Tenvir-EM

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Tenvir-EM uses


WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B and RISK OF DRUG RESISTANCE WITH USE OF Tenvir-EM FOR PRE-EXPOSURE PROPHYLAXIS IN UNDIAGNOSED EARLY HIV-1 INFECTION

Tenvir-EM is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of Tenvir-EM have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Tenvir-EM. Therefore, hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are infected with HBV and discontinue Tenvir-EM. If appropriate, initiation of anti-hepatitis B therapy may be warranted .

Tenvir-EM used for a PrEP indication must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and periodically (at least every 3 months) during use. Drug-resistant HIV-1 variants have been identified with use of Tenvir-EM for a PrEP indication following undetected acute HIV-1 infection. Do not initiate Tenvir-EM for a PrEP indication if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed .

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B and RISK OF DRUG RESISTANCE WITH USE OF Tenvir-EM FOR PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED EARLY HIV-1 INFECTION

See full prescribing information for complete boxed warning.

Tenvir-EM is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued Tenvir-EM. Therefore, hepatic function should be monitored closely in HBV-infected patients who discontinue Tenvir-EM. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.1)

Tenvir-EM used for a PrEP indication must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initial use and periodically during use. Drug-resistant HIV-1 variants have been identified with the use of Tenvir-EM for a PrEP indication following undetected acute HIV-1 infection. Do not initiate Tenvir-EM for a PrEP indication if signs or symptoms of acute HIV infection are present unless negative infection status is confirmed. (5.8)

  • Boxed Warning, Lactic Acidosis/Severe Hepatomegaly with Steatosis
  • Removed 04/2017
  • Indications and Usage, Treatment of HIV-1 infection (1.1)
  • 04/2017
  • Warnings and Precautions, Lactic Acidosis/Severe
  • Hepatomegaly with Steatosis (5.3)

    Warnings and Precautions, Coadministration with Other Products (5.4)

  • 04/2017

    04/2017

  • Warnings and Precautions, Fat Redistribution
  • Removed 04/2017
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1 INDICATIONS AND USAGE

Tenvir-EM is a combination of EMTRIVA and VIREAD, both nucleoside analog HIV-1 reverse transcriptase inhibitors.

  • Tenvir-EM is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg.
  • Tenvir-EM is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. (1)

1.1 Treatment of HIV-1 Infection

Tenvir-EM®, a combination of EMTRIVA® and VIREAD®, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg .

The following points should be considered when initiating therapy with Tenvir-EM for the treatment of HIV-1 infection:

  • It is not recommended that Tenvir-EM be used as a component of a triple nucleoside regimen.
  • Tenvir-EM should not be coadministered with ATRIPLA®, COMPLERA®, DESCOVY®, EMTRIVA, GENVOYA®, ODEFSEY®, STRIBILD®, VEMLIDY®, VIREAD, or lamivudine-containing products .
  • In treatment experienced patients, the use of Tenvir-EM should be guided by laboratory testing and treatment history .

1.2 Pre-Exposure Prophylaxis

Tenvir-EM is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. This indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual serodiscordant couples .

When considering Tenvir-EM for pre-exposure prophylaxis the following factors may help to identify individuals at high risk:

  • has partner(s) known to be HIV-1 infected, or
  • engages in sexual activity within a high prevalence area or social network and one or more of the following:
    • 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

When prescribing Tenvir-EM for pre-exposure prophylaxis, healthcare providers must:

  • prescribe Tenvir-EM as part of a comprehensive prevention strategy because Tenvir-EM is not always effective in preventing the acquisition of HIV-1 infection ;
  • counsel all uninfected individuals to strictly adhere to the recommended Tenvir-EM dosing schedule because the effectiveness of Tenvir-EM in reducing the risk of acquiring HIV-1 was strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials ;
  • confirm a negative HIV-1 test immediately prior to initiating Tenvir-EM for a PrEP indication. 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 approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection ; and
  • screen for HIV-1 infection at least once every 3 months while taking Tenvir-EM for PrEP.
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2 DOSAGE AND ADMINISTRATION

Treatment of HIV-1 Infection

  • Recommended dose in adults and pediatric patients weighing greater than or equal to 35 kg: One Tenvir-EM tablet (containing 200 mg/300 mg of Tenvir-EM and tenofovir disoproxil fumarate) once daily taken orally with or without food. (2.1)
  • Recommended dose in pediatric patients weighing greater than or equal to 17 kg and able to swallow a whole tablet: one Tenvir-EM low-strength tablet (100 mg/150 mg, 133 mg/200 mg, or 167 mg/250 mg based on body weight) once daily taken orally with or without food. (2.2)
  • Recommended dose in renally impaired HIV-1 infected adult patients:
    • Creatinine clearance 30–49 mL/min: 1 tablet every 48 hours. (2.4)
    • CrCl below 30 mL/min or hemodialysis: Do not use Tenvir-EM. (2.4)

Pre-exposure Prophylaxis (2.3)

  • Recommended dose in HIV-1 uninfected adults: One tablet (containing 200 mg/300 mg of Tenvir-EM and tenofovir disoproxil fumarate) once daily taken orally with or without food. (2.3)
  • Recommended dose in renally impaired HIV-uninfected individuals: Do not use Tenvir-EM in HIV-uninfected individuals if CrCl is below 60 mL/min. If a decrease in CrCl is observed in uninfected individuals while using Tenvir-EM for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use. (2.4)

2.1 Recommended Dose for Treatment of HIV-1 Infection in Adults and Pediatric Patients Weighing 35 Kg or More

The recommended dose of Tenvir-EM in adults and in pediatric patients with body weight greater than or equal to 35 kg is one tablet (containing 200 mg of Tenvir-EM and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

2.2 Recommended Dose for Treatment of HIV-1 Infection in Pediatric Patients Weighing at Least 17 kg and Able to Swallow a Whole Tablet

The recommended oral dose for pediatric patients weighing greater than or equal to 17 kg and who are able to swallow a whole tablet is one Tenvir-EM low-strength tablet (167 mg/250 mg, 133 mg/200 mg, or 100 mg/150 mg based on body weight) taken orally once daily with or without food.

The recommended oral dosage of Tenvir-EM low-strength tablets is presented in Table 1. Weight should be monitored periodically and the Tenvir-EM dose adjusted accordingly.

Body Weight (kg) Dosing of FTC (mg)/TDF (mg)
17 to less than 22 one 100/150 tablet once daily
22 to less than 28 one 133/200 tablet once daily
28 to less than 35 one 167/250 tablet once daily

2.3 Recommended Dose for Pre-exposure Prophylaxis

The dose of Tenvir-EM in HIV-1 uninfected adults is one tablet (containing 200 mg of Tenvir-EM and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

2.4 Dose Adjustment for Renal Impairment

Treatment of HIV-1 Infection

Significantly increased drug exposures occurred when EMTRIVA or VIREAD were administered to subjects with moderate to severe renal impairment . Therefore, adjust the dosing interval of Tenvir-EM in HIV-1 infected adult patients with baseline creatinine clearance 30–49 mL/min using the recommendations in Table 2. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment; therefore, clinical response to treatment and renal function should be closely monitored in these patients .

No dose adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). No data are available to make dose recommendations in pediatric patients with renal impairment.

Creatinine Clearance (mL/min)Calculated using ideal (lean) body weight
≥50 30–49 <30

(Including Patients Requiring Hemodialysis)

Recommended Dosing Interval Every 24 hours Every 48 hours Tenvir-EM should not be administered.

Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment .

Pre-exposure Prophylaxis

Do not use Tenvir-EM for a PrEP indication in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min .

Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using Tenvir-EM for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use .

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3 DOSAGE FORMS AND STRENGTHS

Tenvir-EM tablets are available in four dose strengths:

  • Tablet: 100 mg of Tenvir-EM and 150 mg of tenofovir DF (equivalent to 123 mg of tenofovir disoproxil): blue, oval shaped, film coated, debossed with "GSI" on one side and with "703" on the other side.
  • Tablet: 133 mg of Tenvir-EM and 200 mg of tenofovir DF (equivalent to 163 mg of tenofovir disoproxil): blue, rectangular shaped, film coated, debossed with "GSI" on one side and with "704" on the other side.
  • Tablet: 167 mg of Tenvir-EM and 250 mg of tenofovir DF (equivalent to 204 mg of tenofovir disoproxil): blue, modified capsule shaped, film coated, debossed with "GSI" on one side and with "705" on the other side.
  • Tablet: 200 mg of Tenvir-EM and 300 mg of tenofovir DF (equivalent to 245 mg of tenofovir disoproxil): blue, capsule shaped, film coated, debossed with "GILEAD" on one side and with "701" on the other side.

Tablets: 200 mg/300 mg, 167 mg/250 mg, 133 mg/200 mg, and 100 mg/150 mg of Tenvir-EM and tenofovir disoproxil fumarate, respectively. (3)

4 CONTRAINDICATIONS

Do not use Tenvir-EM for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status. Tenvir-EM should be used in HIV-infected patients only in combination with other antiretroviral agents.

