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Black Box Warning Post-treatment acute exacerbation of hepatitis B, and risk of drug resistance with use of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) in undiagnosed early HIV-1 infection Severe acute exacerbations of hepatitis B (HBV) have been reported in HBV-infected patients who have discontinued TDF/FTC. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in HBV-infected patients who discontinue TDF/FTC. If appropriate, initiation of anti-hepatitis B therapy may be warranted (see special warnings and precautions for use). TDF/FTC used for HIV-1 PrEP must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and at least every 3 months during use. Drug-resistant HIV-1 variants have been identified with use of TDF/FTC for a PrEP indication following undetected acute HIV-1 infection. Do not initiate TDF/FTC for a PrEP if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed (see special warnings and precautions for use).

Qualitative And Quantitative Composition

Tenvir-EM Tablets

Each tablet contains:

Emtricitabine ………………………..200 mg

Tenofovir Disoproxil Fumarate……..300 mg

Equivalent to Tenofovir disoproxil….245 mg

Dosage Form and Strength

Oral, fixed-dose tablet of Emtricitabine (FTC) 200 mg and Tenofovir disoproxil fumarate (TDF) 300 mg.

Clinical Particulars

Therapeutic Indications

Treatment of HIV-1 Infection

TENVIR-EM Tablets are indicated for the treatment of HIV-1 infection in adults.

HIV-1 Pre-Exposure Prophylaxis

TENVIR-EM Tablets are indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.

Individuals must have a negative HIV-1 test immediately prior to initiating TENVIR-EM Tablets for HIV-1 PrEP.

Posology and Method of Administration

Testing Prior to Initiation of TENVIR-EM Tablets for Treatment of HIV-1 Infection or for HIV-1 PrEP

Prior to or when initiating TENVIR-EM Tablets, test patients for HBV (hepatitis B virus) infection (see Special Warnings and Precautions for Use).

Prior to initiation and during use of TENVIR-EM Tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus (see Special Warnings and Precautions for Use).

HIV-1 Screening for Individuals Receiving TENVIR-EM Tablets for HIV-1 PrEP

Screen all individuals for HIV-1 infection before initiating TENVIR-EM Tablets for HIV-1 PrEP and at least once every 3 months while taking TENVIR-EM Tablets, and upon diagnosis of any other sexually transmitted infections (STIs) (see Therapeutic Indications, Contraindications and Special Warnings and Precautions for Use ).

If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection (see Special Warnings and Precautions for Use and Use in Special Populations).

Recommended Dose for Treatment of HIV-1 Infection in Adults

The recommended dose of TENVIR-EM in adults is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily, taken orally with or without food.

Recommended Dose for HIV-1 PrEP in adults

The dose of TENVIR-EM in HIV-1 uninfected adults is one tablet (containing 200 mg of Emtricitabine and 300 mg of TDF) once daily, taken orally with or without food.

Dose Adjustment in Individuals with Renal Impairment

Treatment of HIV-1 infection

Table 1 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). The safety and effectiveness of the dosing interval adjustment recommendations in patients with moderate renal impairment (creatinine clearance 30–49 mL/min) have not been clinically evaluated; therefore, clinical response to treatment and renal function should be closely monitored in these patients (see Special Warnings and Precautions for Use).

	Creatinine Clearance (mL/min)a
	≥ 50	30-49	<30 (including patients requiring hemodialysis)
Recommended Dosing Interval	Every 24 hours	Every 48 hours	TENVIR-EM is not recommended.

HIV-1 Pre-exposure Prophylaxis

TENVIR-EM for a HIV-1 PrEP is not recommended  in HIV-1 uninfected individuals with estimated  creatinine clearance <60 mL/min (see Special Warnings and Precautions for Use).

If a decrease in creatinine clearance is observed in uninfected individuals while using TENVIR-EM Tablets for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see Special Warnings and Precautions for Use).

