Vitekta

Dosage Forms And Strengths

• Tablets: 85 mg green, pentagon-shaped, film-coated, debossed with “GSI” on one side and “85” on the other side.
• Tablets: 150 mg green, triangle-shaped, film-coated, debossed with “GSI” on one side and “150” on the other side.

Storage And Handling

VITEKTA tablets are available in bottles containing 30 tablets with a child-resistant closure as follows:

85 mg tablets are green, pentagon-shaped, film-coated, debossed with “GSI” on one side and “85” on the other side: NDC 61958-1301-1

150 mg tablets are green, triangle-shaped, film-coated, debossed with “GSI” on one side and “150” on the other side: NDC 61958-1302-1

Store at room temperature below 30 °C (86 °F).

Dispense only in original container.

Do not use if seal over bottle opening is broken or missing.

Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404. Revised: July 2015

VITEKTA in combination with an HIV protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) is indicated for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults.

Limitations of Use

• There are no comparative pharmacokinetic or clinical data evaluating VITEKTA with cobicistat as single entities compared to STRIBILD®.
• VITEKTA coadministered with protease inhibitors and cobicistat is not recommended.
• Coadministration of VITEKTA with dosage regimens or HIV-1 protease inhibitors other than those presented in Table 1 is not recommended.

VITEKTA must be administered once daily with food in combination with a protease inhibitor coadministered with ritonavir and another antiretroviral drug. The protease inhibitor and ritonavir dosing regimens presented in Table 1 are the recommended regimens for use with VITEKTA. For additional dosing instructions for these protease inhibitors and other concomitant antiretroviral drugs, refer to their respective prescribing information.

Table 1 : Recommended Regimens*

Treatment history and, when available, resistance testing should guide the use of VITEKTA-containing regimens.

There are no contraindications to VITEKTA. Due to the need to use VITEKTA with a protease inhibitor coadministered with ritonavir, prescribers should consult the complete prescribing information of the coadministered protease inhibitor and ritonavir for a description of contraindications.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Adverse Reactions Or Loss Of Virologic Response Due To Drug Interactions

The concomitant use of VITEKTA and other drugs may result in known or potentially significant drug interactions, some of which may lead to :

• Loss of therapeutic effect of VITEKTA and possible development of resistance
• Possible clinically significant adverse reactions from greater exposures of concomitant drugs or elvitegravir.

See Table 4 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 VITEKTA therapy; review concomitant medications during VITEKTA therapy; and monitor for the adverse reactions associated with the concomitant drugs.

Use With Other Antiretroviral Agents

Use of VITEKTA in combination with the fixed dose combination STRIBILD is not recommended, because elvitegravir is a component of STRIBILD.

VITEKTA is indicated for use in combination with a protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s). VITEKTA in combination with a protease inhibitor and cobicistat is not recommended because dosing recommendations for such combinations have not been established and may result in suboptimal plasma concentrations of VITEKTA and/or the protease inhibitor, leading to loss of therapeutic effect and development of resistance.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. 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).

A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with VITEKTA. A Patient Package Insert for VITEKTA is available for patient information.

Information For Patients

Advise patients of the following:

• Inform patients that they should remain under the care of a healthcare provider when using VITEKTA.
• Inform patients that VITEKTA is not a cure for HIV infection. Patients must stay on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses. 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 continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Advise patients never to re-use or share needles.
• Inform patients that it is important to take VITEKTA on a regular dosing schedule with food and to avoid missing doses.
• Inform patients that VITEKTA must be taken with an HIV protease inhibitor combined with ritonavir in order to achieve adequate drug levels.
• VITEKTA may interact with many drugs; therefore, inform patients of the potential serious drug interactions with VITEKTA, and that some drugs should not be taken with VITEKTA. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.
• In some patients with advanced HIV infection (AIDS), 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. Advise patients to inform their healthcare provider immediately of any symptoms of infection.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term carcinogenicity studies of elvitegravir were carried out in mice (104 weeks) and in rats (up to 88 weeks in males and 90 weeks in females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day ritonavir at exposures 3-and 14-fold, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12-to 27-fold, respectively, in male and female, the human systemic exposure.

Mutagenesis

Elvitegravir was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation.

Fertility

Elvitegravir did not affect fertility in male and female rats at approximately 16-and 30fold higher exposures (AUC), respectively, than in humans at the therapeutic 150 mg daily dose.

Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18-fold higher than human exposures at the recommended 150 mg daily dose.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of VITEKTA in pregnant women. Because animal reproduction studies are not always predictive of human response, VITEKTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

To monitor fetal outcomes of pregnant women exposed to VITEKTA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Animal Data

Elvitegravir studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with VITEKTA during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans at the recommended daily dose of 150 mg.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir is secreted in milk. It is not known whether elvitegravir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving VITEKTA.

Pediatric Use

Safety and efficacy in pediatric patients have not been established.