Do not use Tenvir-EM for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status. Tenvir-EM should be used in HIV-infected patients only in combination with other antiretroviral agents. (4)

5 WARNINGS AND PRECAUTIONS

  • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with Tenvir-EM. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein before initiating treatment with Tenvir-EM and periodically during treatment. Avoid administering Tenvir-EM with concurrent or recent use of nephrotoxic drugs.
  • Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.3)
  • Coadministration with other products: Do not use with drugs containing Tenvir-EM, tenofovir alafenamide, or tenofovir disoproxil fumarate including ATRIPLA, COMPLERA, EMTRIVA, DESCOVY, GENVOYA, ODEFSEY, STRIBILD, VEMLIDY, VIREAD; or with drugs containing lamivudine. Do not administer in combination with HEPSERA. (5.4)
  • Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.5)
  • Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.6)
  • Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. (5.7)
  • Comprehensive management to reduce the risk of acquiring HIV-1: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule. (5.8)
  • Management to reduce the risk of acquiring HIV-1 drug resistance:
    • Prior to initiating Tenvir-EM for 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 negative HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.
    • While using Tenvir-EM for PrEP − HIV-1 screening tests should be repeated at least every 3 months. (5.8)

5.1 HBV Infection

It is recommended that all individuals be tested for the presence of chronic hepatitis B virus (HBV) before initiating Tenvir-EM. Tenvir-EM is not approved for the treatment of chronic HBV infection, and the safety and efficacy of Tenvir-EM have not been established in patients infected with HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Tenvir-EM. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are infected with HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with Tenvir-EM. If appropriate, initiation of anti-hepatitis B therapy may be warranted. HBV-uninfected individuals should be offered vaccination.

5.2 New Onset or Worsening Renal Impairment

Tenvir-EM and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported with the use of VIREAD .

It is recommended that estimated creatinine clearance be assessed in all individuals prior to initiating therapy and as clinically appropriate during therapy with Tenvir-EM. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA®, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of Tenvir-EM, and periodically during Tenvir-EM therapy.

Tenvir-EM should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) . Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

Treatment of HIV-1 Infection

Dosing interval adjustment of Tenvir-EM and close monitoring of renal function are recommended in all patients with estimated creatinine clearance 30–49 mL/min . No safety or efficacy data are available in patients with renal impairment who received Tenvir-EM using these dosing guidelines, so the potential benefit of Tenvir-EM therapy should be assessed against the potential risk of renal toxicity. Tenvir-EM should not be administered to patients with estimated creatinine clearance below 30 mL/min or patients requiring hemodialysis.

Pre-exposure Prophylaxis

Tenvir-EM for a PrEP indication should not be used if estimated creatinine clearance is less than 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using Tenvir-EM for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use .

5.3 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF and Tenvir-EM, components of Tenvir-EM, alone or in combination with other antiretrovirals. Treatment with Tenvir-EM should be suspended in any patient or uninfected individual who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.4 Coadministration with Other Products

Tenvir-EM is a fixed-dose combination of Tenvir-EM and tenofovir DF. Do not coadminister Tenvir-EM with other drugs containing Tenvir-EM, tenofovir DF, or tenofovir alafenamide, including ATRIPLA, COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, VEMLIDY, or VIREAD. Due to similarities between Tenvir-EM and lamivudine, do not coadminister Tenvir-EM with other drugs containing lamivudine, including Combivir, Dutrebis (lamivudine/raltegravir), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), Triumeq (abacavir sulfate/dolutegravir/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).

Do not coadminister Tenvir-EM with HEPSERA (adefovir dipivoxil).

5.5 Bone Effects of Tenofovir DF

Bone Mineral Density

In clinical trials in HIV-1 infected adults and in a clinical trial of HIV-1 uninfected individuals, tenofovir DF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [see Adverse Reactions (6.2) and VIREAD prescribing information]. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF.

Clinical trials evaluating tenofovir DF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir DF treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. For more information, consult the VIREAD prescribing information.

The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. If bone abnormalities are suspected then appropriate consultation should be obtained.

Mineralization Defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF . Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF .

5.6 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including Tenvir-EM. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections, 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.

5.7 Early Virologic Failure

Clinical trials in HIV-1 infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTIs) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a HIV-1 protease inhibitor. In particular, early virologic failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

5.8 Comprehensive Management to Reduce the Risk of Acquiring HIV-1

Use Tenvir-EM for pre-exposure prophylaxis only as part of a comprehensive prevention strategy that includes other prevention measures, such as safer sex practices, because Tenvir-EM is not always effective in preventing the acquisition of HIV-1 .

  • Counsel uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their HIV-1 status and that of their partner(s), and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis and gonorrhea).
  • Inform uninfected individuals about and support their efforts in reducing sexual risk behavior.

Use Tenvir-EM to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only Tenvir-EM, because Tenvir-EM alone does not constitute a complete treatment regimen for HIV-1 treatment ; therefore, care should be taken to minimize drug exposure in HIV-infected individuals.

  • Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating Tenvir-EM for a PrEP indication, evaluate seronegative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g., fever, fatigue, myalgia, skin rash) and ask about potential exposure events (e.g., unprotected, or condom broke during, sex with an HIV-1 infected partner) that may have occurred within the last month.
    • 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 approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.
  • While using Tenvir-EM for a PrEP indication, HIV-1 screening tests should be repeated at least every 3 months. If symptoms consistent with acute HIV-1 infection develop following a potential exposure event, PrEP should be discontinued until negative infection status is confirmed using a test approved by the FDA as an aid in the diagnosis of HIV-1, including acute or primary HIV-1 infection.

Counsel uninfected individuals to strictly adhere to the recommended Tenvir-EM dosing schedule. The effectiveness of Tenvir-EM in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials .

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6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

  • Severe Acute Exacerbations of Hepatitis B .
  • New Onset or Worsening Renal Impairment .
  • Lactic Acidosis/Severe Hepatomegaly with Steatosis .
  • Bone Effects of Tenofovir DF .
  • Immune Reconstitution Syndrome .
  • In HIV-1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6.1)
  • In HIV-1 uninfected individuals in PrEP trials, adverse reactions that were reported by more than 2% of Tenvir-EM subjects and more frequently than by placebo subjects were headache, abdominal pain, and weight decreased. (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-445-3235 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Subjects

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.

Clinical Trials in Adult Subjects

The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934, an active-controlled clinical trial of efavirenz, Tenvir-EM, and tenofovir DF, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. See also Table 3 for the frequency of treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group in this trial.

Skin discoloration, manifested by hyperpigmentation on the palms and/or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Study 934 Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve subjects received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254) for 144 weeks. Subjects had a mean age of 40 years (range 20 to 73 years) and were predominantly male (88%). Overall, 65% were White, 17% were Black, and 13% were Hispanic. Adverse reactions observed in this trial were generally consistent with those seen in other trials in treatment-experienced or treatment-naïve subjects receiving VIREAD and/or EMTRIVA (Table 3).

FTC+TDF+EFVFrom Weeks 96 to 144 of the trial, subjects received Tenvir-EM with efavirenz in place of VIREAD + EMTRIVA with efavirenz. AZT/3TC+EFV
N=257 N=254
Gastrointestinal Disorder
Diarrhea 9% 5%
Nausea 9% 7%
Vomiting 2% 5%
General Disorders and Administration Site Condition
Fatigue 9% 8%
Infections and Infestations
Sinusitis 8% 4%
Upper respiratory tract infections 8% 5%
Nasopharyngitis 5% 3%
Nervous System Disorders
Headache 6% 5%
Dizziness 8% 7%
Psychiatric Disorders
Depression 9% 7%
Insomnia 5% 7%
Skin and Subcutaneous Tissue Disorders
Rash eventRash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. 7% 9%

In addition to the events described above for Study 934, other adverse reactions that occurred in at least 5% of subjects receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, and rhinitis.

Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of VIREAD and/or EMTRIVA (Table 4).

FTC+TDF+EFVFrom Weeks 96 to 144 of the trial, subjects received Tenvir-EM with efavirenz in place of VIREAD + EMTRIVA with efavirenz. AZT/3TC+EFV
N=257 N=254
Any ≥ Grade 3 Laboratory Abnormality 30% 26%
Fasting Cholesterol (>240 mg/dL) 22% 24%
Creatine Kinase

(M: >990 U/L)

(F: >845 U/L)

9% 7%
Serum Amylase (>175 U/L) 8% 4%
Alkaline Phosphatase (>550 U/L) 1% 0%
AST

(M: >180 U/L)

(F: >170 U/L)

3% 3%
ALT

(M: >215 U/L)

(F: >170 U/L)

2% 3%
Hemoglobin (<8.0 mg/dL) 0% 4%
Hyperglycemia (>250 mg/dL) 2% 1%
Hematuria (>75 RBC/HPF) 3% 2%
Glycosuria (≥3+) <1% 1%
Neutrophils (<750/mm3) 3% 5%
Fasting Triglycerides (>750 mg/dL) 4% 2%

In addition to the laboratory abnormalities described above for Study 934, Grades 3−4 laboratory abnormalities of increased bilirubin (>2.5 × ULN), increased pancreatic amylase (>2.0 × ULN), increased or decreased serum glucose (<40 or >250 mg/dL), and increased serum lipase (>2.0 × ULN) occurred in up to 3% of subjects treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials.

Clinical Trials in Pediatric Subjects

Tenvir-EM: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with EMTRIVA in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, consult the EMTRIVA prescribing information.

Tenofovir DF: In pediatric clinical trials (Studies 352 and 321) conducted in 184 HIV-1 infected subjects 2 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults.

Eighty-nine pediatric subjects (2 to less than 12 years of age) received VIREAD in Study 352 for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score. For additional information, consult the VIREAD prescribing information.

6.2 Adverse Reactions from Clinical Trial Experience in HIV-1 Uninfected Adult Subjects

No new adverse reactions to Tenvir-EM were identified from two randomized placebo-controlled clinical trials, in which 2,830 HIV-1 uninfected adults received Tenvir-EM once daily for pre-exposure prophylaxis. Subjects were followed for a median of 71 weeks and 87 weeks, respectively. These trials enrolled HIV-negative individuals ranging in age from 18 to 67 years. The iPrEx trial enrolled only men or transgender women of Hispanic/Latino (72%), White (18%), Black (9%), and Asian (5%) race. The Partners PrEP trial enrolled both men (61−64% across treatment groups) and women in Kenya and Uganda. Table 5 provides a list of all adverse events that occurred in 2% or more of subjects in any treatment group in the iPrEx and Partners PrEP trials.