Contraindications

TENVIR-EM Tablets for HIV-1 PrEP is contraindicated in individuals with unknown or positive HIV-1 status (see Special Warnings and Precautions for Use).

Special Warnings and Precautions for Use

Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection

All individuals should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating TDF/FTC (see Posology and Method of Administration).

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in HBV-infected individuals who have discontinued TDF/FTC. Individuals infected with HBV who discontinue TDF/FTC should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in individuals with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. HBV-uninfected individuals should be offered vaccination.

Comprehensive Management to Reduce the Risk of Sexually Transmitted Infections, Including HIV-1, and Development of HIV-1 Resistance When TDF/FTC Tablets are Used for HIV­ 1 PrEP

Use TDF/FTC for PrEP only as part of a comprehensive prevention strategy that includes other prevention measures, such as safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). The time from initiation of TDF/FTC for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.

Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use, knowledge of partner(s)’ HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission). Inform uninfected individuals about and support their efforts in reducing sexual risk behavior.

Use TDF/FTC to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative.

HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only TDF/FTC, because TDF/FTC alone does not constitute a complete treatment regimen for HIV-1 treatment; therefore, care should be taken to minimize the risk of initiating or continuing TDF/FTC before confirming the individual is HIV-1 negative.

• Some HIV-1 tests only detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating TDF/FTC for a PrEP indication, evaluate seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, or a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash).

• If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection.

While using TDF/FTC for a HIV-1 PrEP, HIV-1 screening tests should be repeated at least every 3 months and upon diagnosis of any other sexually transmitted infections.

• If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, convert the HIV-1 PrEP regimen to an HIV treatment regimen until negative infection status is confirmed using a test approved or cleared by the FDA as an aid in the diagnosis of HIV-1, including acute or primary HIV-1 infection.

Counsel HIV-1-uninfected individuals to strictly adhere to the once daily TDF/FTC dosing schedule. The effectiveness of TDF/FTC in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials of TDF/FTC for HIV-1 PrEP.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including TDF/FTC. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis), which may necessitate further evaluation and treatment.

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

Bone Loss and Mineralization Defects

Bone Mineral Density

In clinical trials in HIV-1 infected adults and in a clinical trial of HIV-1 uninfected individuals, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators (see Undesirable Effects and Tenofovir Disoproxil Fumarate prescribing information). Serum parathyroid hormone levels and 1, 25 Vitamin D levels were also higher in subjects receiving TDF.

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

Mineralization Defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF (see Undesirable Effects). 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 TDF (see Special Warnings and Precautions for Use).

Lactic Acidosis/Severe Hepatomegaly with Steatosis

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

Risk of Adverse Reactions Due to Drug Interactions

The concomitant use of TDF/FTC and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs (see Drug Interactions).

See Table 2 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TDF/FTC; review concomitant medications during therapy with TDF/FTC; and monitor for adverse reactions associated with the concomitant drugs.

Drug Interactions

Drugs Affecting Renal Function

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

Established and Significant Interactions

Table 2 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with either TDF/FTC, the components of TENVIR-EM Tablets as individual agents and/or in combination, or are predicted drug interactions that may occur with TDF/FTC.

Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
NRTI: didanosinec	↑ didanosine	Patients receiving TDF/FTC and didanosine should be didanosinec monitored closely for didanosine-associated adverse reactions. Discontinue didanosine in patients who develop didanosine-associated adverse reactions. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving TDF with didanosine 400 mg daily. In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with TDF/FTC. Data are not available to recommend a dose adjustment of didanosine for adult patients weighing less than 60 kg. When coadministered, TDF/FTC and didanosine may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat)
HIV-1 Protease Inhibitors: atazanavirc     lopinavir/ritonavirc atazanavir/ritonavirc darunavir/ritonavirc	↓ atazanavir       ↑ tenofovir	When co-administered with TDF/FTC, atazanavir 300 mg should be given with ritonavir 100 mg.   Monitor patients receiving TDF/FTC concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir boosted darunavir for TDF-associated adverse reactions.   Discontinue TDF/FTC in patients who develop TDF associated adverse reactions
Hepatitis C Antiviral Agents: sofosbuvir/velpatasvirc sofosbuvir/velpatasvir/ voxilaprevirc   ledipasvir/sofosbuvirc	↑ tenofovir	Monitor patients receiving TDF/FTC concomitantly with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir for adverse reactions associated with TDF.   Monitor patients receiving TDF/FTC concomitantly with ledipasvir/sofosbuvir without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination for adverse reactions associated with TDF. In patients receiving TDF/FTC concomitantly with ledipasvir/sofosbuvir and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with TDF.

