Black Box Warning

Warnings: Post-treatment acute exacerbation of hepatitis B

Severe acute exacerbations of hepatitis B virus (HBV) have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including tenofovir. If appropriate, resumption of anti-hepatitis B therapy may be warranted (see Special Warnings and Precautions for Use).

Qualitative And Quantitative Composition

Each film-coated tablet contains:

Tenofovir Disoproxil Fumarate IP …………….. 300 mg

Colour: Lake Indigo Carmine and Titanium Dioxide

Dosage form(S) and Strength(S)

Oral, film-coated tablet containing 300 mg of tenofovir disoproxil fumarate

Clinical Particulars

Therapeutic Indications

HIV Infection

TENVIR Tablets are indicated for the treatment of HIV-1 infection in adults in combination with other antiretroviral agents (such as Non-nucleoside reverse transcriptase inhibitors [NNRTIs] or Protease inhibitor [PIs]).

Chronic Hepatitis B

TENVIR Tablets are indicated for the treatment of chronic hepatitis B in adults.

Posology and Method of Administration

Testing Prior to Initiation of TENVIR Tablets for the Treatment of HIV-1 Infection or Chronic Hepatitis B

Prior to or when initiating tenofovir disoproxil fumarate, test patients for HBV infection and HIV-1 infection. Tenofovir disoproxil fumarate alone should not be used in patients with HIV-1 infection (see Special Warnings and Precautions for Use).

Prior to initiation and during use of tenofovir disoproxil fumarate, 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).

Recommended Tablet Dosage in Adults

The recommended dose of TENVIR Tablet is 300 mg once daily taken orally, without regard to food. The dosage for TENVIR Tablets is the same for both HIV and HBV indications.

Dose Adjustment for Renal Impairment in Adults

Significantly increased drug exposures occurred when tenofovir disoproxil fumarate was administered to subjects with moderate-to-severe renal impairment (creatinine clearance below 50 mL/min). Table 1 provides dosage interval adjustment for patients with renal impairment

No dose adjustment of tenofovir tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). (see Special Warnings and Precautions for Use, Pharmacological Properties).

Table 1: Dosage adjustment for patients with altered creatinine clearance

	Creatinine Clearance (mL/min)^a			Hemodialysis Patients
	≥50	30–49	10–29
Recommended 300 mg dosing interval	Every 24 hours	Every 48 hours	Every 72 to 96 hours	Every 7 days or after a total of approximately 12 hours of dialysis^b
^a Calculated using ideal (lean) body weight. ^b Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours’ duration. Tenofovir disoproxil fumarate should be administered following completion of dialysis.

No data are available to make dosage recommendations in patients with creatinine clearance below 10 mL/min who are not on hemodialysis.

Contraindications

None.

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 tenofovir disoproxil fumarate, alone or in combination with other antiretrovirals. Treatment with 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).

Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection

All patients should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating tenofovir disoproxil fumarate (see Posology and Method of Administration).

Discontinuation of anti-HBV therapy, including tenofovir, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue tenofovir should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

New Onset or Worsening Renal Impairment

Tenofovir is principally eliminated by the kidneys. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir disoproxil fumarate

Prior to initiation and during use of tenofovir disoproxil fumarate, 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.

Dosing interval adjustment of tenofovir disoproxil fumarate and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min (see Posology and Method of Administration). No safety or efficacy data are available in patients with renal impairment who received tenofovir disoproxil fumarate using these dosing guidelines, so the potential benefit of tenofovir therapy should be assessed against the potential risk of renal toxicity.

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

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

Patients Co-infected with HIV-1 and HBV

Due to the risk of development of HIV-1 resistance, tenofovir should only be used in HIV-1 and HBV co-infected patients as part of an appropriate antiretroviral combination regimen.

HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with tenofovir. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with tenofovir.

Bone Loss and Mineralization Defects

Bone Mineral Density

In clinical trials in HIV-1 infected adults, tenofovir disoproxil fumarate 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. Serum parathyroid hormone levels and 1,25 vitamin D levels were also higher in subjects receiving tenofovir disoproxil fumarate.