Laboratory Abnormalities: Table 6 provides a list of laboratory abnormalities observed in both trials. Six subjects in the TDF-containing arms of the Partners PrEP trial discontinued participation in the study due to an increase in blood creatinine compared with no discontinuations in the placebo group. One subject in the Tenvir-EM arm of the iPrEx trial discontinued from the study due to an increase in blood creatinine and another due to low phosphorous.

In addition to the laboratory abnormalities described above, Grade 1 proteinuria (1+) occurred in 6% of subjects receiving Tenvir-EM in the iPrEx trial. Grades 2−3 proteinuria (2–4+) and glycosuria (3+) occurred in less than 1% of subjects treated with Tenvir-EM in the iPrEx trial and Partners PrEP trial.

iPrEx Trial Partners PrEP Trial
FTC/TDF

(N=1251)

Placebo

(N=1248)

FTC/TDF

(N=1579)

Placebo

(N=1584)

Gastrointestinal Disorders
Diarrhea 7% 8% 2% 3%
Abdominal pain 4% 2% -Not reported or reported below 2%. -
Infections and Infestations
Pharyngitis 13% 16% - -
Urethritis 5% 7% - -
Urinary tract infection 2% 2% 5% 7%
Syphilis 6% 5% - -
Secondary syphilis 6% 4% - -
Anogenital warts 2% 3% - -
Musculoskeletal and Connective Tissue Disorders
Back pain 5% 5% - -
Nervous System Disorders
Headache 7% 6% - -
Psychiatric Disorders
Depression 6% 7% - -
Anxiety 3% 3% - -
Reproductive System and Breast Disorders
Genital ulceration 2% 2% 2% 2%
Investigations
Weight decreased 3% 2% - -
iPrEx Trial Partners PrEP Trial
GradeGrading is per DAIDS criteria. FTC/TDF

(N=1251)

Placebo

(N=1248)

FTC/TDF

(N=1579)

Placebo

(N=1584)

Creatinine 1 (1.1 – 1.3 × ULN) 27 (2%) 21 (2%) 18 (1%) 12 (<1%)
2–4 (>1.4 × ULN) 5 (<1%) 3 (<1%) 2 (<1%) 1 (<1%)
Phosphorus 1 (2.5 – <LLN mg/dL) 81 (7%) 110 (9%) NR Grade 1 phosphorus was not reported for the Partners PrEP trial. NR
2–4 (<2.0 mg/dL) 123 (10%) 101 (8%) 140 (9%) 136 (9%)
AST 1 (1.25 – <2.5 × ULN) 175 (14%) 175 (14%) 20 (1%) 25 (2%)
2–4 (>2.6 × ULN) 57 (5%) 61 (5%) 10 (<1%) 4 (<1%)
ALT 1 (1.25 – <2.5 × ULN) 178 (14%) 194 (16%) 21 (1%) 13 (<1%)
2–4 (>2.6 × ULN) 84 (7%) 82 (7%) 4 (<1%) 6 (<1%)
Hemoglobin 1 (8.5–10 mg/dL) 49 (4%) 62 (5%) 56 (4%) 39 (2%)
2–4 (<9.4 mg/dL) 13 (1%) 19 (2%) 28 (2%) 39 (2%)
Neutrophils 1 (1000 – 1300/mm3) 23 (2%) 25 (2%) 208 (13%) 163 (10%)
2–4 (<750/mm3) 7 (<1%) 7 (<1%) 73 (5%) 56 (3%)

Changes in Bone Mineral Density

In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the iPrEx trial, a substudy of 503 subjects found mean changes from baseline in BMD ranging from –0.4% to –1.0% across total hip, spine, femoral neck, and trochanter in the Tenvir-EM group compared with the placebo group, which returned toward baseline after discontinuation of treatment. Thirteen percent of subjects receiving Tenvir-EM versus 6% of subjects receiving placebo lost at least 5% of BMD at the spine during treatment. Bone fractures were reported in 1.7% of the Tenvir-EM group compared with 1.4% in the placebo group. No correlation between BMD and fractures was noted . The Partners PrEP trial found similar fracture rates between treatment and placebo groups (0.8% and 0.6%, respectively); no BMD evaluations were performed during this trial .

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of VIREAD. No additional adverse reactions have been identified during postapproval use of EMTRIVA. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders

allergic reaction, including angioedema

Metabolism and Nutrition Disorders

lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders

dyspnea

Gastrointestinal Disorders

pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders

hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)

Skin and Subcutaneous Tissue Disorders

rash

Musculoskeletal and Connective Tissue Disorders

rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders

acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions

asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

7 DRUG INTERACTIONS

No drug interaction trials have been conducted using Tenvir-EM tablets. Drug interaction trials have been conducted with Tenvir-EM and tenofovir DF, the components of Tenvir-EM. This section describes clinically relevant drug interactions observed with Tenvir-EM and tenofovir DF .

  • Didanosine: Tenofovir disoproxil fumarate increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when coadministered. Consider dose reductions or discontinuations of didanosine if warranted. (7.1)
  • HIV-1 protease inhibitors: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations. When coadministered with Tenvir-EM, use atazanavir given with ritonavir. Coadministration of Tenvir-EM with atazanavir and ritonavir, darunavir and ritonavir, or lopinavir/ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.2)

7.1 Didanosine

Coadministration of Tenvir-EM and didanosine should be undertaken with caution, and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.

When tenofovir DF was administered with didanosine the Cmax and AUC of didanosine increased significantly . The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.

In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with Tenvir-EM. Data are not available to recommend a dose adjustment of didanosine for adult or pediatric patients weighing less than 60 kg. When coadministered, Tenvir-EM and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat).

7.2 HIV-1 Protease Inhibitors

Tenofovir decreases the AUC and Cmin of atazanavir . When coadministered with Tenvir-EM, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Tenvir-EM should not be coadministered with atazanavir without ritonavir.

Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations . Tenofovir DF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When tenofovir DF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving Tenvir-EM concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for tenofovir DF-associated adverse reactions. Tenvir-EM should be discontinued in patients who develop tenofovir DF-associated adverse reactions.

7.3 Hepatitis C Antiviral Agents

Coadministration of Tenvir-EM and EPCLUSA® (sofosbuvir/velpatasvir) or HARVONI® (ledipasvir/sofosbuvir has been shown to increase tenofovir exposure .

In patients receiving Tenvir-EM concomitantly with EPCLUSA, monitor for adverse reactions associated with tenofovir DF.

In patients receiving Tenvir-EM concomitantly with HARVONI without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir DF.

In patients receiving Tenvir-EM concomitantly with HARVONI and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with tenofovir DF.

7.4 Drugs Affecting Renal Function

Tenvir-EM and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion . No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of Tenvir-EM with drugs that are eliminated by active tubular secretion may increase concentrations of Tenvir-EM, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs . Drugs that decrease renal function may increase concentrations of Tenvir-EM and/or tenofovir.

8 USE IN SPECIFIC POPULATIONS

Nursing mothers: Women infected with HIV-1 should be instructed not to breastfeed.

8.1 Pregnancy

Pregnancy Category B

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

Risk Summary

Tenvir-EM has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that Tenvir-EM does not increase the risk of major birth defects overall compared to the background rate. There are, however, no adequate and well-controlled trials in pregnant women. Because the studies in humans cannot rule out the possibility of harm, Tenvir-EM should be used during pregnancy only if clearly needed. If an uninfected individual becomes pregnant while taking Tenvir-EM for a PrEP indication, careful consideration should be given to whether use of Tenvir-EM should be continued, taking into account the potential increased risk of HIV-1 infection during pregnancy.

Clinical Considerations

As of July 2011, the APR has received prospective reports of 764 and 1219 exposures to emtricitabine- and tenofovir-containing regimens, respectively, in the first trimester; 321 and 455 exposures, respectively, in second trimester; and 140 and 257 exposures, respectively, in the third trimester. Birth defects occurred in 18 of 764 (2.4%) live births for emtricitabine-containing regimens and 27 of 1219 (2.2%) live births for tenofovir-containing regimens (first trimester exposure); and 10 of 461 (2.2%) live births for emtricitabine-containing regimens and 15 of 714 (2.1%) live births for tenofovir-containing regimens (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between Tenvir-EM or tenofovir and overall birth defects observed in the APR.

Animal Data

Tenvir-EM

The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with Tenvir-EM in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose.

Tenofovir DF

Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

8.3 Nursing Mothers

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.

Studies in humans have shown that both tenofovir and Tenvir-EM are excreted in human milk. Because the risks of low-level exposure to Tenvir-EM and tenofovir to infants are unknown, mothers should be instructed not to breastfeed if they are receiving Tenvir-EM, whether they are taking Tenvir-EM for treatment or to reduce the risk of acquiring HIV-1.

Tenvir-EM

Samples of breast milk obtained from five HIV-1 infected mothers show that Tenvir-EM is secreted in human milk. Breastfeeding infants whose mothers are being treated with Tenvir-EM may be at risk for developing viral resistance to Tenvir-EM. Other emtricitabine-associated risks in infants breastfed by mothers being treated with Tenvir-EM are unknown.

Tenofovir DF

Samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk. Tenofovir-associated risks, including the risk of viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir DF are unknown.