^aThis table is not all inclusive.
^b↑=Increase, ↓=Decrease
^cIndicates that a drug-drug interaction trial was conducted.

Use in Special Populations

Pregnant Women

Risk Summary

Data on the use of TDF/FTC during pregnancy from observational studies have shown no increased risk of major birth defects. Available data from the Antiretroviral Pregnancy Registry (APR) show no increase in the overall risk of major birth defects with first trimester exposure for FTC (FTC) (2.3%) or TDF (TDF) (2.1%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%.

In animal reproduction studies, no adverse developmental effects were observed when the components of TDF/FTC were administered separately at doses/exposures ≥60 (FTC), ≥14 (TDF) and 2.7 (tenofovir) times those of the recommended daily dose of TDF/FTC.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

HIV-1 PrEP: Published studies indicate an increased risk of HIV-1 infection during pregnancy and an increased risk of mother to child transmission during acute HIV-1 infection. In women at risk of acquiring HIV-1, consideration should be given to methods to prevent acquisition of HIV, including continuing or initiating TDF/FTC for HIV-1 PrEP, during pregnancy.

Data

Human Data

TDF/FTC for HIV-1 PrEP: In an observational study based on prospective reports to the APR, 78 HIV-seronegative women exposed to TDF/FTC during pregnancy delivered live-born infants with no major malformations. All except for one were first trimester exposures, and the median duration of exposure was 10.5 weeks. There were no new safety findings in the women receiving TDF/FTC for HIV-1 PrEP compared with HIV-1 infected women treated with other antiretroviral medications.

FTC

Based on prospective reports to the APR of 3,749 exposures to FTC-containing regimens during pregnancy resulting in live births (including 3,300 exposed in the first trimester and 1,300 exposed in the second/third trimester), the prevalence of major birth defects in live births was 2.6% (95% CI: 2.1% to 3.2%) and 2.3% (95% CI: 1.6% to 3.3%) following first and second/third trimester exposure, respectively, to FTC-containing regimens.

TDF

Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 4,000 exposed in the first trimester and over 1,700 exposed in the second/third trimester), the prevalence of major birth defects in live births was 2.4% (95% CI: 2.0% to 2.9%) and 2.4% (95% CI: 1.7% to 3.2%) following first and second/third trimester exposure, respectively, to TDF-containing regimens.

Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.

Additionally, published observational studies on FTC and tenofovir exposure in pregnancy have not shown an increased risk for major malformations.

Animal Data

FTC

FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.

TDF

TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of TDF/FTC.

Lactating Women

Risk Summary

Based on published data, FTC and tenofovir have been shown to be present in human breast milk (see Data). It is not known if the components of TDF/FTC affect milk production or have effects on the breastfed child.

Treatment of HIV-1 Infection

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking TDF/FTC for the treatment of HIV-1.

HIV-1 PrEP

In HIV-uninfected women, the developmental and health benefits of breastfeeding and the mother’s clinical need for TDF/FTC for HIV-1 PrEP should be considered along with any potential adverse effects on the breastfed child from TDF/FTC and the risk of HIV-1 acquisition due to nonadherence and subsequent mother to child transmission.