Adolescents (12 through 17 Years Old)

Study 152 was an open-label, multicenter trial of VITEKTA in HIV-1 infected, antiretroviral treatment-experienced adolescent subjects 12 through 17 years of age. The trial included a 10-day pharmacokinetic evaluation phase of VITEKTA followed by an optional extended treatment phase. Dosage regimens were similar to those evaluated in adults, either VITEKTA 150 mg plus darunavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir (n=11) or VITEKTA 85 mg plus lopinavir/ritonavir or atazanavir/ritonavir (n=14).

Twenty-five subjects were enrolled and 23 completed the pharmacokinetic phase. Nine subjects with baseline HIV-1 RNA greater than 1,000 copies/mL who completed the 10-day pharmacokinetic evaluation phase enrolled in the optional 48 week treatment phase. All nine completed treatment through 48 weeks; 2/9 subjects (22%) achieved HIV-1 RNA less than 50 copies/mL at Week 48, and 4/9 (44%) achieved HIV-1 RNA less than 400 copies/mL. During the treatment phase of the trial, 8/9 subjects (89%) were found to have undetectable elvitegravir levels during treatment, suggesting that adherence to the regimen was poor and may have contributed to the low response rate in this trial. Although adolescents achieved acceptable VITEKTA plasma levels in the pharmacokinetic phase, the 48-week treatment phase data were insufficient to establish safety and effectiveness in this age group.

Pediatric Patients Less Than 12 Years Old

Pharmacokinetics, safety and effectiveness of VITEKTA in the treatment of HIV-1 infection in pediatric patients less than 12 years of age have not been evaluated in clinical trials.

Geriatric Use

Clinical trials of VITEKTA did not include sufficient numbers of subjects aged 65 and older, to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

No clinically relevant differences in elvitegravir pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. No dose adjustment of VITEKTA is required for patients with renal impairment.

Hepatic Impairment

No clinically relevant differences in elvitegravir pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dose adjustment of VITEKTA is required in patients with mild (Child-Pugh Class A) or moderate hepatic impairment. VITEKTA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, VITEKTA is not recommended for use in patients with severe hepatic impairment.

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety assessment of VITEKTA is primarily based on data from a controlled clinical trial, Study 145, in which 712 HIV-1 infected, antiretroviral treatment-experienced adults received VITEKTA (N=354) or raltegravir (N=358), each administered with a background regimen consisting of a fully active protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) for at least 96 weeks.

The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 3% in the VITEKTA group and 4% in the raltegravir group. The most common adverse reaction (all Grades, incidence greater than or equal to 5%) in subjects receiving VITEKTA in Study 145 was diarrhea. See also Table 2 for the frequency of adverse reactions occurring in at least 2% of subjects in any treatment group in Study 145.

Table 2 : Selected Adverse Reactions (All Grades) Reported in ≥ 2% of HIV-1 Infected Treatment-Experienced Adults in Either Treatment Group in Study 145 (Week 96 Analysis)^a

Less Common Adverse Reactions Observed in Treatment-Experienced Studies

The following adverse reactions occurred in < 2% of subjects receiving VITEKTA combined with a protease inhibitor and ritonavir. These reactions have been included because of their seriousness, increased frequency on VITEKTA compared with raltegravir, or investigator's assessment of potential causal relationship.

Gastrointestinal Disorders: abdominal pain, dyspepsia, vomiting

General Disorders and Administration Site Conditions: fatigue

Psychiatric Disorders: depression, insomnia, suicidal ideation and suicide attempt ( < 1%, most in subjects with a pre-existing history of depression or psychiatric illness)

Skin and Subcutaneous Tissue Disorders: rash

Laboratory Abnormalities

The frequency of laboratory abnormalities (Grades 3–4), occurring in at least 2% of subjects in either treatment group in Study 145, is presented in Table 3.

Table 3 : Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of HIV-1 Infected Treatment-Experienced Adults in Either Treatment Group in Study 145 (Week 96 Analysis)

DRUG INTERACTIONS

See also DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY.

Effect Of Concomitant Drugs On The Pharmacokinetics Of Elvitegravir

Elvitegravir is metabolized by CYP3A. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir, as well as ritonavir. This may result in decreased plasma concentrations of elvitegravir and/or a concomitantly administered protease inhibitor and lead to loss of therapeutic effect and to possible resistance.

Established And Other Potentially Significant Interactions

Table 4 provides dosing recommendations as a result of potentially clinically significant drug interactions with VITEKTA. These recommendations are based on either drug-drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect.

For additional drug-drug interactions related to protease inhibitors coadministered with ritonavir, consult the prescribing information of the coadministered protease inhibitor and ritonavir.

The table is not all-inclusive.

