddenly returns in worse way than before.oDo not run out of DOVATO. Refill your prescription or talk to your healthcare provider before your DOVATO is all gone.oDo not stop DOVATO without first talking to your healthcare provider. oIf you stop taking DOVATO, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking DOVATO. For more information about side effects, see What are the possible side effects of DOVATOWhat is DOVATODOVATO is prescription medicine that is used without other HIV-1 medicines to treat HIV-1 infection in adults:owho have not received HIV-1 medicines in the past, or oto replace their current HIV-1 medicines when their healthcare provider determines that they meet certain requirements.HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).It is not known if DOVATO is safe and effective in children.Do not take DOVATO if you:ohave ever had an allergic reaction to medicine that contains dolutegravir or lamivudine. See the end of this Patient Information for complete list of ingredients in DOVATO.otake dofetilide. Taking DOVATO and dofetilide can cause side effects that may be serious or life-threatening.Before you take DOVATO, tell your healthcare provider about all of your medical conditions, including if you:ohave or have had liver problems, including hepatitis or infection.ohave kidney problems.oare pregnant or plan to become pregnant. One of the medicines in DOVATO (dolutegravir) may harm your unborn baby. oYour healthcare provider may prescribe different medicine than DOVATO if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy.oIf you can become pregnant, your healthcare provider may perform pregnancy test before you start treatment with DOVATO.oIf you can become pregnant, you and your healthcare provider should talk about the use of effective birth control (contraception) during treatment with DOVATO.oTell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with DOVATO. Pregnancy Registry. There is pregnancy registry for individuals who take DOVATO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.oare breastfeeding or plan to breastfeed. Do not breastfeed if you take DOVATO.oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. oOne of the medicines in DOVATO (lamivudine) passes into your breast milk.oTalk with your healthcare provider about the best way to feed your baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Some medicines interact with DOVATO. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with DOVATO.oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take DOVATO with other medicines.How should take DOVATOoTake DOVATO time day exactly as your healthcare provider tells you.oTake DOVATO with or without food.oDo not change your dose or stop taking DOVATO without talking with your healthcare provider. oIf you take antacids, laxatives, or other medicines that contain aluminum, magnesium, or buffered medicines, DOVATO should be taken at least hours before or hours after you take these medicines.oIf you need to take iron or calcium supplements, including multivitamins that contain iron or calcium, by mouth during treatment with DOVATO:oYou may take these supplements at the same time that you take DOVATO with food.oIf you do not take these supplements with DOVATO and food, take DOVATO at least hours before or hours after you take these supplements.oDo not miss dose of DOVATO. If you miss dose of DOVATO, take it as soon as you remember. Do not take doses at the same time or take more than your prescribed dose.oStay under the care of healthcare provider during treatment with DOVATO.oDo not run out of DOVATO. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.oIf you take too much DOVATO, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of DOVATODOVATO can cause serious side effects, including:oSee What is the most important information should know about DOVATOoAllergic reactions. Call your healthcare provider right away if you develop rash with DOVATO. Stop taking DOVATO and get medical help right away if you develop rash with any of the following signs or symptoms: ofeverogenerally ill feelingotirednessomuscle or joint achesoblisters or sores in mouthoblisters or peeling of the skinoredness or swelling of the eyesoswelling of the mouth, face, lips, or tongueoproblems breathingoLiver problems. People with history of hepatitis or 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 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:oyour skin or the white part of your eyes turns yellow (jaundice)odark or tea-colored urineolight-colored stools (bowel movements)onausea or vomiting oloss of appetite opain, aching, or tenderness on the right side of your stomach areaoToo much lactic acid in your blood (lactic acidosis). Too much lactic acid is 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: ofeel very weak or tiredounusual (not normal) muscle painotrouble breathingostomach pain with nausea and vomitingofeel cold, especially in your arms and legsofeel dizzy or light-headedohave fast or irregular heartbeatoLactic 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. oYou may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).oChanges 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 long time. Tell your healthcare provider right away if you start having new symptoms after you start taking DOVATO.oThe most common side effects of DOVATO include:oheadacheonauseaodiarrheaotrouble sleepingotirednessoanxietyThese 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.How should store DOVATOoStore DOVATO below 86F (30C).oDOVATO comes in child-resistant package.Keep DOVATO and all medicines out of the reach of children.General information about the safe and effective use of DOVATO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use DOVATO for condition for which it was not prescribed. Do not give DOVATO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about DOVATO that is written for health professionals.What are the ingredients in DOVATOActive ingredients: dolutegravir and lamivudine.Inactive ingredients: magnesium stearate, mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, sodium stearyl fumarate.The tablet film-coating contains: hypromellose, polyethylene glycol, titanium dioxide.Manufactured for:ViiV HealthcareResearch Triangle Park, NC 27709by:GlaxoSmithKlineResearch Triangle Park, NC 27709Trademark is owned by or licensed to the ViiV Healthcare group of companies.(C)2021 ViiV Healthcare group of companies or its licensor.DVT:6PILFor more information go to www.DOVATO.com or call 1-877-844-8872.This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 03/2021. oResistant HBV. Your healthcare provider will test you for HBV infection before you start treatment with DOVATO. If you have HIV-1 and hepatitis B, the HBV can change (mutate) during your treatment with DOVATO and become harder to treat (resistant). It is not known if DOVATO is safe and effective in people who have HIV-1 and HBV infection.. oWorsening of HBV infection. If you have HBV infection and take DOVATO, your HBV may get worse (flare-up) if you stop taking DOVATO. flare-up is when your HBV infection suddenly returns in worse way than before.oDo not run out of DOVATO. Refill your prescription or talk to your healthcare provider before your DOVATO is all gone.oDo not stop DOVATO without first talking to your healthcare provider. oIf you stop taking DOVATO, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking DOVATO. oDo not run out of DOVATO. Refill your prescription or talk to your healthcare provider before your DOVATO is all gone.. oDo not stop DOVATO without first talking to your healthcare provider. oIf you stop taking DOVATO, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking DOVATO.. owho have not received HIV-1 medicines in the past, or oto replace their current HIV-1 medicines when their healthcare provider determines that they meet certain requirements.. ohave ever had an allergic reaction to medicine that contains dolutegravir or lamivudine. See the end of this Patient Information for complete list of ingredients in DOVATO.. otake dofetilide. Taking DOVATO and dofetilide can cause side effects that may be serious or life-threatening.. ohave or have had liver problems, including hepatitis or infection.. ohave kidney problems.. oare pregnant or plan to become pregnant. One of the medicines in DOVATO (dolutegravir) may harm your unborn baby. oYour healthcare provider may prescribe different medicine than DOVATO if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy.oIf you can become pregnant, your healthcare provider may perform pregnancy test before you start treatment with DOVATO.oIf you can become pregnant, you and your healthcare provider should talk about the use of effective birth control (contraception) during treatment with DOVATO.oTell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with DOVATO.. oYour healthcare provider may prescribe different medicine than DOVATO if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy.. oIf you can become pregnant, your healthcare provider may perform pregnancy test before you start treatment with DOVATO.. oIf you can become pregnant, you and your healthcare provider should talk about the use of effective birth control (contraception) during treatment with DOVATO.. oTell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with DOVATO.. Pregnancy Registry. There is pregnancy registry for individuals who take DOVATO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.. oare breastfeeding or plan to breastfeed. Do not breastfeed if you take DOVATO.oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. oOne of the medicines in DOVATO (lamivudine) passes into your breast milk.oTalk with your healthcare provider about the best way to feed your baby.. oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. oOne of the medicines in DOVATO (lamivudine) passes into your breast milk.. oTalk with your healthcare provider about the best way to feed your baby.. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with DOVATO.. oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take DOVATO with other medicines.. oTake DOVATO time day exactly as your healthcare provider tells you.. oTake DOVATO with or without food.. oDo not change your dose or stop taking DOVATO without talking with your healthcare provider. oIf you take antacids, laxatives, or other medicines that contain aluminum, magnesium, or buffered medicines, DOVATO should be taken at least hours before or hours after you take these medicines.. oIf you need to take iron or calcium supplements, including multivitamins that contain iron or calcium, by mouth during treatment with DOVATO:oYou may take these supplements at the same time that you take DOVATO with food.oIf you do not take these supplements with DOVATO and food, take DOVATO at least hours before or hours after you take these supplements.. oYou may take these supplements at the same time that you take DOVATO with food.. oIf you do not take these supplements with DOVATO and food, take DOVATO at least hours before or hours after you take these supplements.. oDo not miss dose of DOVATO. If you miss dose of DOVATO, take it as soon as you remember. Do not take doses at the same time or take more than your prescribed dose.. oStay under the care of healthcare provider during treatment with DOVATO.. oDo not run out of DOVATO. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.. oIf you take too much DOVATO, call your healthcare provider or go to the nearest hospital emergency room right away.. oSee What is the most important information should know about DOVATO. oAllergic reactions. Call your healthcare provider right away if you develop rash with DOVATO. Stop taking DOVATO and get medical help right away if you develop rash with any of the following signs or symptoms: ofever. ogenerally ill feeling. otiredness. omuscle or joint aches. oblisters or sores in mouth. oblisters or peeling of the skin. oredness or swelling of the eyes. oswelling of the mouth, face, lips, or tongue. oproblems breathing. oLiver problems. People with history of hepatitis or 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 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:. oyour skin or the white part of your eyes turns yellow (jaundice). odark or tea-colored urine. olight-colored stools (bowel movements). onausea or vomiting oloss of appetite opain, aching, or tenderness on the right side of your stomach area. oToo much lactic acid in your blood (lactic acidosis). Too much lactic acid is 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: ofeel very weak or tired. ounusual (not normal) muscle pain. otrouble breathing. ostomach pain with nausea and vomiting. ofeel cold, especially in your arms and legs. ofeel dizzy or light-headed. ohave fast or irregular heartbeat. oLactic 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. oYou may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).. oChanges 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 long time. Tell your healthcare provider right away if you start having new symptoms after you start taking DOVATO.. oThe most common side effects of DOVATO include:. oheadache. onausea. odiarrhea. otrouble sleeping. otiredness. oanxiety. oStore DOVATO below 86F (30C).. oDOVATO comes in child-resistant package.