Women should not breastfeed if acute HIV-1 infection is suspected because of the risk of HIV-1 transmission to the infant.

Data

HIV-1 PrEP: In a study of 50 breastfeeding women who received TDF/FTC for HIV-1 PrEP between 1 and 24 weeks postpartum (median 13 weeks), after 7 days of treatment, tenofovir was undetectable but FTC was detectable in the plasma of most infants. In these infants, the average FTC plasma concentration was less than 1% of the FTC C_max observed in HIV-infected infants (up to 3 months of age) receiving the therapeutic dose of FTC (3 mg/kg/day). There were no serious adverse events. Two infants (4%) had an adverse event of mild diarrhea which resolved.

Pediatric Patients

Treatment of HIV-1 Infection

No pediatric clinical trial was conducted to evaluate the safety and efficacy of  TENVIR-EM tablets.

HIV-1 PrEP

The safety and effectiveness of TENVIR-EM tablets for HIV-1 PrEP in at-risk adolescents has not be evaluated. p

Geriatric Patients

Clinical trials of FTC, TDF, or TDF/FTC did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

Patients with Renal Impairment

The dosing interval for TDF/FTC should be modified in HIV-infected adult patients with creatinine clearance of 30–49 mL/min. TDF/FTC is not recommended in patients with estimated creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis (see Posology and Method of Administration).

HIV-1 PrEP

TDF/FTC for a HIV-1 PrEP indication is not recommended 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 TDF/FTC for HIV -1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see Posology and Method of Administration).

Effects on Ability to Drive and Use of Machines

No studies on the effects on the ability to drive and use machines have been performed. However, individuals should be informed that dizziness has been reported during treatment with both FTC and tenofovir disoproxil fumarate.

Undesirable Effects

The following are the adverse reactions:

• Severe Acute Exacerbations of Hepatitis B in Patients with HBV Infection (see Special Warnings and Precautions for use).
• New Onset or Worsening Renal Impairment (see Special Warnings and Precautions for Use).
• Lactic Acidosis/Severe Hepatomegaly with Steatosis (see Special Warnings and Precautions for Use).
• Bone Loss and Mineralization Defects (see Special Warnings and Precautions for Use).
• Immune Reconstitution Syndrome (see Special Warnings and Precautions for Use).

Clinical Trials Experience

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

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

Clinical Trials In Adult Subjects

In Study 934, 511 antiretroviral naïve subjects received either TDF + FTC administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, any severity) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 3 provides the treatment-emergent adverse reactions (Grades 2-4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Skin discoloration, manifested by hyperpigmentation, occurred in 3% of subjects taking FTC+TDF, and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

	FTC + TDF + EFVb	AZT/3TC + EFV
	N=257	N=254
Fatigue Depression Nausea Diarrhea Dizziness Upper respiratory tract infections Sinusitis Rash eventc Headache Insomnia Nasopharyngitis Vomiting	9% 9% 9% 9% 8% 8% 8% 7% 6% 5% 5% 2%	8% 7% 7% 5% 7% 5% 4% 9% 5% 7% 3% 5%

^aFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.

^bFrom Weeks 96 to 144 of the trial, subjects received TDF/ FTC with efavirenz in place of TDF + FTC with efavirenz.

^cRash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.

LABORATORY ABNORMALITIES: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of TDF and/or FTC (Table 4).

	FTC + TDF + EFVa	AZT/3TC + EFV
	N=257	N=254
Any ≥ Grade 3 Laboratory Abnormality	30%	26%
Fasting Cholesterol (>240 mg/dL)	22%	24%
Creatinine Kinase (M: >990 U/L) (F: >845 U/L)	9%	7%
Serum Amylase (>175 U/L)	8%	4%
Alkaline Phosphatase (>550 U/L)	1%	0%
AST (M: >180 U/L) (F: >170 U/L)	3%	3%
ALT (M: >215 U/L) (F: >170 U/L)	2%	3%
Hemoglobin (<8.0 mg/dL)	0%	4%
Hyperglycemia (>250 mg/dL)	2%	1%
Hematuria (>75 RBC/HPF)	3%	2%
Glycosuria (≥ 3+)	< 1%	1%
Neutrophils (<750/mm3)	3%	5%
Fasting Triglycerides (>750 mg/dL)	4%	2%

^aFrom Weeks 96 to 144 of the trial, subjects received TDF + FTC with efavirenz in place of TDF + FTC with efavirenz.