Table 4 : Established and Other Potentially Significant^a Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Drugs Without Clinically Significant Interactions With Elvitegravir

Based on drug interaction studies conducted with elvitegravir, no clinically significant drug interactions have been either observed or expected when elvitegravir is combined with the following drugs: abacavir, darunavir, emtricitabine, etravirine, fosamprenavir, maraviroc, stavudine, tipranavir, tenofovir disoproxil fumarate, zidovudine; H2-receptor antagonists such as famotidine; proton-pump inhibitors such as omeprazole; and the HMG-CoA reductase inhibitors atorvastatin, pravastatin, and rosuvastatin.

When any of the above drugs are used concomitantly with VITEKTA in combination with a protease inhibitor coadministered with ritonavir, consult the prescribing information of the protease inhibitor for dosing recommendation for these drugs.

Pregnancy Category B

There are no adequate and well-controlled studies of VITEKTA in pregnant women. Because animal reproduction studies are not always predictive of human response, VITEKTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

To monitor fetal outcomes of pregnant women exposed to VITEKTA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Animal Data

Elvitegravir studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with VITEKTA during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans at the recommended daily dose of 150 mg.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety assessment of VITEKTA is primarily based on data from a controlled clinical trial, Study 145, in which 712 HIV-1 infected, antiretroviral treatment-experienced adults received VITEKTA (N=354) or raltegravir (N=358), each administered with a background regimen consisting of a fully active protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) for at least 96 weeks.

The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 3% in the VITEKTA group and 4% in the raltegravir group. The most common adverse reaction (all Grades, incidence greater than or equal to 5%) in subjects receiving VITEKTA in Study 145 was diarrhea. See also Table 2 for the frequency of adverse reactions occurring in at least 2% of subjects in any treatment group in Study 145.

Table 2 : Selected Adverse Reactions (All Grades) Reported in ≥ 2% of HIV-1 Infected Treatment-Experienced Adults in Either Treatment Group in Study 145 (Week 96 Analysis)^a

Less Common Adverse Reactions Observed in Treatment-Experienced Studies

The following adverse reactions occurred in < 2% of subjects receiving VITEKTA combined with a protease inhibitor and ritonavir. These reactions have been included because of their seriousness, increased frequency on VITEKTA compared with raltegravir, or investigator's assessment of potential causal relationship.

Gastrointestinal Disorders: abdominal pain, dyspepsia, vomiting

General Disorders and Administration Site Conditions: fatigue

Psychiatric Disorders: depression, insomnia, suicidal ideation and suicide attempt ( < 1%, most in subjects with a pre-existing history of depression or psychiatric illness)

Skin and Subcutaneous Tissue Disorders: rash

Laboratory Abnormalities

The frequency of laboratory abnormalities (Grades 3–4), occurring in at least 2% of subjects in either treatment group in Study 145, is presented in Table 3.

Table 3 : Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of HIV-1 Infected Treatment-Experienced Adults in Either Treatment Group in Study 145 (Week 96 Analysis)

If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with VITEKTA consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.

Limited clinical experience is available at doses higher than the therapeutic dose of elvitegravir. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Cardiac Electrophysiology

The effect of multiple doses of elvitegravir 125 mg (1.5 times the lowest recommended dosage) and 250 mg (1.7 times the maximum recommended dosage) (coadministered with 100 mg ritonavir) on QT interval was evaluated in a randomized, placebo-and active-controlled (moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects. No clinically meaningful changes in QTc interval were observed with either 125 mg dose or the 250 mg dose. The dose of 250 mg elvitegravir (with 100 mg ritonavir) is expected to cover the high exposure clinical scenario.

Absorption

Following oral administration of VITEKTA and ritonavir with food, in HIV-1 infected subjects, peak elvitegravir plasma concentrations were observed approximately 4 hours post-dose. The steady-state mean elvitegravir pharmacokinetic parameters are presented in Table 5. Elvitegravir plasma exposures increased in a less than dose proportional manner, likely due to solubility-limited absorption.

Table 5 : Pharmacokinetic Parameters of Elvitegravir Following Oral Administration of VITEKTA in HIV-1 Infected Adults

VITEKTA must be taken with food.

Distribution

Elvitegravir is 98–99% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 ng/mL to 1.6 μg/mL. The mean plasma-toblood drug concentration ratio is 1.37.

Metabolism and Elimination

Elvitegravir undergoes primarily oxidative metabolism via CYP3A, and is secondarily glucuronidated via UGT1A1/3 enzymes. Following oral administration of [¹⁴C]elvitegravir/ritonavir, elvitegravir was the predominant species in plasma, representing ~94% of the circulating radioactivity. Aromatic and aliphatic hydroxylation or glucuronidation metabolites were present in very low levels, displayed considerably lower anti-HIV activity and did not contribute to the overall antiviral activity of elvitegravir.

Following oral administration of [¹⁴C]elvitegravir/ritonavir, 94.8% of the dose was recovered in feces, consistent with the hepatobiliary excretion of elvitegravir; 6.7% of the administered dose was recovered in urine as metabolites. The median terminal plasma half-life of elvitegravir following administration of VITEKTA and ritonavir was approximately 8.7 hours.