SPL UNCLASSIFIED SECTION.


2.1Testing Prior to or When Initiating Treatment with DOVATO Prior to or when initiating DOVATO, test patients for HBV infection [see Warnings and Precautions (5.1)]. Pregnancy testing is recommended before initiation of DOVATO in individuals of childbearing potential [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS. oPregnancy: Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. (2.1, 5.4, 8.1, 8.3)oLactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2)oFemales and males of reproductive potential: Pregnancy testing is recommended in individuals of childbearing potential. Patients should be counseled on the consistent use of effective contraception (8.1, 8.3)oRenal impairment: DOVATO is not recommended in patients with creatinine clearance less than 30 mL/min. (8.6)oHepatic impairment: DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C). (8.7). oPregnancy: Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. (2.1, 5.4, 8.1, 8.3). oLactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2). oFemales and males of reproductive potential: Pregnancy testing is recommended in individuals of childbearing potential. Patients should be counseled on the consistent use of effective contraception (8.1, 8.3). oRenal impairment: DOVATO is not recommended in patients with creatinine clearance less than 30 mL/min. (8.6). oHepatic impairment: DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C). (8.7). 8.1Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to DOVATO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk Summary Data from an ongoing birth outcome surveillance study have identified an increased risk of neural tube defects when dolutegravir, component of DOVATO, is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first weeks of gestation are at potential risk. Advise individuals of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of DOVATO. Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see Warnings and Precaution (5.4)].There are insufficient human data on the use of DOVATO during pregnancy to definitively assess drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see Data). Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the RHD; however, no adverse developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD (see Data). DataHuman Data: Dolutegravir: In birth outcome surveillance study in Botswana, there were cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included cases of myelomeningocele, cases of encephalocele, and one case each of anencephaly and iniencephaly. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had neural tube defect, compared with infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively address the risk of neural tube defects with dolutegravir.Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births (including 512 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir-containing regimens and 4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%. Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third 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 U.S. reference population of the MACDP. The prevalence of defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.Lamivudine pharmacokinetics were studied in pregnant women during clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using lamivudine 150 mg twice daily with zidovudine, 10 women at 38 weeks gestation using lamivudine 150 mg twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9-fold (1.2- to 12.8-fold) greater compared with paired maternal serum concentration (n 8).Animal Data: Dolutegravir: Dolutegravir was administered orally to pregnant rats and rabbits (up to 1,000 mg/kg/day) on Gestation Days to 17 and to 18, respectively, and also to rats on Gestation Day to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the RHD and in rats were approximately 50 times the exposure in humans at the RHD. In the rat pre/postnatal development study, decreased body weight of the developing offspring was observed during lactation at maternally toxic dose (approximately 50 times human exposure at the RHD). Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg/kg/day) and rabbits (at 90, 300 and 1,000 mg/kg/day and at 15, 40, and 90 mg/kg/day) during organogenesis (on Gestation Days through 16 [rat] and through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the RHD. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the RHD. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg/kg/day (from prior to mating through Postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by the maternal administration of lamivudine.. 8.2Lactation. Risk SummaryThe 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, component of DOVATO, is present in human milk. It is not known whether dolutegravir, component of DOVATO, is present in human milk. When administered to lactating rats, dolutegravir was present in milk (see Data). There is no information on the effects of DOVATO or the components of DOVATO on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving DOVATO.DataAnimal Data: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following single oral dose of 50 mg/kg on Lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed hours postdose.. 8.3Females and Males of Reproductive Potential. In individuals of childbearing potential currently on DOVATO who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing DOVATO and discuss with the patient if an alternative treatment should be considered [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].Pregnancy TestingPregnancy testing is recommended in individuals of childbearing potential before initiation of DOVATO [see Dosage and Administration (2.1)].ContraceptionIndividuals of childbearing potential who are taking DOVATO should be counseled on the consistent use of effective contraception.. 8.4Pediatric Use. The safety and efficacy of DOVATO have not been established in pediatric patients.. 8.5Geriatric Use. Clinical trials of DOVATO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of DOVATO in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. 8.6Renal Impairment. DOVATO is not recommended for patients with creatinine clearance <30 mL/min because DOVATO is fixed-dose combination and the dosage of the individual components cannot be adjusted. If dose reduction of lamivudine, component of DOVATO, is required for patients with creatinine clearance <30 mL/min, then the individual components should be used. Patients with creatinine clearance between 30 and 49 mL/min receiving DOVATO may experience 1.6- to 3.3-fold higher lamivudine exposure (AUC) than patients with creatinine clearance >=50 mL/min. There are no safety data from randomized, controlled trials comparing DOVATO to the individual components in patients with creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects. Patients with sustained creatinine clearance between 30 and 49 mL/min who receive DOVATO should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, DOVATO should be discontinued and the individual components should be used to construct the treatment regimen.. 8.7Hepatic Impairment. No dosage adjustment of DOVATO is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Score or B). Dolutegravir has not been studied in patients with severe hepatic impairment (Child-Pugh Score C); therefore, DOVATO is not recommended for patients with severe hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.


5WARNINGS AND PRECAUTIONS. oHypersensitivity 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 delay in stopping treatment may result in life-threatening reaction. (5.2)oHepatotoxicity has been reported in patients receiving dolutegravir-containing regimen. Patients with underlying hepatitis or may be at increased risk for worsening or development of transaminase elevations with DOVATO. Monitoring for hepatotoxicity is recommended. (5.3)oEmbryo-fetal toxicity may occur when used at the time of conception and in early pregnancy. Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. Individuals of childbearing potential should be counseled on the consistent use of effective contraception. (2.1, 5.4, 8.1, 8.3)oLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.5)oImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. (5.7). oHypersensitivity 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 delay in stopping treatment may result in life-threatening reaction. (5.2). oHepatotoxicity has been reported in patients receiving dolutegravir-containing regimen. Patients with underlying hepatitis or may be at increased risk for worsening or development of transaminase elevations with DOVATO. Monitoring for hepatotoxicity is recommended. (5.3). oEmbryo-fetal toxicity may occur when used at the time of conception and in early pregnancy. Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. Individuals of childbearing potential should be counseled on the consistent use of effective contraception. (2.1, 5.4, 8.1, 8.3). oLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.5). oImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. (5.7). 5.1Patients 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 HBVSafety 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 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 HBVSevere 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.. 5.2Hypersensitivity Reactions. Hypersensitivity reactions have been reported with the use of dolutegravir, component of DOVATO, and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in <1% of subjects receiving dolutegravir in Phase 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 life-threatening reaction [see Contraindications (4)].. 5.3Hepatotoxicity. Hepatic adverse events have been reported in patients receiving dolutegravir-containing regimen [see Adverse Reactions (6.1)]. Patients with underlying hepatitis or may be at increased risk for worsening or development of transaminase elevations with use of DOVATO [see Adverse Reactions (6.1)]. 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 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.. 5.4Embryo-Fetal Toxicity An ongoing observational study showed an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. As there is limited understanding of the association of reported types of neural tube defects with dolutegravir use, inform individuals of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with DOVATO. Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester [see Use in Specific Populations (8.1, 8.3)].Pregnancy testing is recommended before initiation of DOVATO in individuals of childbearing potential [see Dosage and Administration (2.1)]. Individuals of childbearing potential should be counseled on the consistent use of effective contraception [see Use in Specific Populations (8.1, 8.3)].DOVATO may be considered during the second and third trimesters of pregnancy if the expected benefit justifies the potential risk to the pregnant woman and the fetus.. 5.5Lactic 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). 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.. 5.6Risk 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 [see Contraindications (4), Drug Interactions (7.4)]:oLoss of therapeutic effect of DOVATO and possible development of resistance. oPossible clinically significant adverse reactions from greater exposures of coadministered drugs. See Table 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.. oLoss of therapeutic effect of DOVATO and possible development of resistance. oPossible clinically significant adverse reactions from greater exposures of coadministered drugs. 5.7Immune 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-Barre 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.

ADVERSE REACTIONS SECTION.


6ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:oPatients co-infected with HIV-1 and HBV [see Warnings and Precautions (5.1)]oHypersensitivity reactions [see Warnings and Precautions (5.2)]oHepatotoxicity [see Warnings and Precautions (5.3)]oLactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.5)]oImmune reconstitution syndrome [see Warnings and Precautions (5.7)]. oPatients co-infected with HIV-1 and HBV [see Warnings and Precautions (5.1)]. oHypersensitivity reactions [see Warnings and Precautions (5.2)]. oHepatotoxicity [see Warnings and Precautions (5.3)]. oLactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.5)]. oImmune reconstitution syndrome [see Warnings and Precautions (5.7)]. The most common adverse reactions (all grades) observed in >=2% (in those receiving DOVATO) were headache, nausea, diarrhea, insomnia, fatigue, and anxiety. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Clinical Trials in Adults with No Antiretroviral Treatment HistoryThe safety assessment of DOVATO in HIV-1-infected adults with no antiretroviral treatment history and with plasma viral load <=500,000 HIV-1 RNULL copies/mL at the screening visit, is based on the pooled primary Week 96 analyses of data from identical, multicenter, double-blind, controlled trials, GEMINI-1 and GEMINI-2. total of 1,433 HIV-1-infected adults with no antiretroviral treatment history received either dolutegravir (TIVICAY) 50 mg plus lamivudine (EPIVIR) 300 mg, as complete regimen once daily, or TIVICAY 50 mg plus fixed-dose combination tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (TRUVADA), administered once daily.The rates of adverse events leading to discontinuation in the pooled analysis were 3% of subjects in both treatment arms. The most common adverse events leading to discontinuation were psychiatric disorders: 1% of subjects in both treatment arms. Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm of the Week 96 pooled analysis from GEMINI-1 and GEMINI-2 trials are provided in Table 2.The adverse reactions observed for TIVICAY plus EPIVIR in the Week 96 analysis of the pooled data from GEMINI-1 and GEMINI-2 were generally consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents.Table 2. Adverse Reactions (All Grades) Reported in >=2% of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in GEMINI-1 and GEMINI-2 (Week 96 Pooled Analysis) Fatigue: includes fatigue, asthenia, and malaise.Adverse ReactionTIVICAY plus EPIVIR(n 716)TIVICAY plus TRUVADA(n 717)Headache3%4%Nausea2%5%Diarrhea2%3%Insomnia2%3%Fatiguea 2%2%Anxiety2%1%Dizziness1%2%Adverse reactions of at least Grade occurring in >=1% of subjects treated with TIVICAY plus EPIVIR were headache, anxiety, and suicidal ideation (all at 1%).Less Common Adverse Reactions: The following adverse reactions occurred in <2% of subjects receiving dolutegravir plus lamivudine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine). Some events have been included because of their seriousness and assessment of potential causal relationship. 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: Abnormal dreams, depression. Suicidal ideation, attempt, behavior, or completion; these events were observed primarily in subjects with pre-existing history of depression or other psychiatric illness. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus, rash.Clinical Trials in Virologically Suppressed AdultsThe safety of DOVATO in virologically suppressed adults was based on Week 48 data from 740 subjects in randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 200 weeks. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials [see Clinical Studies (14.3)]. Laboratory AbnormalitiesSelected laboratory abnormalities with worsening grade from baseline and representing the worst-grade toxicity are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4.Table 3. Selected Laboratory Abnormalities (Grades to 4; Week 96 Pooled Analyses) in GEMINI-1 and GEMINI-2 TrialsULN Upper limit of normal. Laboratory Parameter AbnormalityTIVICAY plus EPIVIR (n 716)TIVICAY plus TRUVADA(n 717)Alanine aminotransferase(ALT) Grade (2.5 to <5.0 ULN)3%4% Grade to (>=5.0 ULN)3%3%Aspartate aminotransferase (AST) Grade (2.5 to <5.0 ULN)4%4% Grade to (>=5.0 ULN)3%3%Total bilirubin Grade (1.6 to <2.6 ULN)2%3% Grade to (>=2.6 ULN)1%1%Creatine kinase Grade (6.0 to <10 ULN)4%4% Grade to (>=10.0 ULN)6%7%Hyperglycemia (glucose) Grade (126 to 250 mg/dL)9%6% Grade to (>250 mg/dL)1%1%Hypophosphatemia (phosphate) Grade (1.4 to <2.0 mg/dL)9%10% Grade to (<1.4 mg/dL)1%1%Lipase Grade (1.5 to <3.0 ULN)6%6% Grade to (>=3.0 ULN)2%4%Table 4. Mean Change from Baseline in Fasted Lipid Values (Week 96 Pooled Analysesa) in GEMINI-1 and GEMINI-2 Trialsa Subjects on lipid-lowering agents at baseline are excluded (TIVICAY plus EPIVIR, = 30; TIVICAY plus TRUVADA, = 23). The last available fasted, on-treatment lipid value prior to initiation of lipid-lowering agent was carried forward in place of observed values after initiation of lipid-lowering agent. total of 40 and 16 subjects receiving TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively, initiated lipid-lowering agents post-baseline.Laboratory Parameter Preferred TermTIVICAY plus EPIVIR(n 716)TIVICAY plus TRUVADA(n 717)Cholesterol (mg/dL)15-6HDL cholesterol (mg/dL)73LDL cholesterol (mg/dL)6-7Triglycerides (mg/dL)11-11Total cholesterol/HDL cholesterol ratio-0.1-0.4Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first weeks of treatment in both arms and remained stable through 96 weeks. mean change from baseline of 0.138 mg/dL and 0.176 mg/dL was observed after 96 weeks of treatment with TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively. These changes are not considered to be clinically relevant.. 6.2Postmarketing Experience. The following adverse reactions have been identified during postmarketing experience in patients receiving dolutegravir- or lamivudine-containing regimen. Because postmarketing reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Body as WholeRedistribution/accumulation of body fat.Endocrine and MetabolicHyperglycemia.GeneralWeakness. Hemic and LymphaticAnemia (including pure red cell aplasia and severe anemias progressing on therapy).Hepatic and Pancreatic Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.5)], pancreatitis, posttreatment exacerbations of HBV [see Warnings and Precautions (5.1)].Hepatobiliary DisordersAcute liver failure, hepatotoxicity.HypersensitivityAnaphylaxis, urticaria.InvestigationsWeight increased.MusculoskeletalArthralgia, CPK elevation, muscle weakness, myalgia, rhabdomyolysis.Nervous System Paresthesia, peripheral neuropathy. SkinAlopecia.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3Females and Males of Reproductive Potential. In individuals of childbearing potential currently on DOVATO who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing DOVATO and discuss with the patient if an alternative treatment should be considered [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].Pregnancy TestingPregnancy testing is recommended in individuals of childbearing potential before initiation of DOVATO [see Dosage and Administration (2.1)].ContraceptionIndividuals of childbearing potential who are taking DOVATO should be counseled on the consistent use of effective contraception.

BOXED WARNING SECTION.


WARNING: PATIENTS CO-INFECTED WITH HEPATITIS 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, component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment [see Warnings and Precautions (5.1)].. WARNING: PATIENTS CO-INFECTED WITH HEPATITIS VIRUS (HBV) AND HUMAN IMMUNODEFICIENCY VIRUS (HIV-1): EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBVSee full prescribing information for complete boxed warning.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, component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityDolutegravir: Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg/kg, and rats were administered doses of up to 50 mg/kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 26 times higher than those in humans at the recommended dose. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 17 times higher than those in humans at the recommended dose. Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the recommended dose. MutagenicityDolutegravir: Dolutegravir was not genotoxic in the bacterial reverse mutation assay, in mouse lymphoma assay, or in the in vivo rodent micronucleus assay.Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNULL synthesis in rat liver. Impairment of FertilityDolutegravir or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 44 or 112 times, respectively, higher than the exposures in humans at the recommended dose.

