The Food and Drug Administration approved revisions to the Truvada (emtricitabine and tenofovir disoproxil fumarate) labeling to expand the Pre-Exposure Prophylaxis (PrEP) indication to include adolescents weighing at least 35 kg who are at risk of HIV-1 acquisition. The major labeling changes with respect to this expanded indication are summarized below. In addition, Section 8 was reformatted per the Pregnancy and Lactation Labeling Rule (PLLR) and includes updated information specific to the use of Truvada for PrEP during pregnancy and breastfeeding. Other sections of labeling were reformatted for consistency with current and best labeling practices, as well as with labeling for other HIV fixed-dose combination products.
INDICATIONS AND USAGE
1.2 HIV-1 Pre-Exposure Prophylaxis (PrEP)
TRUVADA is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in at-risk adults and adolescents weighing at least 35 kg. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP.
DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of TRUVADA for Treatment of HIV-1 Infection or for HIV-1 PrEP
Prior to or when initiating TRUVADA, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].
Prior to initiation and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus
2.2 HIV-1 Screening for Individuals Receiving TRUVADA for HIV-1 PrEP
Screen all patients for HIV-1 infection before initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA
2.5 Recommended Dosage for HIV-1 PrEP
The dosage of TRUVADA in HIV-1 uninfected adults and adolescents weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food.
6. ADVERSE REACTIONS
Clinical Trials in Adolescent Subjects
In a single-arm, open-label clinical trial (ATN113), in which 67 HIV-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received TRUVADA once daily for HIV-1 PrEP, the safety profile of TRUVADA was similar to that observed in adults. Median duration to exposure of TRUVADA was 47 weeks.
In the ATN113 trial, median BMD increased from baseline to Week 48, +2.58% for lumbar spine and +0.72% for total body. One subject had significant (greater than or equal to 4%) total body BMD loss at Week 24. Median changes from baseline BMD Z-scores were 0.0 for lumbar spine and −0.2 for total body at Week 48. Three subjects showed a worsening (change from > −2 to ≤ −2) from baseline in their lumbar spine or total body BMD Z-scores at Week 24 or 48. Interpretation of these data, however, may be limited by the low rate of adherence to TRUVADA by Week 48.
8.4 Pediatric Use
HIV-1 PrEP
The safety and effectiveness of TRUVADA for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from adequate and well-controlled studies of TRUVADA for HIV-1 PrEP in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, FTC and TDF, in HIV-1 infected adults and pediatric subjects.
Safety, adherence, and resistance were evaluated in a single-arm, open-label clinical trial (ATN113) in which 67 HIV-1 uninfected at-risk adolescent men who have sex with men received TRUVADA once daily for HIV-1 PrEP. The mean age of subjects was 17 years (range 15 to 18 years); 46% were Hispanic, 52% Black, and 37% White. The safety profile of TRUVADA in ATN113 was similar to that observed in the adult HIV-1 PrEP trials.
In the ATN113 trial, HIV-1 seroconversion occurred in 3 subjects. Tenofovir diphosphate levels in dried blood spot assays indicate that these subjects had poor adherence. No tenofovir- or FTC-associated HIV-1 resistance substitutions were detected in virus isolated from the 3 subjects who seroconverted.
Adherence to study drug, as demonstrated by tenofovir diphosphate levels in dried blood spot assays, declined markedly after Week 12 once subjects switched from monthly to quarterly visits, suggesting that adolescents may benefit from more frequent visits and counseling.
12 CLINICAL PHARMACOLOGY
HIV-1 PrEP: The pharmacokinetic data for tenofovir and FTC following administration of TRUVADA in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of TRUVADA for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial [see Use in Specific Populations (8.4)] and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment.
Resistance:
ATN113 Trial: In ATN113, a clinical trial of HIV-1 seronegative adolescent subjects [see Use in Specific Populations (8.4)], no amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion from any of the 3 subjects who became infected with HIV-1 during the trial. All 3 subjects who seroconverted were nonadherent to the recommended TRUVADA dosage.