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. 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. If bone abnormalities are suspected, appropriate consultation should be obtained.

Mineralization Defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir. 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 disoproxil fumarate-containing products.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including tenofovir disoproxil fumarate. 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 (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

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

Risk of Adverse Reactions Due to Drug Interactions

The concomitant use of tenofovir disoproxil fumarate 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 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 tenofovir disoproxil fumarate; review concomitant medications during therapy with tenofovir disoproxil fumarate, and monitor for adverse reactions associated with the concomitant drugs.

Drug Interactions

Drugs Affecting Renal Function

Since tenofovir is primarily eliminated by the kidneys (see Pharmacological Properties), co-administration of tenofovir disoproxil fumarate with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs. Drugs that decrease renal function may increase concentrations of tenofovir.

In the treatment of chronic hepatitis B, tenofovir should not be administered in combination with adefovir dipivoxil.

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 tenofovir disoproxil fumarate.

Table 2: Established and significanta drug interactions: alteration in dose or regimen may be recommended based on drug interaction trials

Concomitant Drug Class: Drug Name

Effect on Concentration ^b

Clinical Comment

NRTI:

Didanosine

↑ didanosine

Patients receiving tenofovir disoproxil fumarate and didanosine should be 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 tenofovir disoproxil fumarate with didanosine 400 mg daily.

In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with tenofovir disoproxil fumarate. In patients weighing less than 60 kg, reduce the didanosine dose to 200 mg when it is coadministered with tenofovir disoproxil fumarate. When coadministered, tenofovir disoproxil fumarate and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat).

HIV-1 Protease Inhibitors: atazanavir

lopinavir/ritonavir atazanavir/ritonavir darunavir/ritonavir

↓ atazanavir

↑ tenofovir

When co-administered with tenofovir disoproxil fumarate, atazanavir 300 mg should be given with ritonavir 100 mg.

Monitor patients receiving tenofovir disoproxil fumarate concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir for tenofovir disoproxil fumarate-associated adverse reactions. Discontinue tenofovir disoproxil fumarate in patients who develop tenofovir disoproxil fumarate-associated adverse reactions.

Hepatitis C Antiviral Agents: sofosbuvir/velpatasvir sofosbuvir/

velpatasvir/

voxilaprevir

ledipasvir/sofosbuvir

↑ tenofovir

Monitor patients receiving tenofovir disoproxil fumarate concomitantly with sofosbuvir/velpatasvir for adverse reactions associated with tenofovir disoproxil fumarate.

Monitor patients receiving tenofovir disoproxil fumarate concomitantly with ledipasvir/sofosbuvir without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, for adverse reactions associated with tenofovir disoproxil fumarate. In patients receiving tenofovir disoproxil fumarate 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 co-administration is necessary, monitor for adverse reactions associated with tenofovir disoproxil fumarate.

^a This table is not all inclusive.

^b ↑=Increase, ↓=Decrease

At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low.

Tenofovir disoproxil fumarate has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Table 3 summarizes the pharmacokinetic effects of co-administered drug on tenofovir pharmacokinetics and effects of tenofovir disoproxil fumarate on the pharmacokinetics of the co-administered drug.

Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is co-administered with an inhibitor of these transporters, an increase in absorption may be observed.

No clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.

Table 3: Drug interactions: changes in pharmacokinetic parameters for tenofovira in the presence of the co-administered drug

