Sandoz Emtricitabine-Tenofovir Product Monograph

SUMMARY PRODUCT INFORMATION

Sandoz Emtricitabine-Tenofovir tablets are a fixed-dose combination containing emtricitabine and tenofovir disoproxil fumarate (DF).

INDICATIONS AND CLINICAL USE

Treatment of HIV-1 Infection

Sandoz Emtricitabine-Tenofovir is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults.

Additional important information regarding the use of Sandoz Emtricitabine-Tenofovir for the treatment of HIV-1 infection:

• It is not recommended that Sandoz Emtricitabine-Tenofovir be used as a component of a triple nucleoside regimen.
• Sandoz Emtricitabine-Tenofovir should not be coadministered with ATRIPLA® (efavirenz / emtricitabine / tenofovir disoproxil fumarate), COMPLERA® (emtricitabine / rilpivirine / tenofovir disoproxil fumarate), DESCOVY® (emtricitabine / tenofovir alafenamide), EMTRIVA (emtricitabine), GENVOYA® (elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide), ODEFSEY^TM (emtricitabine / rilpivirine / tenofovir alafenamide), STRIBILD® (elvitegravir / cobicistat / emtricitabine / tenofovir disoproxil fumarate), VEMLIDY^TM (tenofovir alafenamide), VIREAD (tenofovir disoproxil fumarate) or lamivudine-containing products (see WARNINGS AND PRECAUTIONS).
• In treatment-experienced patients, the use of Sandoz Emtricitabine-Tenofovir should be guided by laboratory testing and treatment history (see VIROLOGY).

Pre-Exposure Prophylaxis (PrEP) of HIV-1 Infection

Sandoz Emtricitabine-Tenofovir is indicated in combination with safer sex practices for PrEP to reduce the risk of sexually acquired HIV-1 infection in adults at high risk.

When considering Sandoz Emtricitabine-Tenofovir for PrEP, 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 Sandoz Emtricitabine-Tenofovir for PrEP, healthcare providers must:

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

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 (see CLINICAL TRIALS).

Geriatrics (> 65 years of age)

Clinical studies of emtricitabine-tenofovir disoproxil fumarate tablets, EMTRIVA or VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Pediatrics (< 18 years of age)

Safety and effectiveness in pediatric patients have not been established.

CONTRAINDICATIONS

Sandoz Emtricitabine-Tenofovir is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

Sandoz Emtricitabine-Tenofovir is contraindicated for use as PrEP in individuals with unknown or positive HIV-1 status.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Lactic Acidosis and 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 dispoxil fumarate (VIREAD), a component of Sandoz Emtricitabine-Tenofovir, alone or in combination with other antiretrovirals (see WARNINGS AND PRECAUTIONS).

• Post-Treatment Exacerbation of Hepatitis B

Sandoz Emtricitabine-Tenofovir is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of emtricitabine-tenofovir disoproxil fumarate tablets have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and HIV and have discontinued emtricitabine-tenofovir disoproxil fumarate tablets. 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 Sandoz Emtricitabine-Tenofovir. If appropriate, initiation of anti-hepatitis B therapy may be warranted (see WARNINGS AND PRECAUTIONS).

• Nephrotoxicity

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported with the use of emtricitabine-tenofovir disoproxil fumarate tablets during clinical practice (see WARNINGS AND PRECAUTIONS).

• Risk of Drug Resistance with Use of Sandoz Emtricitabine-Tenofovir for Pre-Exposure Prophylaxis (PrEP) in Undiagnosed Early HIV-1 Infection

  Sandoz Emtricitabine-Tenofovir used for a PrEP indication must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initial use and periodically (at least every 3 months) during use. Drug-resistant HIV-1 variants have been identified with the use of emtricitabine-tenofovir disoproxil fumarate tablets for a PrEP indication following undetected acute HIV-1 infection. Do not initiate Sandoz Emtricitabine-Tenofovir for a PrEP indication if signs or symptoms of acute HIV infection are present unless negative infection status is confirmed (see WARNINGS AND PRECAUTIONS).

General

Sandoz Emtricitabine-Tenofovir should be used in the treatment of HIV-1 infected patients only in combination with other antiretroviral agents.

Sandoz Emtricitabine-Tenofovir is a fixed-dose combination of emtricitabine and tenofovir DF. Sandoz Emtricitabine-Tenofovir should not be coadministered with other products containing tenofovir DF or emtricitabine (ATRIPLA, COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, or VIREAD), or with medicinal products containing tenofovir alafenamide (DESCOVY^®,GENVOYA^®, ODEFSEY, and VEMLIDY). Due to similarities between emtricitabine and lamivudine, Sandoz Emtricitabine-Tenofovir should not be coadministered with other drugs containing lamivudine (Combivir^®, 3TC^®, Heptovir^®, Kivexa^®, Triumeq^®, or Trizivir^®).

Sandoz Emtricitabine-Tenofovir should not be administered with adefovir dipivoxil (HEPSERA^®).

Clinical studies in HIV-infected patients have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance mutations 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Emtricitabine: In long-term oral carcinogenicity studies of emtricitabine, no drug-related increase in tumor incidence was found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose).

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

Emtricitabine 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: Tenofovir DF did not show any carcinogenic potential in a long-term oral carcinogenicity study in rats. A long-term oral carcinogenicity study in mice showed a low incidence of duodenal tumors, considered likely related to high local concentrations in the gastrointestinal tract at the high dose of 600 mg/kg/day. Liver adenomas were also seen at the high dose in female mice. The mechanism of tumor formation in mice and potential relevance for humans is uncertain.

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 at doses up to 2000 mg/kg when administered orally to male mice.

There were no effects on fertility, mating performance or early embryonic development when tenofovir DF was administered at 600 mg/kg/day to male rats for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats. A dose of 600 mg/kg/day is equivalent to 19 times the human dose based on body surface area comparisons.

Drug Interactions

Use with Certain HCV Regimens

Tenofovir exposure is increased when Sandoz Emtricitabine-Tenofovir is coadministered with HARVONI^® (ledipasvir/sofosbuvir),EPCLUSA^® (sofosbuvir/velpatasvir), or VOSEVI^TM (sofosbuvir/velpatasvir/voxilaprevir). Patients receiving Sandoz Emtricitabine-Tenofovir concomitantly with HARVONI, EPCLUSA or VOSEVI, particularly those at increased risk for renal dysfunction, should be monitored for tenofovir DF-associated adverse reactions (see DRUG INTERACTIONS).

Use with Didanosine

Pharmacokinetic studies have shown that coadministration of didanosine and tenofovir DF results in 40-60% increase in C_max and AUC of didanosine (see Table 8). The mechanism of this interaction is unknown. Increases in didanosine concentrations of this magnitude could potentiate didanosine-associated adverse events, including pancreatitis, lactic acidosis, and neuropathy. In addition, suppression of CD4 counts has been observed in patients receiving tenofovir DF with didanosine at a dose of 400 mg daily (see DRUG INTERACTIONS).