INDICATIONS AND USAGE
1.2 HIV-1 Pre-Exposure Prophylaxis (PrEP)
TRUVADA is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in at-risk adults and adolescents weighing at least 35 kg. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP.
- If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test cleared by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection
- has partner(s) known to be HIV-1 infected, or
- engages in sexual activity within a high prevalence area or social network and has additional risk factors for HIV-1 acquisition, such as:
• inconsistent or no condom use
• diagnosis of sexually transmitted infections
• exchange of sex for commodities (such as money, food, shelter, or drugs)
• use of illicit drugs or alcohol dependence
• incarceration
• partner(s) of unknown HIV-1 status with any of the factors listed above
• diagnosis of sexually transmitted infections
• exchange of sex for commodities (such as money, food, shelter, or drugs)
• use of illicit drugs or alcohol dependence
• incarceration
• partner(s) of unknown HIV-1 status with any of the factors listed above
DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of TRUVADA for Treatment of HIV-1 Infection or for HIV-1 PrEP
Prior to or when initiating TRUVADA, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].
Screen all patients for HIV-1 infection before initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA
2.5 Recommended Dosage for HIV-1 PrEP
The dosage of TRUVADA in HIV-1 uninfected adults and adolescents weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food.
6. ADVERSE REACTIONS
Clinical Trials in Adolescent Subjects
In a single-arm, open-label clinical trial (ATN113), in which 67 HIV-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received TRUVADA once daily for HIV-1 PrEP, the safety profile of TRUVADA was similar to that observed in adults. Median duration to exposure of TRUVADA was 47 weeks.
In the ATN113 trial, median BMD increased from baseline to Week 48, +2.58% for lumbar spine and +0.72% for total body. One subject had significant (greater than or equal to 4%) total body BMD loss at Week 24. Median changes from baseline BMD Z-scores were 0.0 for lumbar spine and −0.2 for total body at Week 48. Three subjects showed a worsening (change from > −2 to ≤ −2) from baseline in their lumbar spine or total body BMD Z-scores at Week 24 or 48. Interpretation of these data, however, may be limited by the low rate of adherence to TRUVADA by Week 48.
8.4 Pediatric Use
HIV-1 PrEP
The safety and effectiveness of TRUVADA for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from adequate and well-controlled studies of TRUVADA for HIV-1 PrEP in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, FTC and TDF, in HIV-1 infected adults and pediatric subjects.
Safety, adherence, and resistance were evaluated in a single-arm, open-label clinical trial (ATN113) in which 67 HIV-1 uninfected at-risk adolescent men who have sex with men received TRUVADA once daily for HIV-1 PrEP. The mean age of subjects was 17 years (range 15 to 18 years); 46% were Hispanic, 52% Black, and 37% White. The safety profile of TRUVADA in ATN113 was similar to that observed in the adult HIV-1 PrEP trials.
In the ATN113 trial, HIV-1 seroconversion occurred in 3 subjects. Tenofovir diphosphate levels in dried blood spot assays indicate that these subjects had poor adherence. No tenofovir- or FTC-associated HIV-1 resistance substitutions were detected in virus isolated from the 3 subjects who seroconverted.
Adherence to study drug, as demonstrated by tenofovir diphosphate levels in dried blood spot assays, declined markedly after Week 12 once subjects switched from monthly to quarterly visits, suggesting that adolescents may benefit from more frequent visits and counseling.
12 CLINICAL PHARMACOLOGY
HIV-1 PrEP: The pharmacokinetic data for tenofovir and FTC following administration of TRUVADA in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of TRUVADA for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial [see Use in Specific Populations (8.4)] and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment.
Resistance:
ATN113 Trial: In ATN113, a clinical trial of HIV-1 seronegative adolescent subjects [see Use in Specific Populations (8.4)], no amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion from any of the 3 subjects who became infected with HIV-1 during the trial. All 3 subjects who seroconverted were nonadherent to the recommended TRUVADA dosage.
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Elizabeth Thompson
Division of Antiviral Products
Food and Drug Administration
Michael Stanfield Jr.
Division of Antiviral Products
Food and Drug Administration
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