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. DOVATO is fixed-dose combination of the HIV-1 antiretroviral agents, dolutegravir and lamivudine [see Microbiology (12.4)]. 12.2Pharmacodynamics. Cardiac ElectrophysiologyThe effect of combination therapy as DOVATO or lamivudine given alone on the QT interval has not been studied. At 250-mg suspension dose (exposures approximately 3-fold that of the 50-mg once-daily dose at steady state), dolutegravir given alone did not prolong the QTc interval to any clinically relevant extent. Effects of Dolutegravir on Renal FunctionNo clinically significant dolutegravir exposure-response relationship on the glomerular filtration rate or effective renal plasma flow was observed. The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n 37) who received dolutegravir 50 mg once daily (n 12), dolutegravir 50 mg twice daily (n 13), or placebo once daily (n 12) for 14 days.. 12.3Pharmacokinetics. The Cmax, Ctrough, and AUCtau parameters of the components of DOVATO are provided in Table 6. Table 6. Multiple-Dose Pharmacokinetic Parameters of the Components of DOVATOa Based on dolutegravir 50-mg once-daily dosage administered to antiretroviral treatment-naive adults. Based on lamivudine 300-mg once-daily dosage administered to healthy subjects. Cmax Maximum concentration; Ctrough Lowest concentration before administration of the next dose; AUCtau Area under the concentration-time curve integrated across the dosing interval.Parameter Mean (%CV)DolutegraviraLamivudinebCmax (mcg/mL)3.67 (20%)2.04 (26%)Ctrough (mcg/mL)1.11 (46%)0.042 (38%)AUCtau (mcg/h/mL)53.6 (27%)8.87 (21%)The absorption, distribution, and elimination pharmacokinetic parameters of the components of DOVATO are provided in Table 7. Table 7. Pharmacokinetic Properties of the Components of DOVATOa After administration of DOVATO (fasted state). High-fat meal is approximately 900 kcal, 56% fat. The geometric mean (90% confidence interval) AUC ratio (fed/fasted) of dolutegravir and lamivudine is 1.33 (1.18, 1.48) and 0.91 (0.87, 0.96), respectively. Based on in vitro data. Based on single-dose, mass balance study of radiolabeled dolutegravir. Based on 24-hour urine collection obtained after oral or IV administration.Tmax Time to maximum concentration (Cmax); t1/2 Elimination half-life.Pharmacokinetic ParametersDolutegravirLamivudineAbsorption Tmax (h), mediana 2.51 Effect of Food High-fat mealb (relative to fasting)No clinically significant differences in the pharmacokinetics of either component (after administration of DOVATO) were observedc DistributionPlasma protein bindingd Approximately 99%36%Blood-to-plasma ratio 0.44 0.541.1 1.2Eliminationt1/2 (h)Approximately 1413 19 Metabolism Metabolic pathwaysUGT1A1 (primary)CYP3A (minor)Not significantly metabolized Excretion Major route of eliminationMetabolismRenal, by OCT system Urine (unchanged)31% (<1%)e Approximately 70%f Feces (unchanged) 64% (53%)e -Specific PopulationsNo clinically significant differences in the pharmacokinetics of the components of DOVATO were observed based on age, sex, or race. Pharmacokinetic data for dolutegravir and lamivudine in subjects aged 65 years and older are limited. Patients with Renal Impairment: The pharmacokinetics for the individual components of DOVATO have been evaluated in patients with renal impairment. See the U.S. prescribing information for the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine).Patients with Hepatic Impairment: The pharmacokinetics for the individual components of DOVATO have been evaluated in patients with varying degrees of hepatic impairment. See the U.S. prescribing information for the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine).Drug Interaction StudiesClinical Studies: No drug interaction studies were conducted with DOVATO. The drug interaction studies described below were conducted with dolutegravir or lamivudine when used alone. Table summarizes the effects of dolutegravir on the pharmacokinetics of coadministered drugs. Table summarizes the effect of other drugs on the pharmacokinetics of dolutegravir when used alone and Table 10 summarizes the effect of sorbitol on the pharmacokinetics of lamivudine when used alone.Table 8. Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugsa OCT2 or MATE1 substrate. Norelgestromin is the active metabolite of norgestimate.Coadministered Drug(s)and Dose(s)Dose of DolutegravirGeometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect 1.00 Cmax AUCCtau or C24 Daclatasvir 60 mg once daily50 mgonce daily1.03(0.84 to 1.25)0.98(0.83 to 1.15)1.06(0.88 to 1.29)Ethinyl estradiol 0.035 mg50 mgtwice daily0.99(0.91 to 1.08)1.03(0.96 to 1.11)1.02(0.93 to 1.11)Grazoprevir 200 mg once daily50 mgsingle dose0.64(0.44, 0.93)0.81(0.67, 0.97)0.86(0.79, 0.93)Metformina 500 mg twice daily50 mgonce daily1.66(1.53 to 1.81)1.79(1.65 to 1.93)Metformina 500 mg twice daily50 mgtwice daily2.11(1.91 to 2.33)2.45(2.25 to 2.66)Methadone 16 to 150 mg50 mgtwice daily1.00(0. 94 to 1.06)0.98(0.91 to 1.06)0.99(0.91 to 1.07)Midazolam mg25 mgonce daily0.95(0.79 to 1.15)Norelgestrominb 0.25 mg50 mgtwice daily0.89(0.82 to 0.97)0.98(0.91 to 1.04)0.93(0.85 to 1.03)Sofosbuvir 400 mg once daily Metabolite (GS-331007)50 mgonce daily0.88(0.80, 0.98)1.01(0.93, 1.10)0.92(0.85, 0.99)0.99(0.97, 1.01)NULL 0.99(0.97, 1.01)Velpatasvir 100 mg once daily50 mgonce daily0.94(0.86, 1.02)0.91(0.84, 0.98)0.88(0.82, 0.94)No clinically significant differences in the pharmacokinetics of tenofovir (organic anion transporter [OAT]1 and OAT3 substrates) or para-amino hippurate (OAT1 and OAT3 substrates) were observed when coadministered with dolutegravir.No clinically significant differences in the pharmacokinetics of trimethoprim/sulfamethoxazole were observed when coadministered with lamivudine.Table 9. Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravira Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.Coadministered Drug(s)and Dose(s)Dose of DolutegravirGeometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect 1.00 Cmax AUCCau or C24 Antacid (MAALOX) simultaneous administration50-mgsingle dose0.28(0.23 to 0.33)0.26(0.22 to 0.32)0.26(0.21 to 0.31)Antacid (MAALOX) h after dolutegravir50-mgsingle dose0.82(0.69 to 0.98)0.74(0.62 to 0.90)0.70(0.58 to 0.85)Calcium carbonate 1,200 mg simultaneous administration (fasted)50-mgsingle dose0.63(0.50 to 0.81)0.61(0.47 to 0.80)0.61(0.47 to 0.80)Calcium carbonate 1,200 mg simultaneous administration (fed)50-mgsingle dose1.07(0.83 to 1.38)1.09(0.84 to 1.43)1.08(0.81 to 1.42)Calcium carbonate 1,200 mg h after dolutegravir50-mgsingle dose1.00(0.78 to 1.29)0.94(0.72 to 1.23)0.90(0.68 to 1.19)Carbamazepine 300 mg twice daily50 mgonce daily0.67(0.61 to 0.73)0.51(0.48 to 0.55)0.27(0.24 to 0.31)Daclatasvir 60 mg once daily50 mgonce daily1.29(1.07 to 1.57)1.33(1.11 to 1.59)1.45(1.25 to 1.68)Ferrous fumarate 324 mg simultaneous administration (fasted)50-mgsingle dose0.43(0.35 to 0.52)0.46(0.38 to 0.56)0.44(0.36 to 0.54)Ferrous fumarate 324 mg simultaneous administration (fed)50-mgsingle dose1.03(0.84 to 1.26)0.98(0.81 to 1.20)1.00(0.81 to 1.23)Ferrous fumarate 324 mg h after dolutegravir50-mgsingle dose0.99(0.81 to 1.21)0.95(0.77 to 1.15)0.92(0.74 to 1.13)Multivitamin (One-A-Day) simultaneous administration50-mgsingle dose0.65(0.54 to 0.77)0.67(0.55 to 0.81)0.68(0.56 to 0.82)Omeprazole 40 mg once daily50-mgsingle dose0.92(0.75 to 1.11)0.97(0.78 to 1.20)0.95(0.75 to 1.21)Prednisone 60 mg once daily with taper50 mgonce daily1.06(0.99 to 1.14)1.11(1.03 to 1.20)1.17(1.06 to 1.28)Rifampina 600 mg once daily50 mgtwice daily0.57(0.49 to 0.65)0.46(0.38 to 0.55)0.28(0.23 to 0.34)Rifampinb 600 mg once daily50 mgtwice daily1.18(1.03 to 1.37)1.33(1.15 to 1.53)1.22(1.01 to 1.48)Rifabutin 300 mg once daily50 mgonce daily1.16(0.98 to 1.37)0.95(0.82 to 1.10)0.70(0.57 to 0.87)Table 10. Effect of Sorbitol on the Pharmacokinetics of Lamivudinea Coadministered with single dose of lamivudine 300 mg. Cmax Maximum concentration; AUC(0-24) Area under the concentration-time curve integrated from time of administration to 24 hours; AUC(inf) Area under the concentration-time curve from the time of administration to infinity.Coadministered Drug and Dosea Lamivudine Pharmacokinetic Parameters(% Decreased)Cmax AUC0-24 AUCinf Sorbitol(Excipient)3.2 grams28%20%14%10.2 grams52%39%32%13.4 grams55%44%36%No clinically significant differences in the pharmacokinetics of lamivudine were observed when coadministered with trimethoprim (MATE1, MATE2-K, and OCT2 inhibitor)/sulfamethoxazole, interferon alfa, or ribavirin.In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically: Dolutegravir: Dolutegravir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. Dolutegravir does not induce CYP1A2, CYP2B6, or CYP3A4.Dolutegravir is substrate of UGT1A3 and UGT1A9. Dolutegravir does not inhibit UGT1A1 or UGT2B7.Dolutegravir is substrate of BCRP and P-gp. Dolutegravir does not inhibit P-gp, BCRP, bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. Dolutegravir is not substrate of OATP1B1 or OATP1B3.Lamivudine: Lamivudine is substrate of P-gp and BCRP. Lamivudine does not inhibit OATP1B1/3, BCRP, P-gp, MATE1, MATE2-K, OCT1, OCT2, or OCT3.. 12.4Microbiology. Mechanism of ActionDolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNULL integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integrase and pre-processed substrate DNULL resulted in IC50 values of 2.7 nM and 12.6 nM. Lamivudine: Lamivudine is synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNULL chain termination after incorporation of the nucleotide analogue.Antiviral Activity in Cell CultureDolutegravir: Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentrations of drug necessary to effect viral replication by 50 percent (EC50) values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade isolates with mean EC50 value of 0.52 nM in viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against panel of HIV-1 clinical isolates (3 in each group of [clades A-G], and in group O) with EC50 values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC50 values against three HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of to 15,000 nM (1 nM 230 ng/mL). The EC50 values of lamivudine against different HIV-1 clades (A-G) and group viruses ranged from to 120 nM, and against HIV-2 isolates from to 120 nM in PBMCs. Antiviral Activity in Combination with Other Antiviral AgentsNeither dolutegravir nor lamivudine were antagonistic to all tested anti-HIV agents.Resistance Cell Culture: Dolutegravir: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions emerged in different passages; the substitution G118R emergence conferred decreased susceptibility to dolutegravir of 10-fold, while substitutions E92Q, S153F or Y, G193E, or R263K conferred decreased susceptibility to dolutegravir of up to 4-fold. Lamivudine: HIV-1 resistance to lamivudine involves the development of M184V or M184I amino acid change close to the active site of the viral RT. This variant arises both in cell culture and in HIV-1-infected patients treated with lamivudine-containing antiretroviral therapy. Substitutions M184V or confer high-level resistance to lamivudine. Clinical Subjects: At Week 96, none of the 11 subjects in the dolutegravir plus lamivudine group or the subjects in the dolutegravir plus TDF/FTC group who met the protocol-defined confirmed virologic withdrawal criteria across the pooled GEMINI-1 and GEMINI-2 trials had emergent INSTI- or NRTI-resistance substitutions.No subject who received DOVATO in the TANGO trial met the protocol-defined confirmed virologic withdrawal criteria through Week 48. No emergent INSTI- or NRTI-resistance was detected by genotypic or phenotypic analyses of the last on-treatment isolate from one subject who received DOVATO with HIV-1 RNULL >=400 copies/mL at withdrawal. No emergent resistance was detected by genotypic or phenotypic analyses of HIV-1 integrase, protease, or reverse transcriptase at the time of virologic failure in one subject in the TBR arm who met the confirmed virologic withdrawal criteria.Cross-ResistanceDolutegravir: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with or more substitutions). The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred >2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M; E92Q/N155H; G140C/Q148R; G140S/Q148H, or K; Q148R/N155H; T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed >2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). Lamivudine: Cross-resistance conferred by the M184V or RT has been observed within the NRTI class of antiretroviral agents. The M184V or substitution confers resistance to emtricitabine and to abacavir, which selects M184V or plus additional RT substitutions K65R, L74V, and Y115F. Zidovudine maintains its antiretroviral activities against lamivudine-resistant HIV-1. Abacavir and tenofovir maintain antiretroviral activity against lamivudine-resistant HIV-1 harboring only the M184V or substitution.