Co-administered Drug	Dose of Co-administered Drug (mg)	N	% Change of Tenofovir Pharmacokinetic Parameters^b (90% CI)
Co-administered Drug	Dose of Co-administered Drug (mg)	N	C_max	AUC	C_min
Atazanavir^c	400 once daily × 14 days	33	↑ 14 (↑ 8 to ↑ 20)	↑ 24 (↑ 21 to ↑ 28)	↑ 22 (↑ 15 to ↑ 30)
Atazanavir/ Ritonavir^c	300/100 once daily	12	↑ 34 (↑ 20 to ↑ 51)	↑ 37 (↑ 30 to ↑ 45)	↑ 29 (↑ 21 to ↑ 36)
Darunavir/ Ritonavir^d	300/100 twice daily	12	↑ 24 (↑ 8 to ↑ 42)	↑ 22 (↑ 10 to ↑ 35)	↑ 37 (↑ 19 to ↑ 57)
Indinavir	800 three times daily × 7 days	13	↑ 14 (↓ 3 to ↑ 33)	No effect	No effect
Ledipasvir/ Sofosbuvir^e,,^f	90/400 once daily × 10 days	24	↑ 47 (↑ 37 to ↑ 58)	↑ 35 (↑ 29 to ↑ 42 )	↑ 47 (↑ 38 to ↑ 57)
Ledipasvir/ Sofosbuvir^e,g	90/400 once daily × 10 days	23	↑ 64 (↑ 54 to ↑ 74)	↑ 50 (↑ 42 to ↑ 59)	↑ 59 (↑ 49 to ↑ 70)
Ledipasvir/ Sofosbuvir^h	90/400 once daily × 14 days	15	↑ 79 (↑ 56 to ↑ 104)	↑ 98 (↑ 77 to ↑ 123)	↑ 163 (↑ 132 to ↑ 197)
Lopinavir/ Ritonavir	400/100 twice daily × 14 days	24	No effect	↑ 32 (↑ 25 to ↑ 38)	↑ 51 (↑ 37 to ↑ 66)
Saquinavir/ Ritonavir	1,000/100 twice daily × 14 days	35	No effect	No effect	↑ 23 (↑ 16 to ↑ 30)
Sofosbuvirⁱ	400 single dose	16	↑ 25 (↑ 8 to ↑ 45)	No effect	No effect
Sofosbuvir/ Velpatasvir^j	400/100 once daily	24	↑ 44 (↑ 33 to ↑ 55)	↑ 40 (↑ 34 to ↑ 46)	↑ 84 (↑ 76 to ↑ 92)
Sofosbuvir/ Velpatasvir^k	400/100 once daily	30	↑ 46 (↑ 39 to ↑ 54)	↑ 40 (↑ 34 to ↑ 45)	↑ 70 (↑ 61 to ↑ 79)
Sofosbuvir/ Velpatasvir/ Voxilaprevir^l	400/100/100 + Voxilaprevir^m 100 once daily	29	↑ 48 (↑ 36 to ↑ 61)	↑ 39 (↑ 32 to ↑ 46)	↑ 47 (↑ 38 to ↑ 56)
Tacrolimus	0.05 mg/kg twice daily × 7 days	21	↑ 13 (↑ 1 to ↑ 27)	No effect	No effect
Tipranavir/ Ritonavirⁿ	500/100 twice daily	22	↓ 23 (↓ 32 to ↓ 13)	↓ 2 (↓ 9 to ↑ 5)	↑ 7 (↓ 2 to ↑ 17)
Tipranavir/ Ritonavirⁿ	750/200 twice daily (23 doses)	20	↓ 38 (↓ 46 to ↓ 29)	↑ 2 (↓ 6 to ↑ 10)	↑ 14 (↑ 1 to ↑ 27)

^a.Subjects received tenofovir disoproxil fumarate 300 mg once daily.

^b.Increase = ↑; Decrease = ↓

^c.Atazanavir/ Ritonavir Prescribing Information.

^d.Darunavir/ Ritonavir Prescribing Information.

^e.Data generated from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart) provided similar results.

^f.Comparison based on exposures when administered as atazanavir/ritonavir + Emtricitabine(FTC)/tenofovir disoproxil fumarate.

^g.Comparison based on exposures when administered as darunavir/ritonavir + Emtricitabine/tenofovir disoproxil fumarate.

^h.Study conducted with efavirenz (EFV)/Emtricitabine/tenofovir disoproxil fumarate co-administered with ledipasvir/sofosbuvir; co-administration with ledipasvir/sofosbuvir also results in comparable increases in tenofovir exposure when tenofovir disoproxil fumarate is administered as Emtricitabine/rilpivirine/tenofovir disoproxil fumarate, or emtricitabine/tenofovir disoproxil fumarate + dolutegravir.