Adverse Reactions from Clinical Trials Experience in Uninfected Adult Subjects Taking TDF/FTC for HIV-1 PrEP

Clinical Trials in Adult Subjects

The safety profile of TDF/FTC for HIV-1 PrEP was comparable to that observed in clinical trials of HIV-infected subjects based on two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2,830 HIV-1 uninfected adults received TDF/FTC once daily for HIV-1 PrEP. Subjects were followed for a median of 71 weeks and 87 weeks, respectively. Table 5 provides a list of selected adverse events that occurred in 2% or more of subjects in any treatment group in the iPrEx trial, with an incidence greater than placebo.

	FTC/TDF (N=1251)	Placebo (N=1248)
Headache	7%	6%
Abdominal pain	4%	2%
Weight decreased	3%	2%

In the Partners PrEP trial, the frequency of adverse events in the TDF/FTC treatment group was generally either less than or the same as in the placebo group.

Laboratory Abnormalities: Table 6 provides a list of Grades 2–4 laboratory abnormalities observed in the iPrEx and Partners PrEP trials. In the TDF-containing arms of the Partners PrEP trial, 6 subjects discontinued participation in the study due to an increase in blood creatinine compared with no discontinuations in the placebo group. In the TDF/FTC arm of the iPrEx trial, 2 subjects discontinued from the study (one due to an increase in blood creatinine and another due to low phosphorous).

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

Grade 2-4a	iPrEx Trial		Partners PrEP trial
	FTC/TDF N= 1251	Placebo N= 1248	FTC/TDF N= 1579	Placebo N= 1584
Creatinine (>1.4 x ULN)	<1%	<1%	<1%	<1%
Phosphorus (<2.0 mg/dL)	10%	8%	9%	9%
AST (>2.6 x ULN)	5%	5%	<1%	<1%
ALT (>2.6 x ULN)	7%	7%	<1%	<1%
Hemoglobin <9.4 mg/dL	1%	2%	2%	2%
Neutrophils (<750/mm3)	<1%	<1%	5%	3%

^aGrading is as per DAIDS criteria.

Changes In Bone Mineral Density: In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the iPrEx trial, a substudy of 503 subjects found mean changes from baseline in BMD ranging from -0.4% to -1.0% across total hip, spine, femoral neck, and trochanter in the TDF/FTC group compared with the placebo group, which returned toward baseline after discontinuation of treatment. During treatment 13% of subjects receiving TDF/FTC 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 TDF/FTC 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.

Postmarketing Experience

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

Immune system disorders: allergic reaction, including angioedema

Metabolism and nutrition disorders: lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, thoracic, and mediastinal disorders: dyspnea

Gastrointestinal disorders: pancreatitis, increased amylase, abdominal pain

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

Skin and Subcutaneous Tissue Disorders: rash

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

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

General Disorders and Administration Site Conditions: asthenia

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

Reporting of Side-effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

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

FTC

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

TDF

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour haemodialysis session removed approximately 10% of the administered tenofovir dose.

Pharmacological Properties

Mechanism of Action

TENVIR-EM Tablets are a fixed-dose combination of antiviral drugs emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF).

FTC

FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form FTC 5'-triphosphate (FTC-TP), which 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. FTC-TP is a weak inhibitor of mammalian DNA polymerases a, b, e and mitochondrial DNA polymerase g.

TDF

TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate (TFV-DP), which 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. TFV-DP is a weak inhibitor of mammalian DNA polymerases a, b, and mitochondrial DNA polymerase g.