CLINICAL STUDIES SECTION.


14CLINICAL STUDIES. 14.1Description of Clinical Trials. The efficacy of DOVATO is supported by data from randomized, double-blind, controlled trials (GEMINI-1 [NCT02831673] and GEMINI-2 [NCT02831764]) in HIV-1-infected adults with no antiretroviral treatment history, and data from randomized, open-label, controlled trial (TANGO [NCT03446573]) in virologically suppressed HIV-1-infected adults.. 14.2Clinical Trial Results in HIV-1-Infected Adult Subjects with No Antiretroviral Treatment History GEMINI-1 and GEMINI-2 are identical 148-week, Phase 3, randomized, multicenter, parallel-group, non-inferiority trials. total of 1,433 HIV-1-infected adults with no antiretroviral treatment history received treatment in the trials. Subjects were enrolled with screening plasma HIV-1 RNULL of 1,000 to <=500,000 copies/mL and without evidence of major resistance-associated mutations or evidence of HBV infection. Subjects were randomized to receive 2-drug regimen of TIVICAY 50 mg plus EPIVIR 300 mg administered once daily or TIVICAY 50 mg plus fixed-dose TRUVADA administered once daily. The primary efficacy endpoint for each GEMINI trial was the proportion of subjects with plasma HIV-1 RNULL <50 copies/mL at Week 48 (Snapshot algorithm) who were randomized and treated. At baseline, in the pooled analysis, the median age of subjects was 33 years, 15% female, 69% white, 9% were CDC Stage (AIDS), the median plasma HIV-1 RNULL was 4.4 log10 copies/mL, 20% had HIV-1 RNULL >100,000 copies/mL, the median CD4+ cell count was 432 cells/mm3, and 8% had CD4+ cell count <=200 cells/mm3; these characteristics were similar between trials and treatment arms within each trial. Week 96 outcomes (including outcomes by key baseline covariates) for the pooled GEMINI-1 and GEMINI-2 trials are shown in Table 11. The results of the pooled analysis are consistent with the results from the individual trials, for which the secondary endpoint is the difference in proportion of subjects with plasma HIV-1 RNULL <50 copies/mL at Week 96 based on the Snapshot algorithm for TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA. The proportions of subjects with plasma HIV-1 RNULL <50 copies/mL in the group receiving TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA were 84% and 89%, respectively, in GEMINI-1 and 88% and 90%, respectively, in GEMINI-2. The adjusted difference was -4.9% (95% CI: -9.8%, 0.0) for GEMINI-1 and -1.8% (95% CI: -6.4%, 2.7%) for GEMINI-2. At Week 96, no subjects had any treatment-emergent substitutions associated with resistance to dolutegravir or NRTIs.Table 11. Pooled Virologic Outcomes of Randomized Treatment of HIV-1-Infected Adults with No Antiretroviral Treatment History in GEMINI-1 and GEMINI-2 Trials at Weeks 48 and 96 (Snapshot Algorithm)a The results of the pooled analysis are similar to the individual trials, for which the primary endpoint (proportion of subjects with plasma HIV-1 RNULL <50 copies/mL at Week 48 based on the Snapshot algorithm for TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA) was met. The adjusted difference was -2.6% (95% CI: -6.7%, 1.5%) for GEMINI-1 and -0.7% (95% CI: -4.3%, 2.9%) for GEMINI-2. Based on Cochran-Mantel-Haenszel-stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNULL (<=100,000 copies/mL versus >100,000 copies/mL) and CD4+ cell count (<=200 cells/mm3 versus >200 cells/mm3). Pooled analysis also stratified by trial.Virologic OutcomesGEMINI-1 and GEMINI-2Pooled Dataa Week 48Week 96TIVICAY plus EPIVIR(n 716)TIVICAY plus TRUVADA(n 717)TIVICAY plus EPIVIR(n 716)TIVICAY plus TRUVADA(n 717)HIV-1 RNULL <50 copies/mL91%93%86%90%Treatment Differenceb -1.7%(95% CI: -4.4%, 1.1%)-3.4%(95% CI: -6.7%, 0.0%)Virologic nonresponse3%2%3%2%Reasons Data in window >=50 copies/mL 1%<1%<1%<1% Discontinued for lack of efficacy<1%<1%1%<1% Discontinued for other reasons and >=50 copies/mL<1%<1%<1%<1% Change in ART<1%<1%<1%<1%No virologic data at Week 48 or Week 96 window6%5%11%9%Reasons Discontinued trial due to adverse event or death 1%2%3%3% Discontinued trial for other reasons4%3%8%5% Missing data during window but on trial<1%00<1%Proportion (%) of Subjects with HIV-1 RNULL <50 copies/mL by Baseline Category% (n/N)% (n/N)% (n/N)% (n/N)Plasma Viral Load (copies/mL)<=100,00091% (526/576)94% (531/564)87% (499/576)90% (510/564)>100,00092% (129/140)90% (138/153)84% (117/140)86% (132/153)CD4+ (cells/mm3)<=200 79% (50/63)93% (51/55)68% (43/63)87% (48/55)>20093% (605/653)93% (618/662)88% (573/653)90% (594/662)GenderMale 92% (555/603)94% (580/619)87% (523/603)90% (557/619)Female 88% (100/113)91% (89/98)82% (93/113)87% (85/98)Race White 93% (447/480)95% (471/497)89% (429/484)91% (453/499)African-American/African Heritage84% (83/99)84% (64/76)73% (66/90)83% (59/71)Asian94% (67/71)94% (68/72)83% (59/71)90% (65/72)Other88% (58/66)92% (66/72)87% (62/71)87% (65/75)EthnicityHispanic or Latino90% (193/215)93% (216/232)86% (185/215)90% (208/232)Not Hispanic or Latino92% (462/501)93% (453/485)86% (431/501)89% (434/485)Age (years)<5092% (597/651)94% (597/637)86% (561/651)90% (572/637)>=5089% (58/65)90% (72/80)85% (55/65)88%(70/80)The primary endpoint was assessed at Week 48 and the virologic success rate was 91% in the group receiving TIVICAY plus EPIVIR and 93% in the group receiving TIVICAY plus TRUVADA, with treatment difference of -1.7% (95% CI: -4.4%, 1.1%) in the pooled data. The results of the pooled analysis are similar to the individual trials, for which the primary endpoint (proportion of subjects with plasma HIV-1 RNULL <50 copies/mL at Week 48 based on the Snapshot algorithm for TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA) was met. The adjusted difference was -2.6% (95% CI: -6.7%, 1.5%) for GEMINI-1 and -0.7% (95% CI: -4.3%, 2.9%) for GEMINI-2.Virologic outcomes by baseline CD4+ (cells/mm3) in GEMINI-1 and GEMINI-2 at Week 96 are shown in Table 12. In both trials, lower response rates (HIV-1 RNULL <50 copies/mL) were observed in subjects with baseline CD4+ <=200 cells/mm3. These findings were seen irrespective of baseline plasma HIV-1 RNULL. Table 12. Virologic Outcomes by Baseline CD4+ in GEMINI-1 and GEMINI-2 Trials at Week 96 in Subjects with No Antiretroviral Treatment Historya Four subjects treated with TIVICAY plus EPIVIR were withdrawn for treatment-related reasons (3 due to confirmed loss of virologic response and due to drug-related adverse reactions). Two subjects also had HIV-1 RNULL >=50 copies/mL at Week 96 but remained in the study. The other 14 subjects treated with TIVICAY plus EPIVIR who did not have HIV-1 RNULL <50 copies/mL at Week 96 (based on Snapshot Algorithm) were discontinued for non-treatment-related reasons by Week 96. One subject in GEMINI-1 whose last HIV-1 RNULL was 64,366 copies/mL was lost to follow-up. Three subjects receiving TIVICAY plus EPIVIR with HIV-1 RNULL >=50 copies/mL at Week 48 remained in the study, all with <50 copies/mL at Week 96, of which had Week 96 HIV-1 RNULL of 46 copies/mL.GEMINI-1GEMINI-2TIVICAY plus EPIVIR(n 356)TIVICAY plus TRUVADA(n 358)TIVICAY plus EPIVIR(n 360)TIVICAY plus TRUVADA(n 359)Proportion (%) of Subjects with HIV-1 RNULL <50 copies/mLa Baseline CD4+ (cells/mm3)<=200>20065% (20/31)86% (280/325)90% (26/29)89% (294/329)72% (23/32)89% (293/328)85% (22/26)90% (300/333)The adjusted mean change from baseline in CD4+ cell count based on the pooled analysis at Week 96 was 269 cells/mm3 for the group receiving TIVICAY plus EPIVIR and 259 cells/mm3 for the group receiving TIVICAY plus TRUVADA.. 14.3Clinical Trial Results in HIV-1-Infected Virologically Suppressed Adult Subjects Who Switched to DOVATO The efficacy of DOVATO in HIV-1-infected, antiretroviral treatment-experienced, virologically suppressed subjects is supported by data from 200-week, Phase 3, randomized, open-label, multicenter, parallel-group, non-inferiority controlled trial (TANGO). total of 741 adult HIV-1-infected subjects who were on stable suppressive TBR received treatment in the trial. Subjects were randomized in 1:1 ratio to receive DOVATO once daily or continue with their TBR for up to 200 weeks. Randomization was stratified by baseline third-agent class (protease inhibitor [PI], INSTI, or non-nucleoside reverse transcriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNULL >=50 copies/mL (virologic non-response) at Week 48 (Snapshot algorithm adjusting for randomization stratification factor).At baseline, the median age of subjects was 39 years, 8% were female, 21% non-white, 5% were CDC Class (AIDS), and 98% of subjects had baseline CD4+ cell count >=200 cells/mm3; these characteristics were similar between treatment arms. Subjects receiving DOVATO and TBR had been on an antiretroviral regimen for median of 2.8 and 2.9 years, respectively, prior to Day 1. Most subjects were on an integrase inhibitor-based TBR (78% and 80% of subjects who received DOVATO and TBR, respectively).In the primary analysis, <1% of subjects in both arms experiencing virologic failure (HIV-1 RNULL >=50 copies/mL) at Week 48 based on the Snapshot algorithm (Table 13).Table 13 Virologic Outcomes of Randomized Treatment in TANGO Trial at Week 48 in Virologically Suppressed Subjects Who Switched to DOVATOa Based on 4% non-inferiority margin, DOVATO was non-inferior to TBR at Week 48 in the primary analysis (proportion of subjects with plasma HIV-1 RNULL >=50 copies/mL); the upper bound of the 95% CI for the adjusted treatment difference was <4%. Based on Cochran-Mantel-Haenszel-stratified analysis adjusting for baseline third-agent class (PI, INSTI, or NNRTI). At Week 48 in the secondary analysis (proportion of subjects achieving plasma HIV-1 RNULL <50 copies/mL), the adjusted treatment difference was 0.2% (95% CI: -3.4%, 3.9%).Virologic OutcomesDOVATO(n 369)TBR(n 372)Virologic nonresponse (>=50 copies/mL)a <1%<1%Treatment Difference (95% CI)b -0.3% (-1.2%, 0.7%)HIV-1 RNULL <50 copies/mLc 93%93%Reasons for virologic nonresponse Data in window >=50 copies/mL 00 Discontinued for lack of efficacy0<1% Discontinued for other reasons and >=50 copies/mL<1%0 Change in ART00Reasons for no virologic data at Week 48 window7%6% Discontinued trial due to adverse event or death 3%<1% Discontinued trial for other reasons3%6% Missing data during window but on trial0<1%In TANGO, treatment outcomes between treatment arms were similar across the stratification factor, baseline third-agent class (PI, INSTI, or NNRTI), and across subgroups by age, sex, race, baseline CD4+ cell count, CDC HIV disease stage, and countries. The median change from baseline in CD4+ count at Week 48 was 22.5 cells/mm3 in subjects who switched to DOVATO and 11.0 cells/mm3 in subjects who stayed on the TBR.