^i.Study conducted with efavirenz, emtricitabine, and tenofovir disoproxil fumarate co-administered with sofosbuvir

^j.Study conducted with emtricitabine/rilpivirine/tenofovir disoproxil fumarate combination co-administered with sofosbuvir/velpatasvir; co-administration with sofosbuvir/velpatasvir also results in comparable increases in tenofovir exposures when tenofovir disoproxil fumarate is administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate, elvitegravir/cobicistat/Emtricitabine/ tenofovir disoproxil fumarate) emtricitabine/tenofovir disoproxil fumarate+ atazanavir/ritonavir, or emtricitabine/tenofovir disoproxil fumarate + darunavir/ritonavir.

^k.Administered as raltegravir + Emtricitabine/tenofovir disoproxil fumarate.

^l.Comparison based on exposures when administered as darunavir + ritonavir + Emtricitabine/tenofovir disoproxil fumarate.

^m.Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

^n. Tipranavir Prescribing Information.

Table 4: Drug interactions: Changes in pharmacokinetic parameters for co-administered drug in the presence of tenofovir

Co-administered Drug	Dose of Co-administered Drug(mg)	N	% Change of Co-administered Drug Pharmacokinetic Parameters^a (90% CI)
Co-administered Drug	Dose of Co-administered Drug(mg)	N	C_max	AUC	C_min
Abacavir	300 once	8	↑ 12 (↓ 1 to ↑ 26)	No effect	NA
Atazanavir^b	400 once daily × 14 days	34	↓ 21 (↓ 27 to ↓ 14)	↓ 25 (↓ 30 to ↓ 19)	↓ 40 (↓ 48 to ↓ 32)
Atazanavir^b	Atazanavir/ Ritonavir 300/100 once daily × 42 days	10	↓ 28 (↓ 50 to ↑ 5)	↓ 25c (↓ 42 to ↓ 3)	↓ 23^c (↓ 46 to ↑ 10)
Darunavir^d	Darunavir/Ritonavir 300/100 once daily	12	↑ 16 (↓ 6 to ↑ 42)	↑ 21 (↓ 5 to ↑ 54)	↑ 24 (↓ 10 to ↑ 69)
Didanosine^e	250 once, simultaneously with VIREAD and a light mealf	33	↓ 20g (↓ 32 to ↓ 7)	No effect ^g	NA
Emtricitabine	200 once daily × 7 days	17	No effect	No effect	↑ 20 (↑ 12 to ↑ 29)
Entecavir	1 mg once daily × 10 days	28	No effect	↑ 13 (↑ 11 to ↑ 15)	No effect
Indinavir	800 three times daily × 7 days	12	↓ 11 (↓ 30 to ↑ 12)	No effect	No effect
Lamivudine	150 twice daily × 7 days	15	↓ 24 (↓ 34 to ↓ 12)	No effect	No effect
Lopinavir Ritonavir	Lopinavir/Ritonavir 400/100 twice daily × 14 days	24	No effect	No effect	No effect
Saquinavir Ritonavir	Saquinavir/Ritonavir 1000/100 twice daily × 14 days	32	↑ 22 (↑ 6 to ↑ 41) No effect	↑ 29^h (↑ 12 to ↑ 48) No effect	↑ 47^h (↑ 23 to ↑ 76) ↑ 23 (↑ 3 to ↑ 46)
Tacrolimus	0.05 mg/kg twice daily × 7 days	21	No effect	No effect	No effect
Tipranavirⁱ	Tipranavir/Ritonavir 500/100 twice daily	22	↓ 17 (↓ 26 to ↓ 6)	↓ 18 (↓ 25 to ↓ 9)	↓ 21 (↓ 30 to ↓ 10)
Tipranavirⁱ	Tipranavir/Ritonavir 750/200 twice daily (23 doses)	20	↓ 11 (↓ 16 to ↓ 4)	↓ 9 (↓ 15 to ↓ 3)	↓ 12 (↓ 22 to 0)

^a.Increase = ↑; Decrease = ↓, NA= Not Applicable

^b.Atazanavir/ Ritonavir Prescribing Information.

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

^d.Darunavir/ Ritonavir Prescribing Information.

^e.Didanosine Prescribing Information. Subjects received didanosine enteric-coated capsules.