Pharmacodynamic Properties

FTC

Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form FTC 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 polymerase alpha, beta, epsilon and mitochondrial DNA polymerase gamma.

TDF

TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF 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 alpha, beta, and mitochondrial DNA polymerase gamma.

Pharmacokinetic Properties

One TDF/FTC Tablet was bioequivalent to one FTC capsule (200 mg) plus one TDF tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).

FTC

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

TDF

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

	Emtricitabine	Tenofovir
Fasted oral bioavailabilityb (%)	92 (83.1-106.4)	25 (NC-45.0)
Plasma terminal elimination half-lifeb (hr)	10 (7.4-18.0)	17 (12.0-25.7)
Cmaxc (µg/mL)	1.8 ± 0.72d	0.30 ± 0.09
AUCc (µg·hr/mL)	10.0 ± 3.12d	2.29 ± 0.69
CL/Fc (mL/min)	302 ± 94	1043 ± 115
CLrenalc (mL/min)	213 ± 89	243 ± 33

^aNC = Not calculated

^bMedian (range)

^cMean (± SD)

^dData presented as steady state values.

Effects of Food on Oral Absorption

TDF/FTC may be administered with or without food. Administration of TDF/FTC 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 trials, TDF was taken under fed conditions. FTC systemic exposures (AUC and C_max) were unaffected when TDF/FTC was administered with either a high fat or a light meal.

Special Populations

Race

FTC

No pharmacokinetic differences due to race have been identified following the administration of FTC.

TDF

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

Gender

TDF/FTC

FTC and TDF pharmacokinetics are similar in male and female subjects.

Geriatric Patients

Pharmacokinetics of FTC and TDF has not been fully evaluated in the elderly (65 years of age and older).

Patients with Renal Impairment

The pharmacokinetics of FTC and TDF are altered in subjects with renal impairment (see Special Warnings and Precautions for Use). In adult subjects with creatinine clearance <50 mL/min, C_max, and AUC_0-∞ of FTC and tenofovir were increased. No data are available to make dosage recommendations in pediatric patients with renal impairment.

Patients with Hepatic Impairment

The pharmacokinetics of tenofovir following a 300 mg dose of TDF 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 TDF/FTC or FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Nonclinical Properties

Animal Toxicology and/or Pharmacology

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

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

FTC

In long-term oral carcinogenicity studies of FTC, no drug-related increases in tumor incidence were 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).

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

FTC 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.

TDF

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

TDF 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, TDF was negative when administered to male mice.

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

Description

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

Emtricitabine

The chemical name of FTC is 5-fluoro-1-(2R,5S)-cytosine. FTC is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

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

Tenofovir Disoproxil Fumarate

TDF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF is 9-methoxy] phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C₁₉H₃₀N₅O₁₀P • C₄H₄O₄ and a molecular weight of 635.52. It has the following structural formula:

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf-Life

As on the pack.

Packaging Information

TENVIR-EM Tablets……..Container of 30 tablets

Storage and Handling Instructions

Store in a cool, dry place.

Patient Counseling Information

• What is the most important information I should know about TENVIR-EM Tablets?

TENVIR-EM Tablets can cause serious side effects, including the following:

Worsening of your hepatitis B infection. If you have hepatitis B virus (HBV) infection it may become worse (flare-up) if you take TENVIR-EM Tablets and then stop it. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.

• Do not run out of TENVIR-EM Tablets. Refill your prescription or talk to your healthcare provider before your TENVIR-EM Tablets is all gone.
• Do not stop taking TENVIR-EM Tablets without first talking to your healthcare provider.
• If you stop taking TENVIR-EM Tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TENVIR-EM Tablets.

For more information about side effects, see the section “What are the possible side effects of TENVIR-EM Tablets?”.