CONTRAINDICATIONS SECTION.


4CONTRAINDICATIONS. DOVATO is contraindicated in patients: owith prior hypersensitivity reaction to dolutegravir [see Warnings and Precautions (5.2)] or lamivudine.oreceiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events [see Drug Interactions (7.2)].. owith prior hypersensitivity reaction to dolutegravir [see Warnings and Precautions (5.2)] or lamivudine.. oreceiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events [see Drug Interactions (7.2)].. oPrior hypersensitivity reaction to dolutegravir or lamivudine. (4)oCoadministration with dofetilide. (4). oPrior hypersensitivity reaction to dolutegravir or lamivudine. (4). oCoadministration with dofetilide. (4).

DESCRIPTION SECTION.


11DESCRIPTION. DOVATO is fixed-dose combination tablet containing dolutegravir (as dolutegravir sodium), an integrase strand transfer inhibitor (INSTI), and lamivudine (also known as 3TC), nucleoside analogue reverse transcriptase inhibitor (NRTI).DOVATO tablets are for oral administration. Each film-coated tablet contains the active ingredients 50 mg of dolutegravir (equivalent to 52.6 mg dolutegravir sodium) and 300 mg of lamivudine and the inactive ingredients magnesium stearate, mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, sodium stearyl fumarate. The tablet film-coating contains the inactive ingredients hypromellose, polyethylene glycol, titanium dioxide.DolutegravirThe chemical name of dolutegravir sodium is sodium (4R,12aS)-9-[(2,4-difluorophenyl)methyl]carbamoyl-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1,2:4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C20H18F2N3NaO5 and the molecular weight is 441.36 g/mol. It has the following structural formula:Dolutegravir sodium is white to light yellow powder and is slightly soluble in water.LamivudineThe chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2,3-dideoxy, 3-thiacytidine. It has molecular formula of C8H11N3O3S and molecular weight of 229.3 g/mol. It has the following structural formula:Lamivudine is white to off-white crystalline solid and is soluble in water.. dolutegravir sodium structural formula. lamivudine structural formula.

DOSAGE & ADMINISTRATION SECTION.


2DOSAGE AND ADMINISTRATION. oPrior to or when initiating DOVATO, test patients for HBV infection. (2.1)oPregnancy testing: Pregnancy testing is recommended before initiation of DOVATO in individuals of childbearing potential. (2.1, 5.4, 8.1, 8.3)oOne tablet taken orally once daily with or without food. (2.2)oThe dolutegravir dose (50 mg) in DOVATO is insufficient when coadministered with carbamazepine or rifampin. If DOVATO is coadministered with carbamazepine or rifampin, take one tablet of DOVATO once daily, followed by an additional dolutegravir 50-mg tablet, approximately 12 hours from the dose of DOVATO. (2.3). oPrior to or when initiating DOVATO, test patients for HBV infection. (2.1). oPregnancy testing: Pregnancy testing is recommended before initiation of DOVATO in individuals of childbearing potential. (2.1, 5.4, 8.1, 8.3). oOne tablet taken orally once daily with or without food. (2.2). oThe dolutegravir dose (50 mg) in DOVATO is insufficient when coadministered with carbamazepine or rifampin. If DOVATO is coadministered with carbamazepine or rifampin, take one tablet of DOVATO once daily, followed by an additional dolutegravir 50-mg tablet, approximately 12 hours from the dose of DOVATO. (2.3). 2.1Testing Prior to or When Initiating Treatment with DOVATO Prior to or when initiating DOVATO, test patients for HBV infection [see Warnings and Precautions (5.1)]. Pregnancy testing is recommended before initiation of DOVATO in individuals of childbearing potential [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].. 2.2Recommended Dosage. DOVATO is 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 [see Clinical Pharmacology (12.3)].. 2.3Recommended Dosage with Certain Coadministered Drugs. The dolutegravir dose (50 mg) in DOVATO is insufficient when coadministered with drugs listed in Table that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended.Table 1. Dosing Recommendations for DOVATO with Coadministered DrugsCoadministered DrugDosing RecommendationCarbamazepine, rifampinAn additional dolutegravir 50-mg tablet, separated by 12 hours from DOVATO, should be taken. 2.4Not Recommended in Patients with Renal Impairment. Because DOVATO is fixed-dose tablet and cannot be dose adjusted, DOVATO is not recommended in patients with creatinine clearance less than 30 mL per minute [see Use in Specific Populations (8.6)].. 2.5Not Recommended in Patients with Severe Hepatic Impairment DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C) [see Use in Specific Populations (8.7)].

INDICATIONS & USAGE SECTION.