^f.373 kcal, 8.2 g fat

^g.Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions.

^h.Increases in AUC and C_min are not expected to be clinically relevant; hence no dose adjustments are required when TDF and ritonavir-boosted saquinavir are co-administered.

^i.Tipranavir Prescribing Information.

Use in Special Populations

Patients with Renal Impairment

It is recommended that the dosing interval for TENVIR Tablets be modified in patients with creatinine clearance below 50 mL/min or in patients with end-stage renal disease (ESRD) who require dialysis (see Posology and Method of Administration, Pharmacological Properties)

Pregnant Women

Risk Summary

Available data from the Antiretroviral Pregnancy Registry (APR) show no increase in the overall risk of major birth defects with first trimester exposure for tenofovir disoproxil fumarate (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%.

Published studies in HBV-infected subjects do not report an increased risk of adverse pregnancy-related outcomes with the use of tenofovir disoproxil fumarate during the third trimester of pregnancy (see Data).

In animal reproduction studies, no adverse developmental effects were observed when tenofovir disoproxil fumarate was administered at doses/exposures ≥14 (tenofovir disoproxil fumarate) and 2.7 (tenofovir) times those of the recommended daily dose of tenofovir disoproxil fumarate

Data

Human Data

Based on prospective reports from the APR exposures to tenofovir disoproxil fumarate-containing regimens during pregnancy resulting in live births (including 3,342 exposed in the first trimester and 1,475 exposed in the second/third trimester), there was no increase in overall major birth defects with tenofovir disoproxil fumarate compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.8%) with first trimester exposure to tenofovir disoproxil fumarate-containing regimens, and 2.1% (95% CI: 1.4% to 3.0%) with the second/third trimester exposure to tenofovir disoproxil fumarate-containing regimens.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to tenofovir disoproxil fumarate are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.

In published data from three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were administered tenofovir disoproxil fumarate from 28 to 32 weeks’ gestation through 1 to 2 months postpartum and followed for up to 12 months after delivery. There were no new safety findings in pregnant women compared with the known safety profile of tenofovir disoproxil fumarate in HBV-infected adults. An increased risk of adverse pregnancy-related outcomes was not observed; 2 stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in tenofovir disoproxil fumarate-exposed infants. Infants were followed for up to 12 months after delivery; there were no clinically relevant drug-related safety findings in infants exposed to tenofovir disoproxil fumarate during late gestation.

Animal Data

Tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate 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, tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate.

Lactating Women

Risk Summary

Based on published data, tenofovir has been shown to be present in human breast milk (see Data). It is not known if tenofovir affects milk production or has effects on the breastfed child.

Treatment Of HIV-1 Infection

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

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 tenofovir disoproxil fumarate for the treatment of HIV-1.

Treatment Of HBV Infection

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for tenofovir disoproxil fumarate and any potential adverse effects on the breastfed infant from tenofovir disoproxil fumarate or from the underlying maternal condition.

Data

In a study of 50 HIV-uninfected, breastfeeding women on a tenofovir-containing regimen initiated between 1 and 24 weeks postpartum (median 13 weeks), tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers. There were no serious adverse events in mothers or infants.

Pediatric Patients

Safety and effectiveness of TENVIR Tablets in pediatric patients have not been established.

Geriatric Patients

Clinical trials of tenofovir did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from 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.

Effects on Ability to Drive and Use Machines

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

Undesirable Effects

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

· Lactic Acidosis/Severe Hepatomegaly with Steatosis (see Black Box Warning, Special Warnings and Precautions for Use).

· Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection (see Black Box Warning, Special Warnings and Precautions for Use).

· New Onset or Worsening Renal Impairment (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 with 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 Adults

More than 12,000 subjects have been treated with tenofovir disoproxil fumarate alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded-access programs. A total of 1,544 subjects have received tenofovir disoproxil fumarate 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir disoproxil fumarate in expanded-access programs.

The most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.