Endocrine and Metabolism

Serum Lipids and Blood Glucose

Serum lipid and blood glucose levels may increase during antiretroviral therapy. Disease control and life style changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders and blood glucose elevations should be managed as clinically appropriate.

Hepatic/Biliary/Pancreatic

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogs, including tenofovir DF, a component of Sandoz Emtricitabine-Tenofovir, alone or in combination with other antiretrovirals in the treatment of HIV infection. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Sandoz Emtricitabine-Tenofovir should be suspended in any patient 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).

Hepatic Impairment

Tenofovir and tenofovir disoproxil are not metabolized by liver enzymes. Clinically relevant pharmacokinetic changes in patients with hepatic impairment are not observed. Therefore, no dose adjustment is required in patients with hepatic impairment. Emtricitabine has not been evaluated in patients with hepatic impairment; however, emtricitabine has not been shown to be metabolized by liver enzymes, so the impact of liver impairment is likely to be limited. The safety and efficacy of emtricitabine-tenofovir disoproxil fumarate tablets have not been established or specifically studied in patients with underlying liver disorders.

Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Hepatitis B Virus Infection

It is recommended that all patients be tested for the presence of hepatitis B virus (HBV) before initiating Sandoz Emtricitabine-Tenofovir. Sandoz Emtricitabine-Tenofovir is not approved for the treatment of chronic HBV infection and the safety and efficacy of emtricitabine-tenofovir disoproxil fumarate tablets have not been established in patients infected with HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and HIV after the discontinuation of emtricitabine-tenofovir disoproxil fumarate tablets. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be closely monitored with both clinical and laboratory follow up for at least several months in patients who are infected with HBV and discontinue Sandoz Emtricitabine-Tenofovir. If appropriate, initiation of anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Therefore, in these patients, discontinuation of treatment without initiation of alternative anti-hepatitis B therapy is not recommended.

Pancreatitis

Pancreatitis has occurred during therapy with combination regimens that included tenofovir DF (VIREAD). Caution should be used when administering nucleoside analogues (including Sandoz Emtricitabine-Tenofovir) to patients with a history of pancreatitis or risk factors for the development of pancreatitis. Therapy should be suspended in patients with suspected pancreatitis.

Immune

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including the components of Sandoz Emtricitabine-Tenofovir. During the initial phase of combination antiretroviral treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infections, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), and tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable, and these events can occur many months after initiation of treatment.

Musculoskeletal

Bone Effects

Bone Mineral Density

In a clinical trial in treatment-naive HIV-1 infected adults through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both tenofovir DF and stavudine treatment arms of the study; significantly greater decreases were seen in the lumbar spine measurement in the tenofovir DF group relative to the stavudine group. Clinically relevant fractures were reported in both treatment groups. Increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) were observed, suggesting increased bone turnover. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. These decreases in BMD and increases in biochemical markers of bone metabolism were also seen in the PrEP trials in HIV-1 uninfected individuals. 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 patients who have a history of pathologic bone fracture or are at risk for osteopenia or osteoporosis. 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 hypophosphatemic osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in the extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). 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. Serum phosphate should be monitored in these patients.

Renal

Nephrotoxicity

Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported in association with the use of tenofovir DF in clinical practice. The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents; however, some cases occurred in patients without identified risk factors. 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. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with Sandoz Emtricitabine-Tenofovir. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA, it is recommended that calculated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of Sandoz Emtricitabine-Tenofovir, and periodically during Sandoz Emtricitabine-Tenofovir therapy (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions and DRUG INTERACTIONS).

If serum phosphate is < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance is decreased to < 50 ml/min in any patient receiving Sandoz Emtricitabine-Tenofovir, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations. Consideration should also be given to interrupting treatment with Sandoz Emtricitabine-Tenofovir in patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dL (0.32 mmol/l). Interrupting treatment with Sandoz Emtricitabine-Tenofovir should also be considered in case of progressive decline of renal function when no other cause has been identified (see ADVERSE REACTIONS).

Sandoz Emtricitabine-Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent [eg, cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides, 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-1 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 (see DRUG INTERACTIONS).

Renal Impairment

Treatment of HIV-1 infection

Dosing interval adjustment of Sandoz Emtricitabine-Tenofovir and close monitoring of renal function are recommended in all patients with creatinine clearance 30-49 mL/min. No safety and efficacy data are available in patients with renal dysfunction who received emtricitabine-tenofovir disoproxil fumarate tablets using these guidelines, and so the potential benefit of Sandoz Emtricitabine-Tenofovir should be assessed against the potential risk of renal toxicity. Sandoz Emtricitabine-Tenofovir should not be administered to patients with creatinine clearance < 30 mL/min or patients requiring hemodialysis (see DOSAGE AND ADMINISTRATION).

Pre-exposure Prophylaxis of HIV-1 infection

Sandoz Emtricitabine-Tenofovir for a PrEP indication should not be used in HIV-1 uninfected individuals with creatinine clearance below 60 mL/min.

If a decrease in creatinine clearance is observed in uninfected individuals while using Sandoz Emtricitabine-Tenofovir for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see DOSAGE AND ADMINISTRATION).

Special Populations

Pregnant Women

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to ART (antiretroviral therapy) including Sandoz Emtricitabine-Tenofovir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 800-258-4263.

Emtricitabine-tenofovir disoproxil fumarate tablets have been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that emtricitabine-tenofovir disoproxil fumarate tablets does not increase the risk of major birth defects overall compared to the background rate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Sandoz Emtricitabine-Tenofovir should be used in pregnant women only if the potential benefits outweigh the potential risks to the fetus. If an uninfected individual becomes pregnant while taking Sandoz Emtricitabine-Tenofovir for a PrEP indication, careful consideration should be given to whether use of Sandoz Emtricitabine-Tenofovir should be continued, taking into account the potential increased risk of HIV-1 infection during pregnancy.

As of July 2015, the APR has received prospective reports of 1984 and 2608 exposures to emtricitabine- and tenofovir-containing regimens, respectively in the first trimester; and 949 and 1258 exposures, respectively, in second/third trimester, respectively. Birth defects occurred in 47 of 1984 (2.4%) live births for emtricitabine-containing regimens and 60 of 2608 (2.3%) live births for tenofovir-containing regimens (first trimester exposure); and 20 of 949 (2.1%) live births for emtricitabine-containing regimens and 26 of 1258 (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 emtricitabine or tenofovir and overall birth defects observed in the APR.

Emtricitabine: The incidence of fetal variations and malformations was not increased in embryo-fetal toxicity studies performed with emtricitabine 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. Reduced pup body weights, survival and delay in sexual maturation was observed in a peri- and postnatal toxicity study in rats at the maternally toxic doses of 450 and 600 mg/kg (approximately 14 and 19 times the human dose based on body surface area comparisons).

Nursing Women

HIV-infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV to the infant.

