Tivicay

Unless your doctor tells you otherwise, continue your normal diet.

Dolutegravir may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• difficulty falling asleep or staying asleep
• headache
• stomach pain
• gas
• diarrhea

Some side effects can be serious. If you experience any of these symptoms or those listed in the SPECIAL PRECAUTION section, stop taking dolutegravir and call your doctor immediately or get emergency medical attention:

• rash
• fever
• feeling sick
• excessive tiredness
• muscle or joint pain
• blistering or peeling skin
• blisters or sores in the mouth
• red or swollen eyes
• swelling of the eyes, face, lips, mouth, tongue, or throat
• difficulty breathing or swallowing
• jaundice
• dark urine
• pale colored bowel movements
• nausea
• vomiting
• loss of appetite
• pain in the upper right part of the stomach

Dolutegravir may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Dolutegravir is an antiviral medication that prevents human immunodeficiency virus (HIV) cells from multiplying in your body.

Dolutegravir is used with other antiviral medications to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). Dolutegravir is not a cure for HIV or AIDS.

This medicine is for use in adults and children who are at least 12 years old and weigh at least 88 pounds.

Dolutegravir may also be used for purposes not listed in this medication guide.

You should not use dolutegravir if you are also taking dofetilide (Tikosyn).

You should not use this medication if you are allergic to dolutegravir or if you are also taking dofetilide (Tikosyn).

To make sure dolutegravir is safe for you, tell your doctor if you have:

• liver disease, especially hepatitis B or C.

Dolutegravir is not expected to harm an unborn baby. However, HIV can be passed to your baby if you are not properly treated during pregnancy. Tell your doctor if you are pregnant and take all of your HIV medicines as directed to control your infection.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of dolutegravir on the baby.

Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Common side effects include trouble sleeping and headache.

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of Tivicay. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088.

• Store Tivicay at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep Tivicay and all medicines out of the reach of children.

Contraindications

• Dolutegravir (Tivicay): Previous hypersensitivity reaction to dolutegravir;1 concomitant use with dofetilide.1 (See Specific Drugs under Interactions.)

• Abacavir/dolutegravir/lamivudine (Triumeq): HLA-B*5701-positive or previous hypersensitivity reaction to abacavir (regardless of HLA-B*5701 status);240 previous hypersensitivity reaction to dolutegravir or lamivudine;240 concomitant use with dofetilide;240 moderate or severe hepatic impairment.240 Consider contraindications associated with each drug in the fixed combination.240 (See Precautions Related to Use of Fixed Combinations under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions reported.1 Reactions include rash and constitutional findings and, occasionally, organ dysfunction including liver toxicity.1

Immediately discontinue dolutegravir, abacavir/dolutegravir/lamivudine, and any other suspect agents if signs or symptoms of hypersensitivity occur, including (but not limited to) severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, or difficulty breathing.1 240 Monitor clinical status, including liver aminotransferases, and initiate appropriate therapy.1 240

Life-threatening reactions could occur if discontinuance of dolutegravir, abacavir/dolutegravir/lamivudine, and any other suspect agents is delayed after onset of hypersensitivity reaction.1 240

Individuals with HBV or HCV Infection

Increased risk of development or worsening of serum aminotransferase elevations in HIV-infected patients with HBV or HCV coinfection.1 In some cases, elevations in serum aminotransferase concentrations may be consistent with immune reconstitution syndrome or HBV reactivation, particularly in the setting where HBV therapy had been discontinued.1

In patients with underlying hepatic disease such as HBV or HCV infection, perform laboratory monitoring for hepatotoxicity prior to and routinely during dolutegravir or abacavir/dolutegravir/lamivudine treatment.1 240 (See Hepatic Impairment under Cautions.)

If abacavir/dolutegravir/lamivudine used in HIV-infected patients coinfected with HBV or HCV, consider that additional precautions apply to these coinfected patients.240 (See Precautions Related to Use of Fixed Combinations under Cautions.)

Precautions Related to Use of Fixed Combinations

Abacavir/dolutegravir/lamivudine: Consider cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination.240 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.240

Do not use abacavir/dolutegravir/lamivudine concomitantly with single-entity dolutegravir, unless needed for adjustment of dolutegravir dosage (e.g., when fixed combination used concomitantly with efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, or rifampin).240 (See Interactions.)

