Elvitegravir

Elvitegravir
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

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Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Elvitegravir FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Elvitegravir in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Elvitegravir in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Elvitegravir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Elvitegravir in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Elvitegravir in pediatric patients.

Contraindications

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

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 syndrome; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Adverse Reactions

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.

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.

Postmarketing Experience

Drug Interactions

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.

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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): 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.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elvitegravir in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Elvitegravir during labor and delivery.

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 [see Clinical Pharmacology (12.3)]. 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.

Geriatic 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 [see Clinical Pharmacology (12.3)].

Gender

There is no FDA guidance on the use of Elvitegravir with respect to specific gender populations.

Race

There is no FDA guidance on the use of Elvitegravir with respect to specific racial populations.

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

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Elvitegravir in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Elvitegravir in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Elvitegravir Administration in the drug label.

Monitoring

There is limited information regarding Elvitegravir Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Elvitegravir and IV administrations.

Overdosage

There is limited information regarding Elvitegravir overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Elvitegravir
Systematic (IUPAC) name
6-[(3-Chloro-2-fluorophenyl)methyl]-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxoquinoline-3-carboxylic acid
Identifiers
CAS number	697761-98-1
ATC code	J05AX11
PubChem	5277135
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	447.883 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Protein binding	98%
Metabolism	liver, via CYP3A
Half life	12.9 hours
Excretion	liver 93%, renal 7%
Therapeutic considerations
Pregnancy cat.	B(US)
Legal status
Routes	oral

Mechanism of Action

Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.

Structure

It has a molecular formula of C23H23ClFNO5 and a molecular weight of 447.9. It has the following structural formula:

Pharmacodynamics

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.

Pharmacokinetics

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.

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-to-blood 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.

Nonclinical Toxicology

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 30-fold 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.

Clinical Studies

There is limited information regarding Elvitegravir Clinical Studies in the drug label.

How Supplied

There is limited information regarding Elvitegravir How Supplied in the drug label.

Storage

There is limited information regarding Elvitegravir Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

There is limited information regarding Elvitegravir Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Elvitegravir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Elvitegravir Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Elvitegravir Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Elvitegravir (EVG) is an investigational drug for the treatment of HIV. It acts as an integrase inhibitor. It is undergoing clinical trials conducted by the pharmaceutical company Japan Tobacco.

According to the results of the phase II clinical trial, patients taking once-daily elvitegravir boosted by ritonavir had greater reductions in viral load after 24 weeks compared to individuals randomized to receive a ritonavir-boosted protease inhibitor.