In humans, samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk at low levels (estimated neonatal concentrations 128 to 266 times lower than the tenofovir IC₅₀). Tenofovir-associated risks, including the risk of developing viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir DF are unknown.

Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk at estimated neonatal concentrations 3 to 12 times higher than the emtricitabine IC₅₀ but 3 to 12 times lower than the C_min achieved from oral administration of emtricitabine. Breast-feeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.

Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Sandoz Emtricitabine-Tenofovir, whether they are taking Sandoz Emtricitabine-Tenofovir for treatment or to reduce the risk of acquiring HIV-1.

Pediatrics (<18 years of age)

Safety and effectiveness in pediatric patients have not been established.

Geriatrics (>65 years of age)

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

PrEP to Reduce the Risk of Acquiring HIV-1 Infection

Comprehensive HIV-1 Infection Prevention Strategy

Use Sandoz Emtricitabine-Tenofovir for PrEP only as part of a comprehensive prevention strategy that includes other prevention measures, such as safer sex practices, because Sandoz Emtricitabine-Tenofovir is not always effective in preventing the acquisition of HIV-1 (see CLINICAL TRIALS).

• 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.

Risk of Resistance

Use Sandoz Emtricitabine-Tenofovir to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative prior to initiating PrEP and re-confirmed routinely while taking PrEP. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only Sandoz Emtricitabine-Tenofovir, because Sandoz Emtricitabine-Tenofovir 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 (see VIROLOGY: Resistance).

• 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 Sandoz Emtricitabine-Tenofovir 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, etc.) 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 negative status or use a test approved by Health Canada as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.
• While using Sandoz Emtricitabine-Tenofovir 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 Health Canada 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 Sandoz Emtricitabine-Tenofovir dosing schedule. The effectiveness of Sandoz Emtricitabine-

Tenofovir in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials (see CLINICAL TRIALS).

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

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

Emtricitabine-tenofovir disoproxil fumarate tablets: Four hundred and forty-seven HIV-1 infected patients have received combination therapy with EMTRIVA or VIREAD with either a non- nucleoside reverse transcriptase inhibitor or protease inhibitor for 48 weeks in ongoing clinical studies. Study 934 - Treatment Emergent Adverse Events: Assessment of adverse reactions is based on data from Study 934 in which 511 antiretroviral-naïve patients received either EMTRIVA + VIREAD administered in combination with efavirenz (N=257) or Combivir^® (lamivudine/zidovudine) administered in combination with efavirenz (N=254). Adverse events observed in this study were generally consistent with those seen in other studies in treatment experienced or treatment-naïve patients (Table 1).

Table 1. Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥3% in Any Treatment Group in Study 934 (0–48 Weeks)

Patients who received treatment up to 144 weeks in Study 934 reported adverse events similar in nature and severity to those reported in the first 48 weeks.

Through 48 weeks, 7 patients in the EMTRIVA + VIREAD group and 5 patients in the lamivudine/zidovudine group experienced a new CDC Class C event (10 and 6 patients, respectively, through 144 weeks). Renal safety assessed by laboratory abnormalities was similar in the two groups and no patient discontinued study drug due to renal events. At

Weeks 48 and 144, total limb fat (as measured by dual-energy x-ray absorptiometry) was significantly less in a subgroup of patients in the lamivudine/zidovudine group compared to the tenofovir/emtricitabine subgroup (see Table 2).

Table 2. Study 934 Total Limb Fat at Week 48 and 144 (Dual-Energy X- Ray Absorptiometry)

¹P=0.03 for the comparison between arms

²P<0.001 for the comparison between arms

Laboratory Abnormalities: Laboratory Abnormalities observed in this study were generally consistent with those seen in other studies (Table 3).

Table 3. Grade 3/4 Laboratory Abnormalities Reported in ≥1% in Any

Treatment Group in Study 934 (0–48 Weeks)

Laboratory abnormalities in patients who received treatment up to 144 weeks in Study 934 were consistent with those observed in the first 48 weeks of treatment.

In addition to the events described above for Study 934, other adverse events that occurred in at least 3-5% of patients receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include: anorexia, anxiety, arthralgia, asthenia, increased cough, depressive disorders, dyspepsia, fever, flatulence, myalgia, pain, abdominal pain, back pain, chest pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction), sweating and weight loss.

Skin discoloration has been reported with higher frequency among EMTRIVA treated patients. Skin discoloration, mainly manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic and of little clinical significance. The mechanism is unknown.

In addition to the laboratory abnormalities described above for Study 934, Grade 3/4 elevations of bilirubin (>2.5 x ULN), pancreatic amylase (>2.0 x ULN), serum glucose (<40 or >250 mg/dL), serum lipase (>2.0 x ULN), and urine glucose (≥3+) occurred in up to 3% of patients treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials.

For more information, please consult the EMTRIVA and VIREAD Product Monographs.

In Study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients in the tenofovir DF group compared with patients in the stavudine group (see Table 4). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through Week 144. Twenty-eight percent of tenofovir DF-treated patients vs. 21% of the stavudine-treated patients lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients in the tenofovir DF group and 6 patients in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the tenofovir DF group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the tenofovir DF group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long- term bone health and future fracture risk are unknown.

Table 4 Changes in Bone Mineral Density Study 903

Adverse Reactions from Clinical Trials Experience in HIV-1 Uninfected Adult Subjects (PrEP)

No new adverse reactions to emtricitabine-tenofovir disoproxil fumarate tablets were identified from two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2830 HIV-1 uninfected adults received emtricitabine-tenofovir disoproxil fumarate tablets 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 ≥2% of subjects in any treatment group in the iPrEx and Partners PrEP trials.

Table 5 Selected Adverse Events (All Grades) Reported in ≥2% of Uninfected Individuals in Any Treatment Group in the iPrEx Trial and Partners PrEP Trial

a. Not reported or reported below 2%.

Laboratory Abnormalities: Table 6 provides a list of laboratory abnormalities observed in both PrEP 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 emtricitabine-tenofovir disoproxil fumarate tablets arm of the iPrEx trial discontinued from the study due to an increase in blood creatinine and another due to low phosphorus.

Table 6 Laboratory Abnormalities (Highest Toxicity Grade) Reported for Each Subject in the iPrEx Trial and Partners PrEP Trial

• a. Grade 1 phosphorus was not reported for the Partners PrEP trial.
• b. Grading is per DAIDS criteria.

In addition to the laboratory abnormalities described above, Grade 1 proteinuria (1+) occurred in 6% of subjects receiving emtricitabine-tenofovir disoproxil fumarate tablets in the iPrEx trial. Grade 2-3 proteinuria (2-4+) and glycosuria (3+) occurred in less than 1% of subjects treated with emtricitabine-tenofovir disoproxil fumarate tablets in the iPrEx trial and Partners PrEP trial.

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 emtricitabine-tenofovir disoproxil fumarate tablets group compared with the placebo group, which returned toward baseline after discontinuation of treatment. Thirteen percent of subjects receiving emtricitabine-tenofovir disoproxil fumarate tablets vs. 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 emtricitabine-tenofovir disoproxil fumarate tablets 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 conducted during this trial (see CLINICAL TRIALS).