Other important information for people who take TENVIR-EM Tablets to help reduce their risk of getting human immunodeficiency virus-1 (HIV-1) infection, also called pre-exposure prophylaxis or “PrEP”:

Before taking TENVIR-EM Tablets to reduce your risk of getting HIV:

• You must be HIV-1 negative to start TENVIR-EM Tablets.. You must get tested to make sure that you do not already have HIV-1 infection..
• Do not take TENVIR-EM Tablets to reduce the risk of getting HIV-1 unless you are confirmed to be HIV-negative.
• Some HIV-1 tests can miss HIV-1 infection in a person who has recently become infected. If you have flu-like symptoms, you could have recently become infected with HIV-1. Tell your healthcare provider if you have had a flu-like illness within the last month before starting TENVIR-EM Tablets or at any time while taking TENVIR-EM Tablets. Symptoms of new HIV-1 infection include::

• Tiredness
• fever
• night sweats
• rash
• vomiting or diarrhea
• joint or muscle aches
• headache
• sore throat
• enlarged lymph nodes in the neck or groin

While you are taking TENVIR-EM Tablets for HIV-1 PrEP:

• TENVIR-EM Tablets does not prevent other sexually transmitted infections (STIs). Practice safer sex by using a latex or polyurethane condom to reduce the risk of getting STIs.
• You must stay HIV-negative to keep taking TENVIR-EM Tablets for HIV-1 PrEP.

• Know your HIV-1 status and the HIV-1 status of your partners.
• Ask your partners with HIV-1 if they are taking anti-HIV-1 medicines and have an undetectable viral load. An undetectable viral load is when the amount of virus in the blood is too low to be measured in a lab test. To maintain an undetectable viral load, your partners must keep taking HIV-1 medicines every day. Your risk of getting HIV-1 is lower if your partners with HIV-1 are taking effective treatment.
• Get tested for HIV-1 at least every 3 months or when your healthcare provider tells you. Get tested for other STIs such as syphilis, chlamydia, and gonorrhea. These infections make it easier for HIV-1 to infect you.
• If you think you were exposed to HIV-1, tell your healthcare provider right away. They may want to do more tests to be sure you are still HIV-1 negative.
• Get information and support to help reduce sexual risk behaviors.
• Do not miss any doses of TENVIR-EM Tablets. Missing doses increases your risk of getting HIV-1 infection.
• If you do become HIV-1 positive, you need more medicine than TENVIR-EM Tablets alone to treat HIV-1. TENVIR-EM Tablets by itself is not a complete treatment for HIV-1.

If you have HIV-1 and take only TENVIR-EM Tablets, over time your HIV-1 may become harder to treat.

• What are TENVIR-EM Tablets?

TENVIR-EM Tablets is a prescription medicine that may be used in two different ways.

TENVIR-EM Tablets is used:

 • to treat HIV-1 infection when used with other anti-HIV-1 medicines in adults

• for HIV-1 PrEP to reduce the risk of getting HIV-1 infection in adults.

HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). TENVIR-EM Tablets contains the prescription medicines emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF).

For people taking TENVIR-EM Tablets for HIV-1 PrEP:

Do not take TENVIR-EM Tablets for HIV-1 PrEP if:

• you already have HIV-1 infection. If you are HIV-1 positive, you need to take other medicines with TENVIR-EM Tablets to treat HIV-1. TENVIR-EM Tablets by itself is not a complete treatment for HIV-1.

• you do not know your HIV-1 infection status. You may already be HIV-1 positive. You need to take other HIV-1 medicines with TENVIR-EM Tablets to treat HIV-1. TENVIR-EM Tablets can only help reduce your risk of getting HIV-1 before you are infected.

• What should I tell my healthcare provider before taking TENVIR-EM Tablets?

See “What is the most important information I should know about TENVIR-EM Tablets?”

Before taking TENVIR-EM Tablets, tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems including HBV infection
• have kidney problems or receive kidney dialysis treatment
• have bone problems
• are pregnant or plan to become pregnant. It is not known if TENVIR-EM Tablets can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with TENVIR-EM Tablets.