1INDICATIONS AND USAGE. DOVATO is indicated as complete regimen for the treatment of human immunodeficiency virus type (HIV-1) infection in adults with no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNULL less than 50 copies per mL) on stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DOVATO.. DOVATO, two-drug combination of dolutegravir (integrase strand transfer inhibitor [INSTI]) and lamivudine (nucleoside analogue reverse transcriptase inhibitor [NRTI]) is indicated as complete regimen for the treatment of human immunodeficiency virus type (HIV-1) infection in adults with no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNULL less than 50 copies per mL) on stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DOVATO. (1).

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Emergence of Lamivudine-Resistant HBV in Hepatitis Co-infection Advise all patients with HIV-1 to be tested for the presence of HBV prior to or when initiating DOVATO. Advise patients co-infected with HIV-1 and HBV that emergence of HBV variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens. Advise patients co-infected with HIV-1 and HBV who are being treated with DOVATO, to discuss with their healthcare provider if additional treatment should be considered for appropriate treatment of chronic HBV [see Warnings and Precautions (5.1)].Severe Acute Exacerbations of Hepatitis in Patients with HBV Co-infectionAdvise all patients with HIV-1 to be tested for the presence of HBV prior to or when initiating DOVATO. Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions (5.1)]. Hypersensitivity ReactionsAdvise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking DOVATO and seek medical attention if they develop rash associated with any of the following symptoms, as it may be sign of more serious reaction such as severe hypersensitivity: fever; generally ill feeling; extreme tiredness; muscle or joint aches; blisters or peeling of the skin; oral blisters or lesions; eye inflammation; facial swelling; swelling of the eyes, lips, tongue, or mouth; breathing difficulty; and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale-colored stools or bowel movements; nausea; vomiting; loss of appetite; or pain, aching, or sensitivity on the right side below the ribs). Advise patients that if hypersensitivity occurs, they will be closely monitored, laboratory tests will be ordered, and appropriate therapy will be initiated [see Warnings and Precautions (5.2)].HepatotoxicityInform patients that hepatotoxicity has been reported with dolutegravir, component of DOVATO [see Warnings and Precautions (5.3), Adverse Reactions (6.1)]. Inform patients that monitoring for hepatotoxicity during therapy with DOVATO is recommended. Embryo-Fetal ToxicityAdvise individuals of childbearing potential, including those actively trying to become pregnant, to discuss the risks and benefits of DOVATO with their healthcare provider to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy. If pregnancy is confirmed in the first trimester, advise patients to contact their healthcare provider [see Warnings and Precaution (5.4), Use in Specific Populations (8.1, 8.3)]. Individuals of childbearing potential taking DOVATO should be counseled on the consistent use of effective contraception [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].Lactic Acidosis/Hepatomegaly with SteatosisInform patients that some HIV medicines, including DOVATO, can cause rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see Warnings and Precautions (5.5)]. Drug InteractionsDOVATO may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. Johns wort [see Contraindications (4), Warnings and Precautions (5.6), Drug Interactions (7)].Immune Reconstitution SyndromeAdvise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including DOVATO, is started [see Warnings and Precautions (5.7)]. Pregnancy RegistryInform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to DOVATO during pregnancy [see Use in Specific Populations (8.1)].LactationInstruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].Missed DoseInstruct patients that if they miss dose of DOVATO, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].DOVATO, EPIVIR, TIVICAY, and TRIUMEQ are trademarks owned by or licensed to the ViiV Healthcare group of companies.The other brand listed is trademark owned by or licensed to its respective owner and is not owned by or licensed to the ViiV Healthcare group of companies. The maker of this brand is not affiliated with and does not endorse the ViiV Healthcare group of companies or its products.Manufactured for: ViiV HealthcareResearch Triangle Park, NC 27709by:GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2021 ViiV Healthcare group of companies or its licensor. DVT:6PIPHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT.

LACTATION SECTION.


8.2Lactation. Risk SummaryThe 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, component of DOVATO, is present in human milk. It is not known whether dolutegravir, component of DOVATO, is present in human milk. When administered to lactating rats, dolutegravir was present in milk (see Data). There is no information on the effects of DOVATO or the components of DOVATO on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving DOVATO.DataAnimal Data: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following single oral dose of 50 mg/kg on Lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed hours postdose.

MECHANISM OF ACTION SECTION.


12.1Mechanism of Action. DOVATO is fixed-dose combination of the HIV-1 antiretroviral agents, dolutegravir and lamivudine [see Microbiology (12.4)].

NONCLINICAL TOXICOLOGY SECTION.


13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityDolutegravir: Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg/kg, and rats were administered doses of up to 50 mg/kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 26 times higher than those in humans at the recommended dose. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 17 times higher than those in humans at the recommended dose. Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the recommended dose. MutagenicityDolutegravir: Dolutegravir was not genotoxic in the bacterial reverse mutation assay, in mouse lymphoma assay, or in the in vivo rodent micronucleus assay.Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNULL synthesis in rat liver. Impairment of FertilityDolutegravir or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 44 or 112 times, respectively, higher than the exposures in humans at the recommended dose.

OVERDOSAGE SECTION.


10OVERDOSAGE. There is no known specific treatment for overdose with DOVATO. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.DolutegravirAs dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. LamivudineBecause negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in lamivudine overdose event.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Principal Display PanelNDC 49702-246-13Dovato(dolutegravir and lamivudine)Tablets50 mg/300 mgRx OnlyNote to pharmacist:Do not cover ALERT box with pharmacy label.ALERT: Find out about medicines that should NOT be taken with DOVATO.30 tabletsEach tablet contains 50 mg of dolutegravir (equivalent to 52.6 mg of dolutegravir sodium) and 300 mg of lamivudine.This package is child-resistant. Keep out of reach of children. Store below 30C (86F).See prescribing information for dosage information.Do not accept if membrane seal under cap is missing or broken.Mfd for:ViiV HealthcareRTP, NC 27709by: GlaxoSmithKline, RTP, NC 27709Trademarks owned or licensed by ViiV Healthcare.(C)2019 ViiV Healthcare or licensor.www.dovato.comRev. 3/1962000000031103. Dovato 30 count label.

PEDIATRIC USE SECTION.


8.4Pediatric Use. The safety and efficacy of DOVATO have not been established in pediatric patients.

PHARMACODYNULLMICS SECTION.


12.2Pharmacodynamics. Cardiac ElectrophysiologyThe effect of combination therapy as DOVATO or lamivudine given alone on the QT interval has not been studied. At 250-mg suspension dose (exposures approximately 3-fold that of the 50-mg once-daily dose at steady state), dolutegravir given alone did not prolong the QTc interval to any clinically relevant extent. Effects of Dolutegravir on Renal FunctionNo clinically significant dolutegravir exposure-response relationship on the glomerular filtration rate or effective renal plasma flow was observed. The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n 37) who received dolutegravir 50 mg once daily (n 12), dolutegravir 50 mg twice daily (n 13), or placebo once daily (n 12) for 14 days.

PHARMACOKINETICS SECTION.


