May 30, 2016
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The US Food and Drug Administration (FDA) has approved a fixed-dose combination of the antiretroviral drug darunavir (800 mg) and the pharmacokinetic enhancer cobicistat (150 mg) for HIV"...





Included as part of the PRECAUTIONS section.


Hypersensitivity Reactions

Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TIVICAY and other suspect agents 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 TIVICAY or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. TIVICAY is contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir.

Effects On Serum Liver Biochemistries In Patients With Hepatitis B Or C Co-infection

Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY [see ADVERSE REACTIONS]. In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TIVICAY are recommended in patients with underlying hepatic disease such as hepatitis B or C.

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TIVICAY. 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-Barré 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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Drug Interactions

TIVICAY should not be coadministered with dofetilide because interactions between these drugs can result in potentially life-threatening adverse events [see CONTRAINDICATIONS].

Hypersensitivity Reactions

Patients should be advised to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking TIVICAY and other suspect agents, and seek medical attention if they develop a rash associated with any of the following symptoms, as it may be a sign of a 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). Patients should understand that if hypersensitivity occurs, they will be closely monitored, laboratory tests will be ordered, and appropriate therapy will be initiated. Patients should also be told that it is very important that they remain under a physician's care during treatment with TIVICAY [see WARNINGS AND PRECAUTIONS].

Effects on Serum Liver Biochemistries in Patients with Hepatitis B or C Co-infection

Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY and should be advised that they are recommended to have laboratory testing before and during therapy [see WARNINGS AND PRECAUTIONS].

Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS].

Immune Reconstitution Syndrome

In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Patients should be advised to inform their healthcare provider immediately of any symptoms of infection [see WARNINGS AND PRECAUTIONS].

Information about HIV-1 Infection

TIVICAY is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.

Advise patients to remain under the care of a physician when using TIVICAY. Advise patients to take all HIV medications exactly as prescribed. Advise patients to avoid doing things that can spread HIV-1 infection to others.

Advise patients not to re-use or share needles or other injection equipment.

Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.

Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Female patients should be advised not to breastfeed because it is not known if TIVICAY can be passed to your baby in your breast milk and whether it could harm your baby. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Instruct patients to read the PATIENT INFORMATION before starting TIVICAY and to reread it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 4 hours of the time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility


Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per 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 14-fold higher than those in humans at the recommended dose of 50 mg twice daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10-fold and 15-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg twice daily.


Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

Impairment of Fertility

In a study conducted in rats, there were no effects on mating or fertility with dolutegravir up to 1,000 mg per kg per day. This dose is associated with an exposure that is approximately 24 times higher than the exposure in humans at the recommended dose of 50 mg twice daily.

Use In Specific Populations


Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and dolutegravir was shown to cross the placenta in animal studies, this drug should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women with HIV exposed to TIVICAY and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Animal Data

Reproduction studies have been performed in rats and rabbits at doses up to 27 times the human dose of 50 mg twice daily and have revealed no evidence of impaired fertility or harm to the fetus due to TIVICAY.

Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg per kg daily, approximately 27 times the 50-mg twice-daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or teratogenicity.

Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg per kg daily, approximately 0.4 times the 50-mg twice-daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg per kg.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is excreted in human milk.

Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, instruct mothers not to breastfeed.

Pediatric Use

Safety and efficacy of TIVICAY have not been established in pediatric patients younger than 12 years, weighing less than 40 kg, or in any pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).

The safety, virologic, and immunologic responses in subjects who received TIVICAY were evaluated in 23 treatment-experienced, INSTI-na´ve, HIV-1–infected subjects aged 12 to less than 18 years in an open-label, multicenter, dose-finding clinical trial, IMPAACT P1093 [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies]. Pharmacokinetic parameters, evaluated in 9 subjects weighing at least 40 kg receiving 50 mg daily and 1 subject (weighing 37 kg) receiving 35 mg once daily, were similar to adults receiving 50 mg once daily. See DOSAGE AND ADMINISTRATION for dosing recommendations for pediatric patients aged 12 years and older and weighing at least 40 kg. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see ADVERSE REACTIONS].

Geriatric Use

Clinical trials of TIVICAY did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TIVICAY 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].

Hepatic Impairment

No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY].

Renal Impairment

Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls. However, no dosage adjustment is necessary for treatment-na´ve or treatment-experienced and INSTI-na´ve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology]) with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents [see CLINICAL PHARMACOLOGY]. Dolutegravir has not been studied in patients on dialysis.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 9/30/2015


Report Problems to the Food and Drug Administration


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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