Because antiretrovirals contained in abacavir/dolutegravir/lamivudine may also be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if the fixed combination is used in conjunction with other antiretrovirals.240

Do not use abacavir/dolutegravir/lamivudine concomitantly with any preparation containing abacavir or lamivudine.240

If abacavir/dolutegravir/lamivudine used, consider that abacavir associated with serious and sometimes fatal hypersensitivity reactions, including multiorgan failure and anaphylaxis.240 Individuals with the HLA-B*5701 allele are at higher risk for hypersensitivity reactions to abacavir, although such reactions reported in patients without the HLA-B*5701 allele.240 Review medical history for prior exposure to any abacavir-containing preparation.240 Screen all patients for the HLA-B*5701 allele prior to initiating or reinitiating abacavir/dolutegravir/lamivudine, unless patient has documentation of prior HLA-B*5701 allele assessment.240 Immediately discontinue abacavir/dolutegravir/lamivudine if a hypersensitivity reaction is suspected, regardless of patient's HLA-B*5701 status and even when other diagnoses are possible.240 Never restart abacavir/dolutegravir/lamivudine or any other abacavir-containing preparation in a patient who experienced a hypersensitivity reaction to an abacavir-containing preparation since more severe reactions can occur within hours and may include life-threatening hypotension and death.240 If hypersensitivity ruled out, manufacturer of abacavir/dolutegravir/lamivudine states that the drug may be reinitiated, but only if medical care is readily accessible.240 Since it is not possible to determine whether hypersensitivity reaction in patient receiving abacavir/dolutegravir/lamivudine is caused by abacavir or dolutegravir,240 never reinitiate abacavir-containing or dolutegravir-containing preparations in patients who stopped therapy with abacavir/dolutegravir/lamivudine due to a hypersensitivity reaction.240

If abacavir/dolutegravir/lamivudine used, consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported in patients receiving HIV NRTIs alone or in conjunction with other antiretrovirals.240 Discontinue abacavir/dolutegravir/lamivudine if clinical or laboratory findings indicate lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations.240

If abacavir/dolutegravir/lamivudine used in patients coinfected with HIV and HBV, consider that severe, acute exacerbations of HBV infection reported following discontinuance of lamivudine in coinfected patients.240 Closely monitor hepatic function (using both clinical and laboratory follow-up) for at least several months after abacavir/dolutegravir/lamivudine discontinued.240 If appropriate, initiation of HBV treatment may be warranted.240 Safety and efficacy of abacavir/dolutegravir/lamivudine not established for treatment of chronic HBV infection.240

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance reported in patients receiving antiretroviral therapy.1 240

Mechanisms and long-term consequences unknown;1 240 causal relationship not established.1 240

Immune Reconstitution Syndrome

During initial treatment, HIV-infected patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium, M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii], varicella-zoster virus [VZV]);1 240 this may necessitate further evaluation and treatment.1 240

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported to occur in the setting of immune reconstitution;1 240 time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1 240

Specific Populations

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 240

Insufficient human data to assess risk of birth defects and miscarriage if dolutegravir used in pregnant women.1

No adequate and well-controlled studies of abacavir/dolutegravir/lamivudine in pregnant women;240 manufacturer states use during pregnancy only if clearly needed or if potential benefits to the woman outweigh risks to fetus.240

Experts state that only limited data available regarding use of dolutegravir during pregnancy and the drug is not recommended for initial treatment in antiretroviral-naive pregnant women.202

Distributed into milk in rats.1 202 Not known whether distributed into human milk,1 202 affects milk production, or affects breast-fed infant.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Dolutegravir (Tivicay): Safety and efficacy not established in pediatric patients weighing <30 kg;1 safety and efficacy not established in INSTI-experienced pediatric patients who have documented or suspected resistance to other INSTIs (e.g., elvitegravir, raltegravir).1 Safety profile in children and adolescents 6 to <18 years of age similar to that in adults.1

Abacavir/dolutegravir/lamivudine (Triumeq): Safety and efficacy not established in pediatric patients.240

Insufficient experience in patients ≥65 years of age to determine whether they respond differently to dolutegravir (Tivicay) or abacavir/dolutegravir/lamivudine (Triumeq) than younger adults.1 240

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 240

Dolutegravir (Tivicay): Not recommended in patients with severe hepatic impairment (Child-Pugh class C);1 pharmacokinetics not evaluated in such patients.1 Pharmacokinetics in patients with moderate hepatic impairment similar to those in healthy individuals; dosage adjustments not needed in those with mild or moderate hepatic insufficiency (Child-Pugh class A or B).1 Risk for further elevations in hepatic enzyme concentrations in patients with HBV or HCV coinfection.1