12.3Pharmacokinetics. The Cmax, Ctrough, and AUCtau parameters of the components of DOVATO are provided in Table 6. Table 6. Multiple-Dose Pharmacokinetic Parameters of the Components of DOVATOa Based on dolutegravir 50-mg once-daily dosage administered to antiretroviral treatment-naive adults. Based on lamivudine 300-mg once-daily dosage administered to healthy subjects. Cmax Maximum concentration; Ctrough Lowest concentration before administration of the next dose; AUCtau Area under the concentration-time curve integrated across the dosing interval.Parameter Mean (%CV)DolutegraviraLamivudinebCmax (mcg/mL)3.67 (20%)2.04 (26%)Ctrough (mcg/mL)1.11 (46%)0.042 (38%)AUCtau (mcg/h/mL)53.6 (27%)8.87 (21%)The absorption, distribution, and elimination pharmacokinetic parameters of the components of DOVATO are provided in Table 7. Table 7. Pharmacokinetic Properties of the Components of DOVATOa After administration of DOVATO (fasted state). High-fat meal is approximately 900 kcal, 56% fat. The geometric mean (90% confidence interval) AUC ratio (fed/fasted) of dolutegravir and lamivudine is 1.33 (1.18, 1.48) and 0.91 (0.87, 0.96), respectively. Based on in vitro data. Based on single-dose, mass balance study of radiolabeled dolutegravir. Based on 24-hour urine collection obtained after oral or IV administration.Tmax Time to maximum concentration (Cmax); t1/2 Elimination half-life.Pharmacokinetic ParametersDolutegravirLamivudineAbsorption Tmax (h), mediana 2.51 Effect of Food High-fat mealb (relative to fasting)No clinically significant differences in the pharmacokinetics of either component (after administration of DOVATO) were observedc DistributionPlasma protein bindingd Approximately 99%36%Blood-to-plasma ratio 0.44 0.541.1 1.2Eliminationt1/2 (h)Approximately 1413 19 Metabolism Metabolic pathwaysUGT1A1 (primary)CYP3A (minor)Not significantly metabolized Excretion Major route of eliminationMetabolismRenal, by OCT system Urine (unchanged)31% (<1%)e Approximately 70%f Feces (unchanged) 64% (53%)e -Specific PopulationsNo clinically significant differences in the pharmacokinetics of the components of DOVATO were observed based on age, sex, or race. Pharmacokinetic data for dolutegravir and lamivudine in subjects aged 65 years and older are limited. Patients with Renal Impairment: The pharmacokinetics for the individual components of DOVATO have been evaluated in patients with renal impairment. See the U.S. prescribing information for the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine).Patients with Hepatic Impairment: The pharmacokinetics for the individual components of DOVATO have been evaluated in patients with varying degrees of hepatic impairment. See the U.S. prescribing information for the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine).Drug Interaction StudiesClinical Studies: No drug interaction studies were conducted with DOVATO. The drug interaction studies described below were conducted with dolutegravir or lamivudine when used alone. Table summarizes the effects of dolutegravir on the pharmacokinetics of coadministered drugs. Table summarizes the effect of other drugs on the pharmacokinetics of dolutegravir when used alone and Table 10 summarizes the effect of sorbitol on the pharmacokinetics of lamivudine when used alone.Table 8. Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugsa OCT2 or MATE1 substrate. Norelgestromin is the active metabolite of norgestimate.Coadministered Drug(s)and Dose(s)Dose of DolutegravirGeometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect 1.00 Cmax AUCCtau or C24 Daclatasvir 60 mg once daily50 mgonce daily1.03(0.84 to 1.25)0.98(0.83 to 1.15)1.06(0.88 to 1.29)Ethinyl estradiol 0.035 mg50 mgtwice daily0.99(0.91 to 1.08)1.03(0.96 to 1.11)1.02(0.93 to 1.11)Grazoprevir 200 mg once daily50 mgsingle dose0.64(0.44, 0.93)0.81(0.67, 0.97)0.86(0.79, 0.93)Metformina 500 mg twice daily50 mgonce daily1.66(1.53 to 1.81)1.79(1.65 to 1.93)Metformina 500 mg twice daily50 mgtwice daily2.11(1.91 to 2.33)2.45(2.25 to 2.66)Methadone 16 to 150 mg50 mgtwice daily1.00(0. 94 to 1.06)0.98(0.91 to 1.06)0.99(0.91 to 1.07)Midazolam mg25 mgonce daily0.95(0.79 to 1.15)Norelgestrominb 0.25 mg50 mgtwice daily0.89(0.82 to 0.97)0.98(0.91 to 1.04)0.93(0.85 to 1.03)Sofosbuvir 400 mg once daily Metabolite (GS-331007)50 mgonce daily0.88(0.80, 0.98)1.01(0.93, 1.10)0.92(0.85, 0.99)0.99(0.97, 1.01)NULL 0.99(0.97, 1.01)Velpatasvir 100 mg once daily50 mgonce daily0.94(0.86, 1.02)0.91(0.84, 0.98)0.88(0.82, 0.94)No clinically significant differences in the pharmacokinetics of tenofovir (organic anion transporter [OAT]1 and OAT3 substrates) or para-amino hippurate (OAT1 and OAT3 substrates) were observed when coadministered with dolutegravir.No clinically significant differences in the pharmacokinetics of trimethoprim/sulfamethoxazole were observed when coadministered with lamivudine.Table 9. Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravira Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.Coadministered Drug(s)and Dose(s)Dose of DolutegravirGeometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect 1.00 Cmax AUCCau or C24 Antacid (MAALOX) simultaneous administration50-mgsingle dose0.28(0.23 to 0.33)0.26(0.22 to 0.32)0.26(0.21 to 0.31)Antacid (MAALOX) h after dolutegravir50-mgsingle dose0.82(0.69 to 0.98)0.74(0.62 to 0.90)0.70(0.58 to 0.85)Calcium carbonate 1,200 mg simultaneous administration (fasted)50-mgsingle dose0.63(0.50 to 0.81)0.61(0.47 to 0.80)0.61(0.47 to 0.80)Calcium carbonate 1,200 mg simultaneous administration (fed)50-mgsingle dose1.07(0.83 to 1.38)1.09(0.84 to 1.43)1.08(0.81 to 1.42)Calcium carbonate 1,200 mg h after dolutegravir50-mgsingle dose1.00(0.78 to 1.29)0.94(0.72 to 1.23)0.90(0.68 to 1.19)Carbamazepine 300 mg twice daily50 mgonce daily0.67(0.61 to 0.73)0.51(0.48 to 0.55)0.27(0.24 to 0.31)Daclatasvir 60 mg once daily50 mgonce daily1.29(1.07 to 1.57)1.33(1.11 to 1.59)1.45(1.25 to 1.68)Ferrous fumarate 324 mg simultaneous administration (fasted)50-mgsingle dose0.43(0.35 to 0.52)0.46(0.38 to 0.56)0.44(0.36 to 0.54)Ferrous fumarate 324 mg simultaneous administration (fed)50-mgsingle dose1.03(0.84 to 1.26)0.98(0.81 to 1.20)1.00(0.81 to 1.23)Ferrous fumarate 324 mg h after dolutegravir50-mgsingle dose0.99(0.81 to 1.21)0.95(0.77 to 1.15)0.92(0.74 to 1.13)Multivitamin (One-A-Day) simultaneous administration50-mgsingle dose0.65(0.54 to 0.77)0.67(0.55 to 0.81)0.68(0.56 to 0.82)Omeprazole 40 mg once daily50-mgsingle dose0.92(0.75 to 1.11)0.97(0.78 to 1.20)0.95(0.75 to 1.21)Prednisone 60 mg once daily with taper50 mgonce daily1.06(0.99 to 1.14)1.11(1.03 to 1.20)1.17(1.06 to 1.28)Rifampina 600 mg once daily50 mgtwice daily0.57(0.49 to 0.65)0.46(0.38 to 0.55)0.28(0.23 to 0.34)Rifampinb 600 mg once daily50 mgtwice daily1.18(1.03 to 1.37)1.33(1.15 to 1.53)1.22(1.01 to 1.48)Rifabutin 300 mg once daily50 mgonce daily1.16(0.98 to 1.37)0.95(0.82 to 1.10)0.70(0.57 to 0.87)Table 10. Effect of Sorbitol on the Pharmacokinetics of Lamivudinea Coadministered with single dose of lamivudine 300 mg. Cmax Maximum concentration; AUC(0-24) Area under the concentration-time curve integrated from time of administration to 24 hours; AUC(inf) Area under the concentration-time curve from the time of administration to infinity.Coadministered Drug and Dosea Lamivudine Pharmacokinetic Parameters(% Decreased)Cmax AUC0-24 AUCinf Sorbitol(Excipient)3.2 grams28%20%14%10.2 grams52%39%32%13.4 grams55%44%36%No clinically significant differences in the pharmacokinetics of lamivudine were observed when coadministered with trimethoprim (MATE1, MATE2-K, and OCT2 inhibitor)/sulfamethoxazole, interferon alfa, or ribavirin.In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically: Dolutegravir: Dolutegravir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. Dolutegravir does not induce CYP1A2, CYP2B6, or CYP3A4.Dolutegravir is substrate of UGT1A3 and UGT1A9. Dolutegravir does not inhibit UGT1A1 or UGT2B7.Dolutegravir is substrate of BCRP and P-gp. Dolutegravir does not inhibit P-gp, BCRP, bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. Dolutegravir is not substrate of OATP1B1 or OATP1B3.Lamivudine: Lamivudine is substrate of P-gp and BCRP. Lamivudine does not inhibit OATP1B1/3, BCRP, P-gp, MATE1, MATE2-K, OCT1, OCT2, or OCT3.

PREGNULLNCY SECTION.


8.1Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to DOVATO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk Summary Data from an ongoing birth outcome surveillance study have identified an increased risk of neural tube defects when dolutegravir, component of DOVATO, is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first weeks of gestation are at potential risk. Advise individuals of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of DOVATO. Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see Warnings and Precaution (5.4)].There are insufficient human data on the use of DOVATO during pregnancy to definitively assess drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see Data). Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the RHD; however, no adverse developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD (see Data). DataHuman Data: Dolutegravir: In birth outcome surveillance study in Botswana, there were cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included cases of myelomeningocele, cases of encephalocele, and one case each of anencephaly and iniencephaly. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had neural tube defect, compared with infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively address the risk of neural tube defects with dolutegravir.Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births (including 512 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir-containing regimens and 4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%. Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third 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 U.S. reference population of the MACDP. The prevalence of defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.Lamivudine pharmacokinetics were studied in pregnant women during clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using lamivudine 150 mg twice daily with zidovudine, 10 women at 38 weeks gestation using lamivudine 150 mg twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9-fold (1.2- to 12.8-fold) greater compared with paired maternal serum concentration (n 8).Animal Data: Dolutegravir: Dolutegravir was administered orally to pregnant rats and rabbits (up to 1,000 mg/kg/day) on Gestation Days to 17 and to 18, respectively, and also to rats on Gestation Day to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the RHD and in rats were approximately 50 times the exposure in humans at the RHD. In the rat pre/postnatal development study, decreased body weight of the developing offspring was observed during lactation at maternally toxic dose (approximately 50 times human exposure at the RHD). Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg/kg/day) and rabbits (at 90, 300 and 1,000 mg/kg/day and at 15, 40, and 90 mg/kg/day) during organogenesis (on Gestation Days through 16 [rat] and through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the RHD. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the RHD. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg/kg/day (from prior to mating through Postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by the maternal administration of lamivudine.

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Indications and Usage (1)08/2020Dosage and Administration, Testing Prior to or When Initiating Treatment with DOVATO (2.1)03/2021Dosage and Administration, Not Recommended in Patients with Renal Impairment (2.4)03/2021Warnings and Precautions, Embryo-Fetal Toxicity (5.4)03/2021.