Post Market Adverse Drug Reactions

Emtricitabine: The following adverse experiences have been reported in post-marketing experience without regard to causality. Because these events are voluntarily reported from a population of unknown size, estimates of frequency cannot be made. These events have been considered possible adverse reactions due to a combination of their seriousness, frequency of reporting or potential causal relationship with treatment.

Tenofovir DF: The following adverse reactions have been identified during post-approval use of VIREAD. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been considered possible adverse reactions due to a combination of their seriousness, frequency of reporting or potential causal relationship with tenofovir DF.

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalemia, muscular weakness, myopathy and hypophosphatemia.

There have been three post marketing reports of acute renal failure in patients on concomitant NSAIDS therapy where a relationship to tenofovir DF could not be excluded. These events mostly occurred in medically complex patients, where underlying disease processes confound interpretation.

Emtricitabine and Tenofovir DF: In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy an inflammatory reaction to infectious pathogens (active or inactive) may arise (see WARNINGS AND PRECAUTIONS).

In HIV infected patients coinfected with HBV, clinical and laboratory evidence of exacerbations of hepatitis has occurred after discontinuation of treatment (see WARNINGS AND PRECAUTIONS).

DRUG INTERACTIONS

Overview

Drug interaction studies have been conducted with either emtricitabine-tenofovir disoproxil fumarate tablets, or the components of emtricitabine-tenofovir disoproxil fumarate tablets as individual agents and/or in combination.

The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF were administered together versus each agent dosed alone (see Table 9 and Table 10).

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP450 mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.

Drug-Drug Interactions

Established and Other Potentially Significant Drug Interactions

The drug interactions described are based on studies conducted with the individual agents of emtricitabine-tenofovir disoproxil fumarate tablets and/or in combination, or are potential drug interactions that may occur with Sandoz Emtricitabine-Tenofovir.

Table 7. Established and Other Potentially Significant^a Drug Interactions

Antiretroviral Agents:

Hepatitis C Virus Antiviral Agents:

a This table is not all inclusive.

b ↑ = increase, ↓ =decrease

Drugs Affecting Renal Function

Emtricitabine 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. Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of Sandoz Emtricitabine-Tenofovir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides and high-dose or multiple NSAIDs.

Sandoz Emtricitabine-Tenofovir should not be administered with HEPSERA (adefovir dipivoxil) (see WARNINGS AND PRECAUTIONS, General).

Drugs without Clinically Significant Interactions with Sandoz Emtricitabine-Tenofovir

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, zidovudine, stavudine, tenofovir DF, sofosbuvir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir (see Table 9 and Table 10). Similarly, no clinically significant drug interactions have been observed between tenofovir DF and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ ritonavir, sofosbuvir and tacrolimus in studies conducted in healthy volunteers (see Table 11 and Table 12).

Assessment of Drug Interactions

Drug-drug interaction studies were conducted with either emtricitabine-tenofovir disoproxil fumarate tablets or the components of emtricitabine-tenofovir disoproxil fumarate tablets

(emtricitabine or tenofovir DF) as individual agents and/or in combination.

The effects of didanosine in the presence of tenofovir are shown in Table 8.

The effects of coadministered drugs on the exposure of emtricitabine are shown in Table 9. The effects of emtricitabine on the exposure of coadministered drugs are shown in Table 10.

The effects of coadministered drugs on the exposure of tenofovir DF are shown in Table 11. The effects of tenofovir DF on the exposure of coadministered drugs are shown in Table 12.

Table 8 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of Tenofovir

Buffered tablets

Enteric coated capsules

1. 1. See PRECAUTIONS regarding use of didanosine with VIREAD.
2. 2. Administration with food was with a light meal (~373 kcal, 20% fat).
3. 3. Increase = ↑; Decrease = ↓
4. 4. Includes 4 subjects weighing <60 kg receiving ddI 250 mg

Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug¹

1. 1. All interaction studies conducted in healthy volunteers.
2. 2. ↑ = Increase; ↓ = Decrease; NC= Not Calculated

Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Emtricitabine¹.

1. 1. All interaction studies conducted in healthy volunteers.
2. 2. ↑ = Increase; ↓ = Decrease; NC=Not Calculated

Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir¹ in the Presence of the Coadministered Drug

1. 1. Patients received VIREAD 300 mg once daily.
2. 2. Increase = ↑; Decrease = ↓; NC = Not Calculated; NA = Not Available
3. 3. Reyataz^® Prescribing Information (Bristol-Myers Squibb)
4. 4. Prezista^® Prescribing Information
5. 5. weight <60kg: 250 mg, ≥60 kg more: 400 mg
6. 6. Data generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provided similar results.
7. 7. Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with HARVONI.
8. 8. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with HARVONI.
9. 9. Study conducted with ATRIPLA (efavirenz/emtricitabine/tenofovir DF) coadministered with HARVONI.
10. 10. Study conducted with COMPLERA (emtricitabine/rilpivirine/tenofovir DF) coadministered with HARVONI.
11. 11. Study conducted with emtricitabine-tenofovir disoproxil fumarate tablets + dolutegravir coadministered with HARVONI.
12. 12. Study conducted with ATRIPLA coadministered with SOVALDI^® (sofosbuvir).
13. 13. Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with EPCLUSA (sofosbuvir/velpatasvir).
14. 14. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with EPCLUSA.
15. 15. Study conducted with ATRIPLA (efavirenz/emtricitabine/tenofovir DF) coadministered with EPCLUSA.
16. 16. Study conducted with COMPLERA (emtricitabine/rilpivirine/tenofovir DF) coadministered with EPCLUSA.
17. 17. Study conducted with STRIBILD (elvitegravir/cobicistat/emtricitabine/tenofovir DF) coadministered with EPCLUSA.
18. 18. Administered as raltegravir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with EPCLUSA.
19. 19. Comparison based on exposures when administered as darunavir + ritonavir + Emtricitabine and Tenofovir DF tablets coadministered with VOSEVI
20. 20. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients
21. 21. Aptivus^® Prescribing Information.

Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir

1. 1. Increase = ↑; Decrease = ↓; NC = Not Calculated; NA = Not Available
2. 2. Study conducted with VIREAD (tenofovir DF)
3. 3. Reyataz Prescribing Information (Bristol-Myers Squibb)
4. 4. Prezista Prescribing Information.
5. 5. 373 kcal, 8.2 g fat
6. 6. Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions.
7. 7. In HIV-infected patients, 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.
8. 8. R-(active), S-and total methadone exposures were equivalent when dosed alone or with VIREAD.
9. 9. Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported.
10. 10. Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD.
11. 11. Increases 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. 12. The predominant circulating nucleoside metabolite of sofosbuvir.
13. 13. Data generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provided similar results.
14. 14. Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with HARVONI.
15. 15. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with HARVONI.
16. 16. Study conducted with ATRIPLA (efavirenz/emtricitabine/tenofovir DF) coadministered with HARVONI.
17. 17. Study conducted with COMPLERA (emtricitabine/rilpivirine/tenofovir) coadministered with HARVONI.
18. 18. Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with EPCLUSA (sofosbuvir/velpatasvir).
19. 19. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with EPCLUSA.
20. 20. Study conducted with ATRIPLA (efavirenz/emtricitabine/tenofovir DF) coadministered with EPCLUSA.
21. 21. Study conducted with COMPLERA (emtricitabine/rilpivirine/tenofovir DF) coadministered with EPCLUSA.
22. 22. Study conducted with STRIBILD (elvitegravir/cobicistat/emtricitabine/tenofovir DF) coadministered with EPCLUSA.
23. 23. Comparison based on exposures when administered as raltegravir + emtricitabine-tenofovir disoproxil fumarate tablets coadministered with EPCLUSA.
24. 24. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
25. 25. Comparison based on exposures when administered as darunavir+ritonavir+emtricitabine-tenofovir disoproxil fumarate tablets coadministered with VOSEVI
26. 26. Study conducted with ATRIPLA coadministered with SOVALDI.
27. 27. Aptivus Prescribing Information

Drug-Food Interactions

Sandoz Emtricitabine-Tenofovir can be taken with or without food. Compared to fasted administration, dosing of emtricitabine-tenofovir disoproxil fumarate tablets following a either a high fat meal or a light meal increased the mean AUC and C_max of tenofovir by 35% and 15%, respectively, without affecting emtricitabine exposures (see ACTIONS AND CLINICAL PHARMACOLOGY, Effect of Food on Absorption).

Drug-Herb Interactions

Interactions of emtricitabine-tenofovir disoproxil fumarate tablets with herbs have not been established.

Drug-Laboratory Interactions

Interactions of emtricitabine-tenofovir disoproxil fumarate tablets with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose

Treatment of HIV-1 Infection

The dose of Sandoz Emtricitabine-Tenofovir is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

Pre-exposure Prophylaxis of HIV-1 Infection

The dose of Sandoz Emtricitabine-Tenofovir is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

Special Populations

Dose Adjustment for Renal Impairment

Treatment of HIV-1 Infection

Significantly increased drug exposures occurred when EMTRIVA or VIREAD were administered to patients with moderate to severe renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency). Therefore, the dosing interval of Sandoz Emtricitabine-Tenofovir should be adjusted in HIV-1 infected adult patients with baseline creatinine clearance 30–49 mL/min using the recommendations in Table 13. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in moderate to severe renal impairment, therefore, clinical response to treatment and renal function should be closely monitored in these patients.

No dose adjustment of Sandoz Emtricitabine-Tenofovir tablets is necessary with mild renal impairment patients (creatinine clearance 50-80 mL/min). Routine monitoring of calculated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed for patients with mild renal impairment (creatinine clearance 50−80 mL/min) (see WARNINGS AND PRECAUTIONS).

Table 13 Dosage Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance

1. 1. Calculated using ideal (lean) body weight.

Pre-exposure Prophylaxis of HIV-1 Infection

Do not use Sandoz Emtricitabine-Tenofovir for PrEP in HIV-1 uninfected individuals with creatinine clearance below 60 mL/min (see WARNINGS AND PRECAUTIONS).

No dose adjustment of Sandoz Emtricitabine-Tenofovir tablets is necessary with mild renal impairment patients (creatinine clearance 50-80 mL/min). Routine monitoring of calculated creatinine clearance, serum phosphorus, urine glucose and urine protein should be performed in all individuals with mild renal impairment. If a decrease in calculated creatinine clearance is observed in uninfected individuals while using Sandoz Emtricitabine-Tenofovir for PrEP, evaluate potential causes and re- assess potential risks and benefits of continued use (see WARNINGS AND PRECAUTIONS).

Hepatic Impairment

No dose adjustment is required in patients with hepatic impairment (see WARNINGS AND PRECAUTIONS).

Geriatrics (>65 years of age)

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

Missed Dose

If a patient misses a dose within 12 hours of the regularly scheduled time, but then remembers it that same day, the patient should take the missed dose with food as soon as possible and resume their normal dosing schedule. If a patient misses a dose of Sandoz Emtricitabine-Tenofovir by more than 12 hours and it is almost time for their next dose, the patient should not take the missed dose and simply resume the usual dosing schedule. The patient should not take more than 1 dose of Sandoz Emtricitabine-Tenofovir in a day, and should not take 2 doses of Sandoz Emtricitabine-Tenofovir at the same time to make up for missing a dose.

Uninfected individuals who miss doses are at greater risk of acquiring HIV-1 than those who do not miss doses (see WARNINGS AND PRECAUTIONS).

OVERDOSAGE

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

Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study single doses of emtricitabine

1200 mg were administered to 11 patients. No severe adverse reactions were reported. The effects of higher doses are not known.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of

400 mL/min and a dialysate flow rate of 600 mL/min); however, a single treatment does not significantly affect emtricitabine C_max or AUC. It is not known whether emtricitabine 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 study, 600 mg tenofovir DF was administered to 8 patients orally for 28 days. 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Sandoz Emtricitabine-Tenofovir is a fixed-dose combination of antiviral drugs, emtricitabine and tenofovir DF (see VIROLOGY).

Pharmacokinetics

Emtricitabine-Tenofovir Disoproxil Fumarate Tablets: One emtricitabine-tenofovir DF 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).

Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table

1. 14. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak

For management of a suspected drug overdose, please contact your regional Poison Control Centre immediately.

plasma concentrations occurring at 1–2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is <4% and is independent of concentration over the range of 0.02− 200 mcg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours.

Tenofovir DF: The pharmacokinetic properties of tenofovir DF are summarized in Table 14. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. In vitro binding of tenofovir to human plasma proteins is <0.7% and is independent of concentration over the range of 0.01–25 mcg/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.

Table 14 Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in Adults

1. 1. NC = Not calculated
2. 2. Median (range)
3. 3. Mean ± SD
4. 4. Data presented as steady state values.

Effects of Food on Oral Absorption

Sandoz Emtricitabine-Tenofovir may be administered with or without food. Administration of emtricitabine-tenofovir DF tablets 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 C_max by approximately 0.75 hour. The mean increases in tenofovir AUC and C_max 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 studies, VIREAD (tenofovir) was taken under fed conditions.

Emtricitabine systemic exposures (AUC and C_max) were unaffected when emtricitabine-tenofovir DF tablets were administered with either a high fat or a light meal.

Special Populations and Conditions

Pediatrics and Geriatrics

Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in children (<18 years) or in the elderly (>65 years).

Race

Emtricitabine: 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.

Gender

Emtricitabine and tenofovir DF: Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.

Hepatic Insufficiency

The pharmacokinetics of tenofovir following a 300 mg single 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 emtricitabine-tenofovir disoproxil fumarate tablets or emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine has not been shown to be significantly metabolized by liver enzymes, so the impact of liver impairment is likely to be limited.