Abacavir/dolutegravir/lamivudine (Triumeq): Do not use in patients with mild hepatic impairment (Child-Pugh class A).240 Because decreased abacavir dosage is recommend in those with mild hepatic impairment,200 switch to the single-entity components to allow adjustment of abacavir dosage in such patients.240 Contraindicated in those with moderate or severe hepatic impairment (Child-Pugh class B or C).240

Dolutegravir (Tivicay): Use with caution in patients with severe renal impairment who are INSTI-experienced and have documented or suspected INSTI resistance;1 10 dolutegravir plasma concentrations decreased in such patients and may result in loss of therapeutic effects and development of resistance to the drug or other antiretrovirals.1

Dolutegravir: May be used in patients with mild or moderate renal impairment; no clinically important effect on dolutegravir pharmacokinetics.1 10 Dosage adjustments not needed in antiretroviral-naive or antiretroviral-experienced, INSTI-naive patients with mild, moderate, or severe renal impairment.1 10 Dosage adjustments not needed in INSTI-experienced patients with mild or moderate renal impairment.1

Not evaluated in dialysis patients;1 unlikely that renal replacement therapy would have clinically important effect on dolutegravir pharmacokinetics.10 (See Renal Impairment under Dosage and Administration.)

Dolutegravir increases Scr by inhibiting tubular secretion of creatinine;1 does not cause clinically important change in GFR or renal plasma flow.1

Abacavir/dolutegravir/lamivudine (Triumeq): Do not use if Clcr <50 mL/minute.240 Because lamivudine substantially eliminated by kidneys and decreased lamivudine dosage recommended in those with Clcr <50 mL/minute, switch to the single-entity components to allow adjustment of lamivudine dosage in such patients.240

Common Adverse Effects

Insomnia; headache; fatigue; diarrhea; hyperglycemia; decreased neutrophils; increased serum aminotransferases, total bilirubin, creatine kinase, lipase, and cholesterol.1

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Also, do not change the dose or stop taking this medicine without checking first with your doctor. When your supply of this medicine is running low, contact your doctor or pharmacist ahead of time. Do not allow yourself to run out of this medicine.

This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Keep taking dolutegravir for the full time of treatment, even if you begin to feel better. It is also important to take this medicine together with other medicines for HIV. Be sure to take all of the medicines your doctor ordered, and to take them at the right times.

You may take this medicine with or without food.

If you are taking antacids or laxatives containing aluminum, calcium, or magnesium, sucralfate, calcium or iron supplements, or buffered medicines, take dolutegravir at least 2 hours before or 6 hours after you take these medicines. Alternatively, calcium or iron supplements may be taken together with this medicine if taken with food

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For treatment of HIV infection:
    • Adults—50 milligrams (mg) once a day. If you are taking or have received certain other HIV medicines, take 50 mg two times a day.
    • Children weighing 40 kilograms (kg) or more—50 milligrams (mg) once a day.
    • Children weighing 30 to less than 40 kg—35 mg once a day (one 25-mg tablet and one 10-mg tablet).
    • Children weighing less than 30 kg—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If it is less than 4 hours until your next dose, skip the missed dose and just take your regular dose at that time. Do not take extra medicine to make up for a missed dose.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Store the medicine in its original bottle. Keep it tightly closed and protect from moisture.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Tablets:

10 mg: Each tablet contains 10 mg of dolutegravir (as dolutegravir sodium). Tablets are white, round, film-coated, biconvex tablets debossed with “SV 572” on one side and “10” on the other side.

25 mg: Each tablet contains 25 mg of dolutegravir (as dolutegravir sodium). Tablets are pale yellow, round, film-coated, biconvex tablets debossed with “SV 572” on one side and “25” on the other side.

50 mg: Each tablet contains 50 mg of dolutegravir (as dolutegravir sodium). Tablets are yellow, round, film-coated, biconvex tablets debossed with “SV 572” on one side and “50” on the other side.

There is no known specific treatment for overdose with Tivicay. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• oral diabetes medication that contains metformin;

• tuberculosis medication that contains rifampin;

• St. John's wort;

• other HIV or AIDS medicines - efavirenz, etravirine, fosamprenavir/ritonavir, nevirapine, tipranavir/ritonavir; or

• seizure medication - carbamazepine, oxcarbazepine, phenobarbital, phenytoin.

This list is not complete. Other drugs may interact with dolutegravir, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.