8.4 Pediatric Use

No pediatric clinical trial was conducted to evaluate the safety and efficacy of Tenvir-EM. Data from previously conducted trials with the individual drug products, EMTRIVA and VIREAD, were relied upon to support dosing recommendations for Tenvir-EM. For additional information, consult the prescribing information for EMTRIVA and VIREAD.

Tenvir-EM should only be administered to HIV-1 infected pediatric patients with body weight greater than or equal to 17 kg and who are able to swallow a whole tablet. Because it is a fixed-dose combination tablet, Tenvir-EM cannot be adjusted for patients of lower weight . Tenvir-EM has not been evaluated for use in pediatric patients weighing less than 17 kg.

8.5 Geriatric Use

Clinical trials of EMTRIVA or VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the 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.

8.6 Patients with Impaired Renal Function

Treatment of HIV-1 Infection

The dosing interval for Tenvir-EM should be modified in HIV-infected adult patients with estimated creatinine clearance of 30–49 mL/min. Tenvir-EM should not be used in patients with estimated creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis .

Pre-exposure Prophylaxis

Tenvir-EM for a PrEP indication should not be used in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using Tenvir-EM for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use .

10 OVERDOSAGE

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Tenvir-EM: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology trial, single doses of Tenvir-EM 1200 mg were administered to 11 subjects. No severe adverse reactions were reported.

Hemodialysis treatment removes approximately 30% of the Tenvir-EM dose over a 3-hour dialysis period starting within 1.5 hours of Tenvir-EM dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether Tenvir-EM can be removed by peritoneal dialysis.

Tenofovir DF: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one trial, 600 mg tenofovir DF was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

Tenvir-EM tablets are fixed-dose combination tablets containing Tenvir-EM and tenofovir DF. Tenvir-EM is a synthetic nucleoside analog of cytidine. Tenofovir DF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Both Tenvir-EM and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.

Tenvir-EM: The chemical name of Tenvir-EM is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Tenvir-EM is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:

Tenvir-EM is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C. The partition coefficient (log p) for Tenvir-EM is −0.43 and the pKa is 2.65.

Chemical Structure

Tenofovir DF: Tenofovir DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir DF is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P ∙ C4H4O4 and a molecular weight of 635.52. It has the following structural formula:

Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of tenofovir DF except where otherwise noted.

Tenvir-EM tablets are for oral administration, and are available in the following strengths:

  • Film-coated tablet containing 200 mg of Tenvir-EM and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients
  • Film-coated tablet containing 167 mg of Tenvir-EM and 250 mg of tenofovir DF (which is equivalent to 204 mg of tenofovir disoproxil) as active ingredients
  • Film-coated tablet containing 133 mg of Tenvir-EM and 200 mg of tenofovir DF (which is equivalent to 163 mg of tenofovir disoproxil) as active ingredients
  • Film-coated tablet containing 100 mg of Tenvir-EM and 150 mg of tenofovir DF (which is equivalent to 123 mg of tenofovir disoproxil) as active ingredients

All strengths of Tenvir-EM tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The 200 mg/300 mg strength tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. The 167 mg/250 mg, 133 mg/200 mg, and 100 mg/150 mg strength tablets are coated with Opadry II Blue, which contains FD&C Blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.

Chemical Structure

12 CLINICAL PHARMACOLOGY

For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, consult the EMTRIVA and VIREAD prescribing information.

12.1 Mechanism of Action

Tenvir-EM is a fixed-dose combination of antiviral drugs Tenvir-EM and tenofovir DF .

12.3 Pharmacokinetics

Tenvir-EM: One Tenvir-EM tablet was bioequivalent to one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).

Tenvir-EM: The pharmacokinetic properties of Tenvir-EM are summarized in Table 7. Following oral administration of EMTRIVA, Tenvir-EM is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours postdose. Less than 4% of Tenvir-EM binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02–200 μg/mL. Following administration of radiolabelled Tenvir-EM, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of Tenvir-EM include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Tenvir-EM is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma Tenvir-EM half-life is approximately 10 hours.

Tenofovir DF: The pharmacokinetic properties of tenofovir DF are summarized in Table 7. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01–25 µg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours.

Tenvir-EM Tenofovir
Fasted Oral BioavailabilityMedian (range) (%) 92 (83.1–106.4) 25 (NC–45.0)
Plasma Terminal Elimination Half-Life (hr) 10 (7.4–18.0) 17 (12.0–25.7)
Cmax Mean (± SD) (μg/mL) 1.8±0.72Data presented as steady state values 0.30±0.09
AUC (μghr/mL) 10.0±3.12 2.29±0.69
CL/F (mL/min) 302±94 1043±115
CLrenal (mL/min) 213±89 243±33

Effects of Food on Oral Absorption

Tenvir-EM may be administered with or without food. Administration of Tenvir-EM following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, VIREAD (tenofovir) was taken under fed conditions. Tenvir-EM systemic exposures (AUC and Cmax) were unaffected when Tenvir-EM was administered with either a high fat or a light meal.

Specific Populations

Race

Tenvir-EM: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.

Tenofovir DF: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.

Gender

Tenvir-EM and Tenofovir DF: Tenvir-EM and tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients

The pharmacokinetic data for tenofovir and Tenvir-EM following administration of Tenvir-EM in pediatric subjects weighing 17 kg and above are not available. The dosing recommendations of Tenvir-EM in this population are based on the dosing recommendations of EMTRIVA and VIREAD in this population. Refer to the EMTRIVA and VIREAD prescribing information for pharmacokinetic information on the individual products in pediatric patients.

Tenvir-EM should not be administered to HIV-1 infected pediatric patients weighing less than 17 kg.

Geriatric Patients

Pharmacokinetics of Tenvir-EM and tenofovir have not been fully evaluated in the elderly (65 years of age and older).

Patients with Impaired Renal Function

The pharmacokinetics of Tenvir-EM and tenofovir are altered in subjects with renal impairment . In adult subjects with creatinine clearance below 50 mL/min, Cmax, and AUC0–∞ of Tenvir-EM and tenofovir were increased. It is recommended that the dosing interval for Tenvir-EM be modified in HIV-infected adult patients with estimated creatinine clearance 30–49 mL/min. No data are available to make dose recommendations in pediatric patients with renal impairment. Tenvir-EM should not be used in patients with estimated creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis .

Tenvir-EM for a PrEP indication should not be used in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using Tenvir-EM for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use .

Patients with Hepatic Impairment

The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of Tenvir-EM or Tenvir-EM have not been studied in subjects with hepatic impairment; however, Tenvir-EM is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Assessment of Drug Interactions

The steady state pharmacokinetics of Tenvir-EM and tenofovir were unaffected when Tenvir-EM and tenofovir DF were administered together versus each agent dosed alone.

In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving Tenvir-EM and tenofovir with other medicinal products is low.

No clinically significant drug interactions have been observed between Tenvir-EM and famciclovir, indinavir, stavudine, tenofovir DF, and zidovudine (Tables 8 and 9). Similarly, no clinically significant drug interactions have been observed between tenofovir DF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir in trials conducted in healthy volunteers (Tables 10 and 11).

Coadministered Drug Dose of Coadministered Drug (mg) Tenvir-EM Dose (mg) N % Change of Tenvir-EM Pharmacokinetic Parameters↑ = Increase; ⇔ = No Effect; NA = Not Applicable (90% CI)
Cmax AUC Cmin
Tenofovir DF 300 once daily × 7 days 200 once daily × 7 days 17 ↑ 20

(↑ 12 to ↑ 29)

Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27
Indinavir 800 × 1 200 × 1 12 NA
Famciclovir 500 × 1 200 × 1 12 NA
Stavudine 40 × 1 200 × 1 6 NA
Coadministered Drug Dose of Coadministered Drug (mg) Tenvir-EM Dose (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters↑ = Increase; ⇔ = No Effect; NA = Not Applicable (90% CI)
Cmax AUC Cmin
Tenofovir DF 300 once daily × 7 days 200 once daily × 7 days 17
Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27 ↑ 17

(↑ 0 to ↑ 38)

↑ 13

(↑ 5 to ↑ 20)

Indinavir 800 × 1 200 × 1 12 NA
Famciclovir 500 × 1 200 × 1 12 NA
Stavudine 40 × 1 200 × 1 6 NA
Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ⇔

(90% CI)

Cmax AUC Cmin
AtazanavirReyataz Prescribing Information. 400 once daily

× 14 days

33 ↑ 14

(↑ 8 to ↑ 20)

↑ 24

(↑ 21 to ↑ 28)

↑ 22

(↑ 15 to ↑ 30)

Atazanavir/ Ritonavir 300/100 once daily 12 ↑ 34

(↑ 20 to ↑ 51)

↑ 37

(↑ 30 to ↑ 45)

↑ 29

(↑ 21 to ↑ 36)

Darunavir/ RitonavirPrezista Prescribing Information. 300/100 twice daily 12 ↑ 24

(↑ 8 to ↑ 42)

↑ 22

(↑ 10 to ↑ 35)

↑ 37

(↑ 19 to ↑ 57)

Indinavir 800 three times daily × 7 days 13 ↑ 14

(↓ 3 to ↑ 33)

Ledipasvir/ SofosbuvirData generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provided similar results. , Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir DF. 90/400 once daily × 10 days 24 ↑ 47

(↑ 37 to ↑ 58)

↑ 35

(↑ 29 to ↑42 )

↑ 47

(↑ 38 to ↑ 57)

Ledipasvir/ Sofosbuvir , Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir DF. 23 ↑ 64

(↑ 54 to ↑ 74)

↑ 50

(↑ 42 to ↑ 59)