Renal Insufficiency

The pharmacokinetics of emtricitabine and tenofovir are altered in patients with renal insufficiency. In patients with creatinine clearance <50 mL/min, C_max and AUC_0-∞ of emtricitabine and tenofovir were increased (see WARNINGS, Nephrotoxicity).

It is recommended that the dosing interval for Sandoz Emtricitabine-Tenofovir be modified in HIV-1 infected patients with creatinine clearance 30–49 mL/min. Sandoz Emtricitabine-Tenofovir should not be used in HIV-1 infected patients with creatinine clearance <30 mL/min and in patients with end-stage renal disease requiring dialysis (see DOSAGE AND ADMINISTRATION).

Sandoz Emtricitabine-Tenofovir for PrEP has not been studied and should not be used in HIV-1 uninfected individuals with creatinine clearance below 60 mL/min. (see DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

Store at 15-30 °C (59-86 °F). Protect from moisture.

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

SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Sandoz Emtricitabine-Tenofovir is available as tablets. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients. The tablets also include the following inactive ingredients: croscarmellose sodium, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Instacoat Universl Blue A05G32672, which contains FD&C Blue #2 aluminum lake, hydropropylmethylcellulose, lactose monohydrate, titanium dioxide, and triacetin. The tablets are blue coloured, capsule-shaped, biconvex, film-coated tablets debossed with “L24” on one side of the tablet and plain on the other surface. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet) and is closed with a child-resistant closure.

PART II. SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Emtricitabine: Common Name:	emtricitabine
Chemical Name:	4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3- oxathiolan-5-yl]-2(1H)-pyrimidinone
Empirical Formula:	C8H10FN3O3S
Molecular Weight:	247.25 g/mol
Structural Formula:
Physicochemical Properties:	Physical Description: Emtricitabine is a white to almost white crystalline powder. Solubility: Freely soluble in methanol and water, practically insoluble in Dichloromethane at 25ºC±2ºC.. The partition coefficient (log p) for emtricitabine is –0.43 and the pKa is 2.65.

Tenofovir DF Common Name:	tenofovir disoproxil fumarate
Chemical Name:	9-[(R)-2[[bis[[(isopropoxycarbonyl)oxy] methoxy]phosphinyl]-methoxy]propyl] adenine fumarate (1:1)
Empirical Formula:	C19H30N5O10P • C4H4O4
Molecular Weight:	635.5 g/mol
Structural Formula:
Physicochemical Properties:	Physical Description: Tenofovir disoproxil fumarate is a white to off-white crystalline powder. Solubility: Freely Soluble in methanol, and in Dimethylformamide, at 25°C + 2oC.. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 1.35 (strongest acidic) and 5.12 (strongest basic).

CLINICAL TRIALS

Comparative Bioavailability Study

A double blind, balanced, randomized, single-dose, two-treatment, two-sequence, two-period, crossover oral bioequivalence study of Sandoz Emtricitabine-Tenofovir (Emtricitabine and Tenofovir disoproxil fumarate Tablets 200 mg/300 mg of Sandoz Canada Inc. and ^PrTRUVADA® (Emtricitabine and Tenofovir disoproxil fumarate) Tablet 200 mg/300 mg of Gilead Sciences Canada, Inc. in 30 healthy, adult, human male subjects under fasting condition. Bioavailability data was measured and the results are summarized in the following tables.

SUMMARY TABLES OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Sandoz Emtricitabine and Tenofovir disoproxil fumarate Tablets 200 mg / 300 mg (Sandoz Canada Inc.).

^{† Pr}Truvada^® (Emtricitabine and Tenofovir disoproxil fumarate) Tablets 200 mg/300 mg were purchased from Canada.

^§ Expressed as the median (range) only

^€ Arithmetic mean (%CV)

^* Sandoz Emtricitabine and Tenofovir disoproxil fumarate Tablets 200 mg/300 mg (Sandoz Canada Inc.).

^{† Pr}Truvada^® (Emtricitabine and Tenofovir disoproxil fumarate) Tablets 200 mg/300 mg were purchased from Canada.

^§ Expressed as the median (range) only

^€ Arithmetic mean (%CV)

Clinical Studies in Patients with HIV-1 Infection

Study Demographics and Trial Design

Description of Clinical Studies

For safety and efficacy studies using EMTRIVA or VIREAD in combination with other antiretroviral agents, also consult the Product Monograph for these products.

Clinical Study 934 supports the use of emtricitabine-tenofovir disoproxil fumarate tablets for the treatment of HIV-1 infection. Additional data in support of the use of emtricitabine-tenofovir disoproxil fumarate tablets are derived from Study 903, in which lamivudine and tenofovir DF were used in combination in treatment-naïve adults, and clinical Study 303 in which EMTRIVA and lamivudine demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens (see Table 19 and Table 20).

Table 15 Study 934 EMTRIVA + VIREAD + Efavirenz Compared with Lamivudine/Zidovudine +Efavirenz

¹From weeks 96 to 144 of the study, patients received emtricitabine-tenofovir DF tablets with efavirenz in place of emtricitabine + VIREAD

Data through 144 weeks are reported for Study 934, a randomized, open-label, active controlled multicenter study comparing EMTRIVA + VIREAD administered in combination with efavirenz versus lamivudine/zidovudine administered in combination with efavirenz in 511 antiretroviral-naïve patients. From weeks 96 to 144 of the study, patients randomized to EMTRIVA + VIREAD received emtricitabine-tenofovir DF tablets with efavirenz in place of EMTRIVA + VIREAD. Patients had a mean age of 38 years (range 18–80), 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-1RNA was 5.01 log₁₀ copies/mL (range

3.56–6.54). Patients were stratified by baseline CD4 count (< or ≥200 cells/mm³); 41% had CD4 cell counts <200 cells/mm³ and 51% of patients had baseline viral loads >100,000 copies/mL.

EMTRIVA:

Table 16 Study 303: EMTRIVA QD + Stable Background Therapy (SBT)

Compared to Lamivudine BID + SBT

Study 303 was a 48-week, open-label, active-controlled multicenter study comparing EMTRIVA (200 mg QD) to lamivudine, in combination with stavudine or zidovudine and a protease inhibitor or NNRTI in 440 patients who were on a lamivudine-containing triple- antiretroviral drug regimen for at least 12 weeks prior to study entry and had HIV-1 RNA

≤400 copies/mL.

Patients were randomized 1:2 to continue therapy with lamivudine (150 mg BID) or to switch to EMTRIVA (200 mg QD). All patients were maintained on their stable background regimen. Patients had a mean age of 42 years (range 22−80), 86% were male, 64% Caucasian, 21% African-American and 13% Hispanic. Patients had a mean baseline CD4 cell count of 527 cells/mm³ (range 37−1909), and a median baseline plasma HIV RNA of

1.7 log₁₀ copies/mL (range 1.7−4.0). The median duration of prior antiretroviral therapy was

27.6 months.