Pregnancy Registry: There is a pregnancy registry for people who take TDF/FTC during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.

• are breastfeeding or plan to breastfeed. TENVIR-EM Tablets can pass to your baby in your breast milk. Do not breastfeed if you take TENVIR-EM Tablets.
  
  • Do not breastfeed if you have HIV-1 or if you think you have recently become infected with HIV-1 because of the risk of passing HIV-1 to your baby.

•  If you take TENVIR-EM Tablets for HIV-1 PrEP, talk with your healthcare provider about the best way to feed your baby. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may interact with TENVIR-EM Tablets. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with TENVIR-EM Tablets.
• Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TENVIR-EM Tablets with other medicines.

• How should I take TENVIR-EM Tablets?

• Take TENVIR-EM Tablets exactly as your healthcare provider tells you to take. If you take TENVIR-EM Tablets to treat HIV-1 infection, you need to take other HIV-1 medicines. Your healthcare provider will tell you what medicines to take and how to take them.
• Take TENVIR-EM Tablets 1 time each day with or without food.
• Do not change your dose or stop taking TENVIR-EM Tablets without first talking with your healthcare provider. Stay under a healthcare provider’s care when taking TENVIR-EM Tablets. Do not miss a dose of TENVIR-EM Tablets.
• If you take too much TENVIR-EM Tablets, call your healthcare provider or go to the nearest hospital emergency room right away.
• When your TENVIR-EM Tablets supply starts to run low, get more from your healthcare provider or pharmacy.

• If you are taking TENVIR-EM Tablets for treatment of HIV-1, the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to TENVIR-EM Tablets and become harder to treat.
• If you are taking TENVIR-EM Tablets for HIV-1 PrEP, missing doses increases your risk of getting HIV-1 infection.

• How should I store TENVIR-EM Tablets?

• Store in a cool, dry place.
• Do not use TENVIR-EM Tablets if the seal over bottle opening is broken or missing. Keep TENVIR-EM Tablets and all other medicines out of the reach of children.

What are the possible side effects of TENVIR-EM Tablets?
TENVIR-EM Tablets may cause the following serious side effects, including the following:

• See “What is the most important information I should know about TENVIR-EM Tablets?”
• New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and during treatment with TENVIR-EM Tablets. Your healthcare provider may tell you to take TENVIR-EM Tablets less often, or to stop taking TENVIR-EM Tablets if you have kidney problems.
• Bone problems can happen in some people who take TENVIR-EM Tablets. Bone problems include bone pain, softening or thinning (which may lead to fractures). Your healthcare provider may need to do tests to check your bones.

• Too much lactic acid in your blood (lactic acidosis) Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.  
• Changes in your immune system (Immune Reconstitution Syndrome) can happen when an HIV-infected person starts taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV medicine.
• Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark “tea-colored” urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.

The most common side effects of TDF/FTC in people with HIV-1 infection include the following:

• Diarrhea
• Nausea
• Tiredness
• Headache
• Dizziness
• Depression
• Problems sleeping
• Abnormal dreams
• Rash

Common side effects in people who take TDF/FTC for HIV-1 PrEP include the following:

• Stomach-area (abdomen) pain
• Headache
• Decreased weight

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

These are not all the possible side effects of TENVIR-EM Tablets. For more information, or medical advice about side effects, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779.  By reporting side effects, you can help provide more information on the safety of this product.

General information about TENVIR-EM Tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TENVIR-EM Tablets for a condition for which it was not prescribed. Do not give TENVIR-EM Tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TENVIR-EM Tablets that is written for health professionals.

Details of the Manufacturer

Mfd. by: Cipla Ltd. Regd. Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400 013, India

Details of Permission or License Number with Date

MF-6433/06           Dated 23.02.2006

MF-07/2016            Dated 17.02.2016

Date of Revision

14/05/2021