↑ 59

(↑ 49 to ↑ 70)

Ledipasvir/ SofosbuvirStudy conducted with ATRIPLA (efavirenz/emtricitabine/tenofovir DF) coadministered with HARVONI. 90/400 once daily × 14 days 15 ↑ 79

(↑ 56 to ↑ 104)

↑ 98

(↑ 77 to ↑ 123)

↑ 163

(↑ 132 to ↑ 197)

Ledipasvir/ SofosbuvirStudy conducted with COMPLERA (emtricitabine/rilpivirine/tenofovir DF) coadministered with HARVONI. 90/400 once daily × 10 days 14 ↑ 32

(↑ 25 to ↑ 39 )

↑ 40

(↑ 31 to ↑ 50 )

↑ 91

(↑ 74 to ↑ 110)

Ledipasvir/ SofosbuvirStudy conducted with Tenvir-EM (emtricitabine/tenofovir DF) + dolutegravir coadministered with HARVONI. 90/400 once daily × 10 days 29 ↑ 61

(↑ 51 to ↑ 72)

↑ 65

(↑ 59 to ↑ 71)

↑ 115

(↑ 105 to ↑ 126)

Lopinavir/ Ritonavir 400/100 twice daily × 14 days 24 ↑ 32

(↑ 25 to ↑ 38)

↑ 51

(↑ 37 to ↑ 66)

Saquinavir/ Ritonavir 1000/100 twice daily × 14 days 35 ↑ 23

(↑ 16 to ↑ 30)

SofosbuvirStudy conducted with ATRIPLA coadministered with SOVALDI® (sofosbuvir). 400 single dose 16 ↑ 25

(↑ 8 to ↑ 45)

Sofosbuvir/ VelpatasvirComparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir DF. 400/100 once daily 24 ↑ 55

(↑ 43 to ↑ 68)

↑ 30

(↑ 24 to ↑ 36)

↑ 39

(↑ 31 to ↑ 48)

Sofosbuvir/ VelpatasvirComparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir DF. 400/100 once daily 29 ↑ 55

(↑ 45 to ↑ 66)

↑ 39

(↑ 33 to ↑ 44)

↑ 52

(↑ 45 to ↑ 59)

Sofosbuvir/ VelpatasvirStudy conducted with ATRIPLA coadministered with EPCLUSA (sofosbuvir/velpatasvir). 400/100 once daily 15 ↑ 77

(↑ 53 to ↑ 104)

↑ 81

(↑ 68 to ↑ 94)

↑ 121

(↑ 100 to ↑ 143)

Sofosbuvir/ VelpatasvirStudy conducted with STRIBILD (elvitegravir/cobicistat/emtricitabine/tenofovir DF) coadministered with EPCLUSA. 400/100 once daily 24 ↑ 36

(↑ 25 to ↑ 47)

↑ 35

(↑ 29 to ↑ 42)

↑ 45

(↑ 39 to ↑ 51)

Sofosbuvir/ VelpatasvirStudy conducted with COMPLERA coadministered with EPCLUSA. 400/100 once daily 24 ↑ 44

(↑ 33 to ↑ 55)

↑ 40

(↑ 34 to ↑ 46)

↑ 84

(↑ 76 to ↑ 92)

Sofosbuvir/ VelpatasvirAdministered as raltegravir + emtricitabine/tenofovir DF. 400/100 once daily 30 ↑ 46

(↑ 39 to ↑ 54)

↑ 40

(↑ 34 to ↑ 45)

↑ 70

(↑ 61 to ↑ 79)

Tacrolimus 0.05 mg/kg twice daily × 7 days 21 ↑ 13

(↑ 1 to ↑ 27)

Tipranavir/RitonavirAptivus Prescribing Information. 500/100 twice daily 22 ↓ 23

(↓ 32 to ↓ 13)

↓ 2

(↓ 9 to ↑ 5)

↑ 7

(↓ 2 to ↑ 17)

750/200 twice daily (23 doses) 20 ↓ 38

(↓ 46 to ↓ 29)

↑ 2

(↓ 6 to ↑ 10)

↑ 14

(↑ 1 to ↑ 27)


No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with Tenvir-EM: abacavir, didanosine (buffered tablets), Tenvir-EM, entecavir, and lamivudine.

Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ⇔; NA = Not Applicable

(90% CI)

Cmax AUC Cmin
Abacavir 300 once 8 ↑ 12

(↓ 1 to ↑ 26)

NA
AtazanavirReyataz Prescribing Information. 400 once daily × 14 days 34 ↓ 21

(↓ 27 to ↓ 14)

↓ 25

(↓ 30 to ↓ 19)

↓ 40

(↓ 48 to ↓ 32)

Atazanavir Atazanavir/Ritonavir

300/100 once daily × 42 days

10 ↓ 28

(↓ 50 to ↑ 5)

↓ 25In HIV-infected subjects, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.

(↓ 42 to ↓ 3)

↓ 23

(↓ 46 to ↑ 10)

DarunavirPrezista Prescribing Information. Darunavir/Ritonavir 300/100 once daily 12 ↑ 16

(↓ 6 to ↑ 42)

↑ 21

(↓ 5 to ↑ 54)

↑ 24

(↓ 10 to ↑ 69)

DidanosineVidex EC Prescribing Information. Subjects received didanosine enteric-coated capsules. 250 once, simultaneously with tenofovir DF and a light meal373 kcal, 8.2 g fat 33 ↓ 20Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions.

(↓ 32 to ↓ 7)

NA
Tenvir-EM 200 once daily × 7 days 17 ↑ 20

(↑ 12 to ↑ 29)

Indinavir 800 three times daily × 7 days 12 ↓ 11

(↓ 30 to ↑ 12)

Entecavir 1 once daily × 10 days 28 ↑ 13

(↑ 11 to ↑ 15)

Lamivudine 150 twice daily × 7 days 15 ↓ 24

(↓ 34 to ↓ 12)

Lopinavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24
Ritonavir
Saquinavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22

(↑ 6 to ↑41)

↑ 29Increases in AUC and Cmin are not expected to be clinically relevant; hence, no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered.

(↑ 12 to ↑ 48)

↑ 47

(↑ 23 to ↑ 76)

Ritonavir ↑ 23

(↑ 3 to ↑ 46)

Tacrolimus 0.05 mg/kg twice daily × 7 days 21
TipranavirAptivus Prescribing Information. Tipranavir/Ritonavir 500/100 twice daily 22 ↓ 17

(↓ 26 to ↓ 6)

↓ 18

(↓ 25 to ↓ 9)

↓ 21

(↓ 30 to ↓ 10)

Tipranavir/Ritonavir 750/200 twice daily (23 doses) 20 ↓ 11

(↓ 16 to ↓ 4)

↓ 9

(↓ 15 to ↓ 3)

↓ 12

(↓ 22 to 0)


Coadministration of tenofovir DF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of tenofovir DF with didanosine enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown. See Drug Interactions (7.1) regarding use of didanosine with VIREAD.

12.4 Microbiology

Mechanism of Action

Tenvir-EM: Tenvir-EM, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form Tenvir-EM 5'-triphosphate. Tenvir-EM 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Tenvir-EM 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε and mitochondrial DNA polymerase γ.

Tenofovir DF: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β and mitochondrial DNA polymerase γ.

Antiviral Activity

Tenvir-EM and Tenofovir DF: No antagonism was observed in combination studies evaluating the cell culture antiviral activity of Tenvir-EM and tenofovir together.

Tenvir-EM: The antiviral activity of Tenvir-EM against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for Tenvir-EM were in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of Tenvir-EM with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonism was observed. Tenvir-EM displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain-specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM).

Tenofovir DF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells, and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 µM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonism was observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–2.2 µM) and showed strain-specific activity against HIV-2 (EC50 values ranged from 1.6 µM to 5.5 µM).

Prophylactic Activity in a Nonhuman Primate Model of HIV Transmission

Tenvir-EM and Tenofovir DF: The prophylactic activity of the combination of daily oral Tenvir-EM (FTC) and tenofovir disoproxil fumarate (TDF) was evaluated in a controlled study of macaques inoculated once weekly for 14 weeks with SIV/HIV-1 chimeric virus (SHIV) applied to the rectal surface. Of the 18 control animals, 17 became infected after a median of 2 weeks. In contrast, 4 of the 6 animals treated daily with oral FTC and TDF remained uninfected and the two infections that did occur were significantly delayed until 9 and 12 weeks and exhibited reduced viremia. An M184I-expressing FTC-resistant variant emerged in 1 of the 2 macaques after 3 weeks of continued drug exposure.

Resistance

Tenvir-EM and Tenofovir DF: HIV-1 isolates with reduced susceptibility to the combination of Tenvir-EM and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in reduced susceptibility to tenofovir.

In a clinical trial of treatment-naïve subjects [Study 934, see Clinical Studies (14.1)], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subject isolates in the EMTRIVA + VIREAD group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R or K70E substitution in their HIV-1 as analyzed through standard genotypic analysis.

Tenvir-EM: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to Tenvir-EM was associated with a substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

Tenofovir DF: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2–4 fold reduction in susceptibility to tenofovir.