VIREAD:

Table 17 Study 903: VIREAD + Lamivudine + Efavirenz Compared with Stavudine + Lamivudine + Efavirenz

1. 1. Stavudine/placebo capsules 20/15 mg BID as need for dose reduction.

Study 903 is a double-blind, active-controlled multicenter study comparing VIREAD

(300 mg QD) administered in combination with lamivudine and efavirenz versus stavudine, lamivudine, and efavirenz in 600 antiretroviral-naïve patients. Patients had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4 cell count was 279 cells/mm³ (range 3–956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000). Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads

>100,000 copies/mL and 39% had CD4 cell counts <200 cells/mm³.

Study Results

EMTRIVA and VIREAD

Study 934: EMTRIVA + VIREAD + Efavirenz Compared with Lamivudine/Zidovudine

+ Efavirenz

Treatment outcomes through 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 18.

Table 18 Outcomes of Randomized Treatment at Weeks 48 and 144 (Study 934)

1. 1. Patients who were responders at Week 48 or Week 96 but did not consent to continue study after Week 48 or Week 96 were excluded from analysis.
2. 2. Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48.
3. 3. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48.
4. 4. Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

In this study, EMTRIVA + VIREAD in combination with efavirenz demonstrated statistically significant superiority to lamivudine/zidovudine in combination with efavirenz in achieving and maintaining HIV-1 RNA <400 copies/mL through 48 weeks and 144 weeks (Table 18). The difference in the percentages of responders, stratified by baseline CD4 cell count (< or ≥200 cells/mm³), between the EMTRIVA + VIREAD group and the lamivudine/zidovudine group was 11.4%, and the 95% CI was 4.3% to 18.6% (p=0.002) at Week 48 and was 13% at Week 144, 95% CI = 4% to 22% (p=0.004). Through 48 weeks of therapy, 80% and 70% of patients in the EMTRIVA + VIREAD and the lamivudine/zidovudine arms, respectively, achieved and maintained HIV-1 RNA <50 copies/mL (64% and 56%, respectively, through Week 144). The difference in the percentages of responders stratified by baseline CD4 cell count (< or ≥200 cells/mm³) between the EMTRIVA + VIREAD group and the lamivudine/zidovudine group was 9.1%, and the 95% CI was 1.6% to 16.6% (p=0.021) at Week 48 and was 8% at Week 144, 95% CI

= −1% to 17% (p=0.082). The mean increase from baseline in CD4 cell count was

190 cells/mm³ for the EMTRIVA + VIREAD + efavirenz arm, and 158 cells/mm³ for the lamivudine/zidovudine + efavirenz arm (p=0.002) at Week 48 (312 and 271 cells/mm³, respectively, at Week 144, p=0.089).

The difference in the proportion of patients 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 study.

EMTRIVA:

Study 303: EMTRIVA QD + Stable Background Therapy (SBT) Compared to Lamivudine BID + SBT

Treatment outcomes through 48 weeks are presented in Table 19.

Table 19 Outcomes of Randomized Treatment at Week 48 (Study 303)

1. 1. Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.
2. 2. Includes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression.
3. 3. Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

The mean increase from baseline in CD4 cell count was 29 cells/mm³ for the EMTRIVA arm and 61 cells/mm³ for the lamivudine arm. Through 48 weeks, in the EMTRIVA group 2 patients (0.7%) experienced a new CDC Class C event, compared to 2 patients (1.4%) in the lamivudine group.

VIREAD:

Study 903: VIREAD + Lamivudine + Efavirenz Compared with Stavudine + Lamivudine + Efavirenz

Treatment outcomes at Week 48 and Week 144 are presented in Table 20 below.

Table 20 Outcomes of Randomized Treatment (Study 903)

1. 1. Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) at Weeks 48 and 144.
2. 2. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144.
3. 3. Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation and other reasons.

Through 48 weeks, the mean increase from baseline in CD4 cell count was 169 cells/mm³ for the VIREAD arm and 167 cells/mm³ for the stavudine arm. Eight patients in the VIREAD group and six patients in the stavudine group experienced a new CDC Class C event.

Through 144 weeks, the mean increase from baseline in CD4 cell count was 263 cells/mm³ for the VIREAD arm and 283 cells/mm³ for the stavudine arm. Eleven patients in the VIREAD group and nine patients in the stavudine group experienced a new CDC Class C event.

Clinical Studies in HIV-1 Uninfected Subjects

The iPrEx study and Partners PrEP study support the use of emtricitabine-tenofovir disoproxil fumarate tablets to help reduce the risk of acquiring HIV-1.

iPrEx Trial

The study demographics and trial design for the iPrEx Trial are summarized in Table 21.

Table 21 Study Demographics and Trial Design of iPrEx Trial

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-1 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.

Partners PrEP Study

The demographics and trial design for the Partners PrEP study are summarized in Table 22.

Table 22 Study Demographics and Trial Design of Partners PrEP Trial

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).

Study Results iPrEx Study

Subjects were followed for 4237 person-years. The primary outcome measure for the study was the incidence of documented HIV-1 seroconversion. The results of the iPrEx study are summarized below in Table 23.

Table 23 iPrEx Study: Relative Risk Reduction Through End-of-Treatment Cutoff (Primary Analysis; mITT Analysis^a)

Abbreviation: CI = confidence interval

• a Modified Intent-to-Treat (mITT) analysis excludes subjects who do not have follow-up HIV test and who were infected at enrollment
• b p-values by log rank test

• c End of treatment is defined as the next post-treatment visit after this date (approximately one month).

  This analysis excludes post-treatment stop seroconversions. d Time to first evidence of seroconversion for those with event

Risk reduction was found to be higher (53%; 95% CI: 34% to 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 emtricitabine-tenofovir DF tablets 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 the greatest in subjects with detectable intracellular tenofovir. Efficacy was therefore strongly correlated with adherence.

Partners PrEP Study

The efficacy analyses results of the Partner’s PrEP study are summarized in Table 24 below.

Table 24 Partners PrEP Study: Relative Risk Reduction and HIV-1 Seroincidence for Partner Subjects (Primary Analysis; mITT Analysis^a)

a Modified Intent-to-Treat (mITT) analysis excludes subjects who were infected at enrollment b Time to first evidence of seroconversion for those with event

c p-values using Cox’s proportional hazards model for the active study drug relative to placebo

Two of the 13 seroconversions in the emtricitabine-tenofovir DF tablets arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction was most pronounced in subjects with detectable plasma tenofovir. Efficacy was therefore strongly correlated with adherence.

VIROLOGY (MICROBIOLOGY)

Mechanism of Action

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 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. Emtricitabine 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

Emtricitabine and tenofovir DF: In combination studies evaluating the in vitro antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed. Additive to synergistic effects were observed in combination studies with protease inhibitors, integrase strand transfer inhibitors, and with nucleoside and non-nucleoside analogue inhibitors of HIV-1 reverse transcriptase.

