June 30, 2016
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Tivicay

"Just one dose of zoledronic acid given at the start of antiretroviral therapy (ART) may prevent ART-associated bone loss during the first 48 weeks of therapy, according to a study published online May 18 in Clinical Infectious Diseases.

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Tivicay

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn.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 is contraindicated with dofetilide because interactions between these drugs can result in potentially life-threatening adverse events [see CONTRAINDICATIONS].

Hypersensitivity Reactions

Advise patients 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) [see WARNINGS AND PRECAUTIONS].

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

Advise patients that it is recommended to have laboratory testing before and during therapy as patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY [see WARNINGS AND PRECAUTIONS].

Fat Redistribution

Inform patients 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

Advise patients to inform their healthcare provider immediately of any signs or symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TIVICAY is started [see WARNINGS AND PRECAUTIONS].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TIVICAY during pregnancy [see Use in Specific Populations].

Lactation

Instruct women 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].

Missed Dosage

Instruct patients that if they miss a dose of TIVICAY, 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].

Storage

Instruct patients to store the TIVICAY 10-mg tablets in the original package, keep the bottle tightly closed, and protect from moisture. Do not remove desiccant [see HOW SUPPLIED/Storage and Handling].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

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.

Mutagenesis

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

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TIVICAY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

There are insufficient human data on the use of TIVICAY during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Given the limited number of pregnancies exposed to dolutegravir-based regimens reported to the APR, no definitive conclusions can be drawn on the safety of TIVICAY in pregnancy, and continued monitoring is ongoing through the APR. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir [see Data]. During organogenesis in the rat and rabbit, systemic exposures (AUC) to dolutegravir were less than (rabbits) and approximately 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD). In the rat pre/post natal developmental study, maternal systemic exposure (AUC) to dolutegravir was approximately 27 times the exposure in humans at the MRHD.

Data

Animal Data: Dolutegravir was administered orally at up to 1,000 mg per kg daily to pregnant rats and rabbits on gestation Days 6 to 17 and 6 to 18, respectively, and also to rats on gestation day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at up to the highest dose tested. During organogenesis systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the maximum recommended human dose (MRHD) and in rats were approximately 27 times the exposure in humans at the MRHD. In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 27 times human exposure at the MRHD).

Lactation

Risk Summary

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. It is not known whether TIVICAY is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, dolutegravir was present in milk [see Data].

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

Data

Animal Data: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 50 mg per kg on lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed 8 hours post-dose.

Pediatric Use

The safety, virologic, and immunologic responses in subjects who received TIVICAY were evaluated in 46 treatment-experienced, INSTI-na´ve, HIV-1–infected subjects aged 6 to less than 18 years in an open-label, multicenter, dose-finding clinical trial, IMPAACT P1093 [see CLINICAL PHARMACOLOGY, Clinical Studies]. Frequency, type, and severity of adverse drug reactions among the 46 pediatric subjects were comparable to those observed in adults [see ADVERSE REACTIONS]. In 17 subjects weighing at least 30 kg, pharmacokinetic parameters of dolutegravir were comparable to adults receiving 50 mg once daily [see CLINICAL PHARMACOLOGY].

Safety and efficacy of TIVICAY have not been established in pediatric patients weighing less than 30 kg or in any pediatric patients who are INSTI-experienced.

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: 6/17/2016

Warnings
Precautions

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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