In treatment-naïve subjects, isolates from 8/47 (17%) analyzed subjects developed the K65R substitution in the VIREAD arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced subjects, 14/304 (5%) isolates from subjects failing VIREAD through Week 96 showed greater than 1.4-fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a K65R amino acid substitution in the HIV-1 RT.

iPrEx Trial: In a clinical study of HIV-1 seronegative subjects [iPrEx Trial, see Clinical Studies (14.2)], no amino acid substitutions associated with resistance to Tenvir-EM or tenofovir were detected at the time of seroconversion among 48 subjects in the Tenvir-EM group and 83 subjects in the placebo group who became infected with HIV-1 during the trial. Ten subjects were observed to be HIV-1 infected at time of enrollment. The M184V/I substitutions associated with resistance to Tenvir-EM were observed in 3 of the 10 subjects (2 of 2 in the Tenvir-EM group and 1 of 8 in the placebo group). One of the two subjects in the Tenvir-EM group harbored wild type virus at enrollment and developed the M184V substitution 4 weeks after enrollment. The other subject had indeterminate resistance at enrollment but was found to have the M184I substitution 4 weeks after enrollment.

Partners PrEP Trial: In a clinical study of HIV-1 seronegative subjects [Partners PrEP Trial, See Clinical Studies (14.3)], no variants expressing amino acid substitutions associated with resistance to Tenvir-EM or tenofovir were detected at the time of seroconversion among 12 subjects in the Tenvir-EM group, 15 subjects in the VIREAD group, and 51 subjects in the placebo group. Fourteen subjects were observed to be HIV-1 infected at the time of enrollment (3 in the Tenvir-EM group, 5 in the VIREAD group, and 6 in the placebo group). One of the three subjects in the Tenvir-EM group who was infected with wild type virus at enrollment selected an M184V expressing virus by Week 12. Two of the five subjects in the VIREAD group had tenofovir-resistant viruses at the time of seroconversion; one subject infected with wild type virus at enrollment developed a K65R substitution by Week 16, while the second subject had virus expressing the combination of D67N and K70R substitutions upon seroconversion at Week 60, although baseline virus was not genotyped and it is unclear if the resistance emerged or was transmitted. Following enrollment, 4 subjects (2 in the VIREAD group, 1 in the Tenvir-EM group, and 1 in the placebo group) had virus expressing K103N or V106A substitutions, which confer high-level resistance to NNRTIs but have not been associated with tenofovir or Tenvir-EM and may have been present in the infecting virus.

Cross Resistance

Tenvir-EM and Tenofovir DF: Cross-resistance among certain NRTIs has been recognized. The M184V/I and/or K65R substitutions selected in cell culture by the combination of Tenvir-EM and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either Tenvir-EM or lamivudine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.

Tenvir-EM: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibility in cell culture to the NRTIs didanosine, stavudine, tenofovir, and zidovudine, and to NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by Tenvir-EM. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to Tenvir-EM. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to Tenvir-EM.

Tenofovir DF: The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R and K70E substitutions also showed reduced susceptibility to Tenvir-EM and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R or K70E substitutions. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Tenvir-EM: In long-term oral carcinogenicity studies of Tenvir-EM, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose).

Tenvir-EM was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays.

Tenvir-EM did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.

Tenofovir DF: Long-term oral carcinogenicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir DF was negative when administered to male mice.

There were no effects on fertility, mating performance, or early embryonic development when tenofovir DF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats.

13.2 Animal Toxicology and/or Pharmacology

Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in four animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

14 CLINICAL STUDIES

Clinical Study 934 supports the use of Tenvir-EM tablets for the treatment of HIV-1 infection. Additional data in support of the use of Tenvir-EM are derived from clinical Study 903, in which lamivudine and tenofovir DF were used in combination in treatment-naïve adults, and clinical Study 303 in which Tenvir-EM and lamivudine demonstrated comparable efficacy, safety, and resistance patterns as part of multidrug regimens. For additional information about these trials, consult the prescribing information for tenofovir DF and Tenvir-EM. The iPrEx study and Partners PrEP study support the use of Tenvir-EM to help reduce the risk of acquiring HIV-1.

14.1 Study 934

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing Tenvir-EM + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received Tenvir-EM with efavirenz in place of Tenvir-EM + tenofovir DF with efavirenz. Subjects had a mean age of 38 years ; 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 12.

Outcomes At Week 48 At Week 144
FTC+TDF +EFV

(N=244)

AZT/3TC+EFV

(N=243)

FTC+TDF+EFV

(N=227)Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue trial after Week 48 or Week 96 were excluded from analysis.

AZT/3TC+EFV

(N=229)

ResponderSubjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144. 84% 73% 71% 58%
Virologic failureIncludes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144. 2% 4% 3% 6%
Rebound 1% 3% 2% 5%
Never suppressed 0% 0% 0% 0%
Change in antiretroviral regimen 1% 1% 1% 1%
Death <1% 1% 1% 1%
Discontinued due to adverse event 4% 9% 5% 12%
Discontinued for other reasonsIncludes lost to follow-up, subject withdrawal, noncompliance, protocol violation, and other reasons. 10% 14% 20% 22%

Through Week 48, 84% and 73% of subjects in the Tenvir-EM + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the Tenvir-EM + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the Tenvir-EM + tenofovir DF group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 subjects in the Tenvir-EM + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

14.2 iPrEx Trial

The iPrEx trial was a randomized, double-blind, placebo-controlled multinational study evaluating Tenvir-EM in 2,499 HIV-seronegative men or transgender women who have sex with men and with evidence of high-risk behavior for HIV-1 infection. Evidence of high-risk behavior included any one of the following reported to have occurred up to six months prior to study screening: no condom use during anal intercourse with an HIV-1 positive partner or a partner of unknown HIV status; anal intercourse with more than 3 sex partners; exchange of money, gifts, shelter, or drugs for anal sex; sex with male partner and diagnosis of sexually transmitted infection; no consistent use of condoms with sex partner known to be HIV-1 positive.

All subjects received monthly HIV-1 testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. Of the 2499 enrolled, 1251 received Tenvir-EM and 1248 received placebo. The mean age of subjects was 27 years; 5% were Asian, 9% Black, 18% White, and 72% Hispanic/Latino.

Subjects were followed for 4,237 person-years. The primary outcome measure for the study was the incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1 seroconversion was observed in 131 subjects, of which 48 occurred in the Tenvir-EM group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18–60%) reduction in risk. Risk reduction was found to be higher (53%; 95% CI: 34–72%) among subjects who reported previous unprotected anal intercourse (URAI) at screening (732 and 753 subjects reported URAI within the last 12 weeks at screening in the Tenvir-EM and placebo groups, respectively). In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable intracellular tenofovir. Efficacy was therefore strongly correlated with adherence.

14.3 Partners PrEP Trial

The Partners PrEP trial was a randomized, double-blind, placebo-controlled 3-arm trial conducted in 4,758 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of TDF (N=1589) and FTC/TDF (N=1583) versus (parallel comparison) placebo (N=1586) in preventing HIV-1 acquisition by the uninfected partner.

All subjects received monthly HIV-1 testing, evaluation of adherence, assessment of sexual behavior, and safety evaluations. Women were also tested monthly for pregnancy. Women who became pregnant during the trial had study drug interrupted for the duration of the pregnancy and while breastfeeding. The uninfected partner subjects were predominantly male (61–64% across study drug groups) and had a mean age of 33–34 years.

Following 7,827 person-years of follow up, 82 emergent HIV-1 seroconversions were reported, with an overall observed seroincidence rate of 1.05 per 100 person-years. Of the 82 seroconversions, 13 and 52 occurred in partner subjects randomized to Tenvir-EM and placebo, respectively. Two of the 13 seroconversions in the Tenvir-EM arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. The risk reduction for Tenvir-EM relative to placebo was 75% (95% CI: 55–87%). In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable plasma tenofovir. Efficacy was therefore strongly correlated with adherence.

16 HOW SUPPLIED/STORAGE AND HANDLING

Tenvir-EM tablets are available in bottles containing 30 tablets with child-resistant closure as follows:

  • 100 mg of Tenvir-EM and 150 mg of tenofovir DF (equivalent to 123 mg of tenofovir disoproxil) tablets are blue, oval shaped, film coated, debossed with "GSI" on one side and "703" on the other side (NDC 61958-0703-1).
  • 133 mg of Tenvir-EM and 200 mg of tenofovir DF (equivalent to 163 mg of tenofovir disoproxil) are blue, rectangular shaped, film coated, debossed with "GSI" on one side and "704" on the other side (NDC 61958-0704-1).
  • 167 mg of Tenvir-EM and 250 mg of tenofovir DF (equivalent to 204 mg of tenofovir disoproxil) are blue, modified capsule shaped, film coated, debossed with "GSI" on one side and "705" on the other side (NDC 61958-0705-1).
  • 200 mg of Tenvir-EM and 300 mg of tenofovir DF (equivalent to 245 mg of tenofovir disoproxil) are blue, capsule shaped, film coated, debossed with "GILEAD" on one side and "701" on the other side (NDC 61958-0701-1).

Store at 25 °C (77 °F), excursions permitted to 15 °C–30 °C (59 °F–86 °F).

  • Keep container tightly closed
  • Dispense only in original container
  • Do not use if seal over bottle opening is broken or missing

17 PATIENT COUNSELING INFORMATION

As a part of patient counseling, healthcare providers must review the Tenvir-EM Medication Guide with every uninfected individual taking Tenvir-EM to reduce the risk of acquiring HIV.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Important Information for All Patients and Uninfected Individuals

Advise patients and uninfected individuals that:

  • The long-term effects of Tenvir-EM are unknown.
  • Tenvir-EM tablets are for oral ingestion only.
  • Patients and uninfected individuals should not discontinue Tenvir-EM without first informing their physicians.
  • Patients and uninfected individuals should remain under the care of a physician when using Tenvir-EM.
  • It is important to take Tenvir-EM on a regular dosing schedule to avoid missing doses.