Emtricitabine: The in vitro antiviral activity of emtricitabine against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The IC₅₀ values for emtricitabine were in the range of 0.0013−0.64 mcM (0.0003−0.158 mcg/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, or zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine), protease inhibitors (amprenavir, nelfinavir, ritonavir, or saquinavir), and with integrase strand transfer inhibitors, additive to synergistic effects were observed. Most of these drug combinations have not been studied in humans. Emtricitabine displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, and G (IC₅₀ values ranged from 0.007−0.075 mcM) and showed strain specific activity against HIV-2 (IC₅₀ values ranged from 0.007−1.5 mcM).

Tenofovir DF: The in vitro 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 IC₅₀ (50% inhibitory concentration) values for tenofovir were in the range of 0.04−8.5 mcM. In drug combination studies of tenofovir with integrase strand transfer inhibitors, nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, or zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, or saquinavir), additive to synergistic effects were observed. Most of these drug combinations have not been studied in humans.

Tenofovir displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G, and O (IC₅₀ values ranged from 0.5−2.2 mcM).

Prophylactic Activity in a Nonhuman Primate Model of HIV Transmission

Emtricitabine and tenofovir DF: The prophylactic activity of the combination of daily oral emtricitabine and tenofovir DF 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 emtricitabine and tenofovir DF 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

Emtricitabine and tenofovir DF: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in vitro. 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 Study 934 (EMTRIVA + VIREAD + efavirenz compared with lamivudine/zidovudine + efavirenz), resistance analysis was performed on HIV isolates from all patients with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Genotypic resistance to efavirenz, predominantly the K103N mutation, was the most common form of resistance that developed. Resistance to efavirenz occurred in 13/19 (68%) analyzed patients in the EMTRIVA + VIREAD group and in 21/29 (72%) analyzed patients in the lamivudine/zidovudine group. The M184V mutation, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 (11%) analyzed patients in the EMTRIVA

+ VIREAD group and in 10/29 (34%) analyzed patients in the lamivudine/zidovudine group.

In treatment-naïve patients treated with EMTRIVA + VIREAD + efavirenz, none of the HIV isolates from 19 patients analyzed for resistance showed reduced susceptibility to tenofovir or the presence of the K65R or K70E mutation.

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

Emtricitabine-resistant isolates of HIV have been recovered from some patients treated with emtricitabine alone or in combination with other antiretroviral agents. In a clinical study, viral isolates from 6/16 (37.5%) treatment-naïve patients with virologic failure showed

>20-fold reduced susceptibility to emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I mutations in the HIV RT gene.

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 emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R or K70E substitutions. HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in RT and showed a 2–4 fold reduction in susceptibility to tenofovir.

Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with VIREAD in combination with certain antiretroviral agents. In treatment-naïve patients, 7/29 (24%) isolates from patients failing VIREAD + lamivudine + efavirenz at 48 weeks showed >1.4 fold (median 3.4) reduced susceptibility in vitro to tenofovir.

In treatment-experienced patients, 14/304 (4.6%, studies 902 and 907) isolates from patients failing VIREAD at 96 weeks showed >1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 RT gene resulting in the K65R amino acid substitution.

iPrEx Trial: In a clinical study of HIV-1 seronegative subjects (iPrEx Trial, see CLINICAL TRIALS), no mutations associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 48 subjects in the emtricitabine-tenofovir DF tablets 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 emtricitabine were observed in 3 of the 10 subjects (2 of 2 in the emtricitabine-tenofovir DF tablets group and 1 of 8 in the placebo group). One of the two subjects in the emtricitabine-tenofovir DF tablets 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 TRIALS), no variants expressing amino acid substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 12 subjects in the emtricitabine-tenofovir DF tablets 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 emtricitabine-tenofovir DF tablets group, 5 in the VIREAD group, and 6 in the placebo group). One of the three subjects in the emtricitabine-tenofovir DF tablets 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 emtricitabine-tenofovir DF tablets 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 emtricitabine and may have been present in the infecting virus.

Cross-resistance

Emtricitabine and tenofovir DF: Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognized. The M184V/I and/or K65R or K70E substitutions selected in vitro by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, 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.

Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in vitro to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). Isolates from heavily treatment-experienced patients containing the M184V/I amino acid substitution in the context of other NRTI resistance-associated substitutions may retain susceptibility to tenofovir. HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring mutations conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.

Tenofovir DF: HIV-1 isolates from patients (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.

Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the RT showed reduced susceptibility to tenofovir.

NON-CLINICAL TOXICOLOGY

Toxicology

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 4 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.

Carcinogenesis

Emtricitabine: In long-term oral carcinogenicity studies of emtricitabine, no drug-related increase in tumor incidence was found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose).

Tenofovir DF: Long-term oral carcinogenicity studies were conducted in mice and rats receiving tenofovir DF. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In the mouse study, (60/sex/group), one male and two female mice in the 600 mg/kg/day group (15 times the human systemic exposure at the recommended human dose of 300 mg/day) developed duodenal tumors. The mechanism underlying this effect is uncertain but may relate to high local drug concentrations in the gastrointestinal tract. No treatment-related tumors were seen in mice in the 100 or

300 mg/kg/day groups. In the rat study (60/sex/group) at doses of 30, 100, and

300 mg/kg/day (approximately 5 times human exposure), no treatment-related increase in tumor incidence was observed.

Mutagenesis

Emtricitabine: Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.

Tenofovir DF: Tenofovir DF was negative in the in vitro bacterial mutation (Ames) assay (Salmonella-Eschericia coli/Mammalian-Microsome Reverse Mutation Assay) but positive in the in vitro mouse lymphoma assay (L5178Y TK +/- Forward Mutation Assay), with and without metabolic activation. Tenofovir DF was negative in the in vivo mouse micronucleus assay at plasma exposure levels of more than 10× the human exposure.

Impairment of Fertility

Emtricitabine: Emtricitabine 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: Reproductive toxicity was evaluated in rats and rabbits. Tenofovir DF had no adverse effects on fertility or general reproductive performance in rats at doses up to

600 mg/kg/day. Tenofovir DF had no adverse effects on embryo-fetal development in rats at doses 450 mg/kg/day and in rabbits at doses up to 300 mg/kg/day. In a study of effects on peri- and postnatal development in rats, effects considered due to maternal toxicity (450–

600 mg/kg/day) were reduced survival and a slight delay in sexual maturation in the F1 generation. There were no adverse effects on growth, development, behavior, or reproductive parameters at non-maternally toxic doses (150 mg/kg/day).

Pregnancy

Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine 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. Reduced pup body weights, survival and delay in sexual maturation was observed in a peri- and postnatal toxicity study in rats at the maternally toxic doses of 450 and 600 mg/kg (approximately 14 and 19 times the human dose based on body surface area comparisons).

Antiretroviral Pregnancy Registry

To monitor fetal outcomes of pregnant women exposed to ART (antiretroviral therapy) including Sandoz Emtricitabine-Tenofovir, an Antiretroviral Pregnancy Registry has been established.

Healthcare providers are encouraged to register patients by calling 800–258–4263.

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