Advise patients and uninfected individuals to avoid doing things that can spread HIV-1 or HBV infection :

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Nursing Mothers

Patients and uninfected individuals should not breastfeed because the drugs in Tenvir-EM can be passed to the baby in breast milk, and it is not known whether they can harm the baby. HIV-positive women should also not breastfeed because of the risk of passing the HIV-1 virus to the baby.

Patients Coinfected with HIV-1 and HBV

Inform patients that severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV-1 and have discontinued Tenvir-EM. Patients should not discontinue Tenvir-EM without first informing their healthcare provider. All patients who are infected with HBV need close medical follow-up for several months after stopping Tenvir-EM to monitor for exacerbations of hepatitis .

New Onset or Worsening Renal Impairment

Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of VIREAD. Tenvir-EM should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) . Dosing interval of Tenvir-EM may need adjustment in HIV-1 infected patients with renal impairment. Tenvir-EM for a PrEP indication should not be used in HIV-1 uninfected individuals if estimated creatinine clearance is less than 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using Tenvir-EM for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use .

Lactic Acidosis and Severe Hepatomegaly

Inform patients and uninfected individuals that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with Tenvir-EM should be suspended in any patient or uninfected individual who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity .

Drug Interactions

Inform patients that:

  • Tenvir-EM should not be coadministered with ATRIPLA, COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, or VIREAD; or with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Dutrebis (lamivudine/raltegravir), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), Triumeq (abacavir sulfate/dolutegravir/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine) .
  • Tenvir-EM should not be coadministered with HEPSERA .

Bone Effects

Inform patients that decreases in bone mineral density have been observed with the use of VIREAD or Tenvir-EM. Consider bone monitoring in patients and uninfected individuals who have a history of pathologic bone fracture or at risk for osteopenia .

Immune Reconstitution Syndrome

In some patients treated with combination antiretroviral therapy, including Tenvir-EM, 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 .

Treatment of HIV-1 Infection

When Tenvir-EM is used in the treatment of HIV-infection, advise patients that:

  • Tenvir-EM is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.
  • It is important to take Tenvir-EM in a regular dosing schedule with combination therapy to avoid missing doses.
  • All patients with HIV-1 should be tested for hepatitis B virus (HBV) before initiating and monitored after discontinuing taking Tenvir-EM.

Pre-Exposure Prophylaxis

When Tenvir-EM is used to reduce the risk of acquiring HIV-1, advise uninfected individuals about the importance of the following:

  • Confirming that they are HIV-negative before starting to take Tenvir-EM to reduce the risk of acquiring HIV-1.
  • Tenvir-EM should only be used as part of a complete prevention strategy including other prevention measures. In clinical trials, Tenvir-EM only protected some subjects from acquiring HIV-1.
  • Using condoms consistently and correctly to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.
  • Knowing their HIV status and the status of their partner(s).
  • Getting tested regularly (at least every 3 months) for HIV-1 and ask their partner(s) to get tested as well.
  • HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking Tenvir-EM, because Tenvir-EM alone does not constitute a complete regimen for HIV-1 treatment
  • Reporting any symptoms of acute HIV-1 infection (flu-like symptoms) to their healthcare provider immediately.
  • Signs and symptoms of acute infection include: fever, headache, fatigue, arthralgia, vomiting, myalgia, diarrhea, pharyngitis, rash, night sweats, and adenopathy (cervical and inguinal).
  • Getting tested for other sexually transmitted infections such as syphilis and gonorrhea that may facilitate HIV-1 transmission.
  • Learning about sexual risk behavior and getting support to help reduce sexual risk behavior.
  • Taking Tenvir-EM on a regular dosing schedule and strictly adhering to the recommended dosing schedule to reduce the risk of acquiring HIV-1. Uninfected individuals who miss doses are at greater risk of acquiring HIV-1 than those who do not miss doses.

Women who are pregnant should learn about the risks and benefits of Tenvir-EM to reduce the risk of acquiring HIV-1 during their pregnancy.

Encourage use of the Agreement Form for Initiating Tenvir-EM for PrEP of Sexually Acquired HIV-1 Infection.

COMPLERA, DESCOVY, EMTRIVA, EPCLUSA, GENVOYA, HARVONI, HEPSERA, ODEFSEY, SOVALDI, STRIBILD, Tenvir-EM, VEMLIDY, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.

© 2017 Gilead Sciences, Inc. All rights reserved.

Manufactured for and distributed by:

Gilead Sciences, Inc.

Foster City, CA 94404

21752-GS-031

This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: April 2017
Medication Guide

Tenvir-EM® (tru-VAH-dah)

(emtricitabine and tenofovir disoproxil fumarate)

tablets


Read this Medication Guide before you start taking Tenvir-EM and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

This Medication Guide provides information about two different ways that Tenvir-EM may be used (see the Medication Guide section "What is Tenvir-EM?" for important information about how Tenvir-EM may be used):

  • to treat Human Immunodeficiency Virus-1 (HIV-1) infection, and
  • to reduce the risk of getting HIV-1 infection in adults who are HIV-negative

HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

What is the most important information I should know about Tenvir-EM?

If you also have hepatitis B virus (HBV) infection and take Tenvir-EM, your hepatitis B may become worse if you stop taking Tenvir-EM.

  • Do not stop taking Tenvir-EM without first talking to your healthcare provider.
  • Do not run out of Tenvir-EM. Refill your prescription or talk to your healthcare provider before your Tenvir-EM is all gone.
  • If your healthcare provider stops Tenvir-EM, your healthcare provider will need to watch you closely for several months to check your hepatitis B infection, or give you a medication to treat hepatitis B.

Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking Tenvir-EM.

For more information about side effects, see the section "What are the possible side effects of Tenvir-EM?" in this Medication Guide.

Other important information for people who take Tenvir-EM to help reduce their risk of getting HIV-1 infection:

Before taking Tenvir-EM to reduce your risk of getting HIV-1 infection:

  • You must be HIV-negative to start Tenvir-EM. You must get tested to make sure that you do not already have HIV-1 infection.
  • Do not take Tenvir-EM to reduce the risk of getting HIV-1 unless you are confirmed to be HIV-negative.
  • Many HIV-1 tests can miss HIV-1 infection in a person who has recently become infected. If you have flu-like symptoms, you could have recently become infected with HIV-1. Tell your healthcare provider if you had a flu-like illness within the last month before starting Tenvir-EM or at any time while taking Tenvir-EM. Symptoms of new HIV-1 infection include:
  • tiredness
  • fever
  • joint or muscle aches
  • headache
  • sore throat
  • vomiting or diarrhea
  • rash
  • night sweats
  • enlarged lymph nodes in the neck or groin

While you are taking Tenvir-EM to reduce your risk of getting HIV-1:

  • Just taking Tenvir-EM may not keep you from getting HIV-1.
  • You must continue using safer sex practices while you are taking Tenvir-EM to reduce your risk of getting HIV-1.
  • You must stay HIV-negative to keep taking Tenvir-EM to reduce your risk of infection.
    • Know your HIV-1 status and the HIV-1 status of your partners.
    • Get tested for HIV-1 at least every 3 months or when your healthcare provider tells you.
    • Get tested for other sexually transmitted infections such as syphilis and gonorrhea. These infections make it easier for HIV-1 to infect you.
    • If you think you were exposed to HIV-1, tell your healthcare provider right away. They may want to do more tests to be sure you are still HIV-negative.
    • Get information and support to help reduce risky sexual behavior.
    • Have fewer sex partners.
    • Do not miss any doses of Tenvir-EM. Missing doses may increase your risk of getting HIV-1 infection.
  • If you do become HIV-positive, you need more medicine than Tenvir-EM alone to treat HIV-1. Tenvir-EM by itself is not a complete treatment for HIV-1.
    • If you have HIV-1 and take only Tenvir-EM, over time your HIV-1 may become harder to treat.

See the section "What should I avoid while taking Tenvir-EM?" and talk to your healthcare provider for more information about how to prevent HIV-1 infection.

What is Tenvir-EM?

Tenvir-EM contains the prescription medicines Tenvir-EM (EMTRIVA®) and tenofovir disoproxil fumarate (VIREAD®). Tenvir-EM is used:

  • to treat HIV-1 infection when used with other HIV-1 medicines in adults and children who weigh at least 37 pounds (at least 17 kg).
  • to help reduce the risk of getting HIV-1 infection when used with safer sex practices in:
    • HIV-negative men who have sex with men, who are at high risk of getting infected with HIV-1 through sex.
    • Male-female sex partners when one partner has HIV-1 infection and the other does not.

Use of Tenvir-EM to treat HIV-1 infection:

  • When used with other HIV-1 medicines to treat HIV-1 infection, Tenvir-EM may help:
    • Reduce the amount of HIV-1 in your blood. This is called "viral load".
    • Increase the number of CD4+ (T) cells in your blood that help fight off other infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

  • Tenvir-EM does not cure HIV-1 or AIDS. If you have HIV-1 infection, you must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.
  • It is not known if Tenvir-EM is safe and effective in children with HIV-1 infection who weigh less than 37 pounds (less than 17 kg).

Use of Tenvir-EM to reduce the risk of HIV-1 infection:

  • When used with safer sex practices, Tenvir-EM may help to reduce the risk of getting HIV-1 infection:
    • Tenvir-EM works better to reduce the risk of getting HIV-1 when the medicines are in your bloodstream before you are exposed to HIV-1.

Who should not take Tenvir-EM?

For people using Tenvir-EM to reduce the risk of getting HIV-1 infection:


Tenvir-EM can only help reduce your risk of getting HIV-1 before you are infected. Do not take Tenvir-EM to help reduce your risk of getting HIV-1 if:

  • you already have HIV-1 infection. If you are HIV-positive, you need to take other medicines with Tenvir-EM to treat HIV-1. Tenvir-EM by itself is not a complete treatment for HIV-1.
  • you do not know your HIV-1 infection status. You may already be HIV-positive. You need to take other HIV-1 medicines with Tenvir-EM to treat HIV-1.

What should I tell my healthcare provider before taking Tenvir-EM?

Tell your healthcare provider if you:

  • have liver problems including hepatitis B virus infection
  • have kidney problems or receive kidney dialysis treatment
  • have bone problems
  • have any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if Tenvir-EM can harm your unborn baby.

    If you are a female who is taking Tenvir-EM to reduce the risk of getting HIV-1 infection and you become pregnant while taking Tenvir-EM, talk to your healthcare provider to decide if you should keep taking Tenvir-EM.

    Pregnancy Registry: A pregnancy registry collects information about your health and the health of your baby. There is a pregnancy registry for women who take medicines to treat or prevent HIV-1 during pregnancy. For more information about the registry and how it works, talk to your healthcare provider.

  • are breastfeeding or plan to breastfeed.
    • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
    • Do not breastfeed if you take Tenvir-EM. Tenvir-EM can pass to your baby in your breast milk.
    • Talk with your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Do not take Tenvir-EM if you also take any of the medicines listed below:

  • medicines which also contain Tenvir-EM or tenofovir disoproxil fumarate, (ATRIPLA®, COMPLERA®, EMTRIVA, GENVOYA®, ODEFSEY®, STRIBILD®, VEMLIDY®, or VIREAD). These medicines contain one or more of the same active ingredients as Tenvir-EM.
  • medicines which contain tenofovir alafenamide (DESCOVY®, GENVOYA®, or ODEFSEY®)
  • medicines which contain lamivudine (Combivir, Dutrebis, Epivir, Epivir-HBV, Epzicom, Triumeq, or Trizivir)
  • adefovir (HEPSERA®)

Tenvir-EM may interact with other medicines. Especially tell your healthcare provider if you take:

  • didanosine (Videx EC)
  • atazanavir (Reyataz)
  • ledipasvir with sofosbuvir (HARVONI®)
  • sofosbuvir with velpatasvir (EPCLUSA®)
  • darunavir (Prezista)
  • lopinavir with ritonavir (Kaletra)

Your healthcare provider may need to check you more often or change your dose if you take any of these medicines and Tenvir-EM.

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.


How should I take Tenvir-EM?

  • Take Tenvir-EM exactly as prescribed.
  • Take Tenvir-EM by mouth, with or without food.
  • Children who take Tenvir-EM are prescribed a lower strength tablet than adults.
    • Children should swallow the tablet whole. Tell your healthcare provider if your child cannot swallow the tablet whole, because they may need a different HIV-1 medicine.
    • Your healthcare provider will change the dose of Tenvir-EM as needed based on your child's weight.
  • Tenvir-EM is usually taken 1 time each day. Take Tenvir-EM at the same time each day to keep Tenvir-EM blood levels constant.
    • If you have kidney problems, your healthcare provider may tell you to take Tenvir-EM less often.
  • Do not miss any doses of Tenvir-EM. Missing a dose lowers the amount of medicine in your blood.
  • If you miss a dose of Tenvir-EM, take it as soon as you remember that day. Do not take more than 1 dose of Tenvir-EM in a day. Do not take 2 doses at the same time to make up for a missed dose. Call your healthcare provider or pharmacist if you are not sure what to do.
  • Do not change your dose or stop taking Tenvir-EM without first talking with your healthcare provider. Stay under a healthcare provider's care when taking Tenvir-EM.
  • Refill your Tenvir-EM prescription before you run out of medicine.
  • If you take too much Tenvir-EM, call your healthcare provider or go to the nearest hospital emergency room right away.
  • If you take Tenvir-EM to treat HIV-1 infection, you need to take other HIV-1 medicines. Your healthcare provider will tell you what medicines to take and how to take them.
  • If you take Tenvir-EM to reduce your risk of getting HIV-1:
    • you must also use other methods to reduce your risk of getting HIV-1. See the section "What should I avoid while taking Tenvir-EM?" in this Medication Guide.
    • Take Tenvir-EM every day, not just when you think you have been exposed to HIV-1.
What should I avoid while taking Tenvir-EM?

While taking Tenvir-EM, avoid doing things that increase your risk of getting HIV-1 or spreading HIV-1 to other people.

  • See the section "What is the most important information I should know about Tenvir-EM?" at the beginning of this Medication Guide.
  • Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom, to lower the chance of sexual contact with semen, vaginal fluids, or blood.
  • Do not share personal items that can have blood or body fluids on them, such as toothbrushes and razor blades.
  • Do not share or re-use needles or other injection equipment.

Ask your healthcare provider if you have any questions about how to prevent getting HIV-1 or spreading HIV-1 to other people.

What are the possible side effects of Tenvir-EM?

Tenvir-EM may cause serious side effects, including:

  • See "What is the most important information I should know about Tenvir-EM?"
  • New or worse kidney problems, including kidney failure. If you had kidney problems in the past or take another medicine that can cause kidney problems, your healthcare provider may do blood tests to check your kidneys before you start and while you are taking Tenvir-EM. Your healthcare provider may tell you to take Tenvir-EM less often, or to stop taking Tenvir-EM if you have kidney problems.
  • Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.
  • Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark "tea-colored" urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.
  • Bone problems can happen in some people who take Tenvir-EM. Bone problems include bone pain, or softening or thinning of bones, which may lead to fractures. Your healthcare provider may need to do tests to check your bones.
  • Changes in your immune system (Immune Reconstitution Syndrome) can happen when an HIV-1 infected person starts taking HIV-1 medicines. Your immune system may get stronger, and can then cause you to develop inflammation in areas of your body where infections may have been hiding for a long time. This inflammation may cause you to have minor symptoms, such as fever, but inflammation can also lead to serious problems. Tell your healthcare provider right away if you start having any new symptoms after starting Tenvir-EM for treatment of HIV-1 infection.

The most common side effects of Tenvir-EM in people taking Tenvir-EM to treat HIV-1 infection include:

  • diarrhea
  • nausea
  • tiredness
  • headache
  • dizziness
  • depression
  • problems sleeping
  • abnormal dreams
  • rash
Common side effects in people who take Tenvir-EM to reduce the risk of getting HIV-1 infection include:
  • stomach-area (abdomen) pain
  • headache
  • decreased weight

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Tenvir-EM. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.


How should I store Tenvir-EM?

  • Store Tenvir-EM at room temperature between 68 °F to 77 °F (20 °C to 25 °C).
  • Keep Tenvir-EM in its original container and keep the container tightly closed.
  • Do not use Tenvir-EM if seal over bottle opening is broken or missing.

Keep Tenvir-EM and all other medicines out of reach of children.


General information about Tenvir-EM.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Tenvir-EM for a condition for which it was not prescribed. Do not give Tenvir-EM to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about Tenvir-EM. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Tenvir-EM that is written for health professionals. For more information, call 1-800-445-3235 or go to www. TRUVADA.com.


What are the ingredients in Tenvir-EM?

Active ingredients: Tenvir-EM and tenofovir disoproxil fumarate.

Inactive ingredients: Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The 200 mg/300 mg strength tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. The 167 mg/250 mg, 133 mg/200 mg, and 100 mg/150 mg strength tablets are coated with Opadry II Blue, which contains FD&C Blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.

Manufactured for and distributed by:

Gilead Sciences, Inc.

Foster City, CA 94404

COMPLERA, DESCOVY, EMTRIVA, EPCLUSA, HARVONI, HEPSERA, GENVOYA, ODEFSEY, STRIBILD, Tenvir-EM, VEMLIDY, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.

© 2017 Gilead Sciences, Inc. All rights reserved.

21752-GS-031


NDC 61958-0701-1

Tenvir-EM ®

(emtricitabine and tenofovir

disoproxil fumarate)

Tablets

30 tablets

Rx only

DISPENSER: Each time Tenvir-EM® is dispensed

give the patient the attached Medication Guide.

NDC 61958-0703-1

Tenvir-EM ®

(emtricitabine and tenofovir

disoproxil fumarate)

Tablets

100 mg/150 mg

30 tablets

Rx only

DISPENSER: Each time Tenvir-EM® is dispensed

give the patient the attached Medication Guide.

NDC 61958-0704-1

Tenvir-EM ®

(emtricitabine and tenofovir

disoproxil fumarate)

Tablets

133 mg/200 mg

30 tablets

Rx only

DISPENSER: Each time Tenvir-EM® is dispensed

give the patient the attached Medication Guide.

NDC 61958-0705-1

Tenvir-EM ®

(emtricitabine and tenofovir

disoproxil fumarate)

Tablets

167 mg/250 mg

30 tablets

Rx only

DISPENSER: Each time Tenvir-EM® is dispensed

give the patient the attached Medication Guide.

Tenvir-EM pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Tenvir-EM available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Tenvir-EM destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Tenvir-EM Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Tenvir-EM pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."EMTRIVA (EMTRICITABINE) CAPSULE EMTRIVA (EMTRICITABINE) SOLUTION [GILEAD SCIENCES, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."VIREAD (TENOFOVIR DISOPROXIL FUMARATE) TABLET, COATED VIREAD (TENOFOVIR DISOPROXIL FUMARATE) POWDER [GILEAD SCIENCES, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."EMTRICITABINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Tenvir-EM?

Depending on the reaction of the Tenvir-EM after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Tenvir-EM not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Tenvir-EM addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Tenvir-EM, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Tenvir-EM consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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