Clinical Trials in Treatment-Naïve HIV-1-Infected Adult Subjects

In Trial 903, 600 treatment-naïve subjects received tenofovir disoproxil fumarate (N=299) or stavudine (d4T) (N=301) administered in combination with lamivudine (3TC) and efavirenz (EFV) for 144 weeks. The most adverse drug reactions were mild-to-moderate gastrointestinal events and dizziness.

Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea and nausea. Table 5 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Table 5: Selected treatment-emergent adverse reactionsa (Grades 2–4) Reported in ≥5% in any treatment group in trial 903 (0–144 Weeks)

	Tenofovir Disoproxil Fumarate + 3TC+EFV	d4T + 3TC + EFV
	N=299	N=301
Headache	14%	17%
Pain	13%	12%
Fever	8%	7%
Abdominal pain	7%	12%
Back pain	9%	8%
Asthenia	6%	7%
Diarrhea	11%	13%
Nausea	8%	9%
Dyspepsia	4%	5%
Vomiting	5%	9%
Lipodystrophy^b	1%	8%
Arthralgia	5%	7%
Myalagia	3%	5%
Depression	11%	10%
Insomnia	5%	8%
Dizziness	3%	6%
Peripheral neuropathy^c	1%	5%
Anxiety	6%	6%
Pneumonia	5%	5%
Rash event^d	18%	12%

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

^bLipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.

^cPeripheral neuropathy includes peripheral neuritis and neuropathy.

^dRash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.

Laboratory Abnormalities

Table 6 provides a list of laboratory abnormalities (Grades 3−4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with tenofovir disoproxil fumarate (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine (d4T) treatment arms. A summary of Grades 3–4 laboratory abnormalities is provided in Table 6.

Table 6: Grades 3–4 laboratory abnormalities reported in ≥1% of tenofovir disoproxil fumarate-treated subjects in trial 903 (0–144 Weeks)

	Tenofovir Disoproxil Fumarate + 3TC + EFV	d4T + 3TC + EFV
	N=299	N=301
Any ≥ Grade 3 Laboratory Abnormality	36%	42%
Fasting Cholesterol (>240 mg/dL)	19%	40%
Creatine Kinase (M: >990 U/L) (F: >845 U/L)	12%	12%
Serum Amylase (>175 U/L)	9%	8%
AST (M: >180 U/L; F: >170 U/L)	5%	7%
ALT (M: >215 U/L; F: >170 U/L)	4%	5%
Hematuria (>100 RBC/HPF)	7%	7%
Neutrophil (<750/mm³)	3%	1%
Fasting Triglyceride (>750 mg/dL)	1%	9%

HPF: High power field; AST: Aspartate amonitransferase test ; ALT: Alanine transaminase test

Changes in Bone Mineral Density (BMD)

In HIV-1-infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir disoproxil fumarate + 3TC + EFV (−2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (−1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (−2.8% ± 3.5 in the tenofovir disoproxil fumarate group vs. −2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24−48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of tenofovir disoproxil fumarate-treated subjects vs. 21% of d4T-treated subjects 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 subjects in the tenofovir disoproxil fumarate group and 6 subjects in the d4T 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) and higher serum parathyroid hormone levels and 1,25 vitamin D levels in the tenofovir disoproxil fumarate group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range.

In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either emtricitabine (FTC) + tenofovir disoproxil fumarate (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks.. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 7 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Table 7: Selected treatment-emergent adverse reactionsa (grades 2–4) reported in ≥5% in any treatment group in trial 934 (0–144 weeks)

	Tenofovir Disoproxil Fumarate^b + Emtricitabine + EFV	AZT/3TC + EFV
	N=257	N=254
Diarrhea	9%	5%
Nausea	9%	7%
Vomiting	2%	5%
Fatigue	9%	8%
Sinusitis	8%	4%
Upper respiratory tract infections	8%	5%
Nasopharyngitis	5%	3%
Headache	6%	5%
Dizziness	8%	7%
Depression	9%	7%
Insomnia	5%	7%
Rash event^c	7%	9%

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

^b From Weeks 96 to 144 of the trial, subjects received tenofovir disoproxil fumarate/ emtricitabine with efavirenz in place of tenofovir disoproxil fumarate + emtricitabine with efavirenz.

^c Rash 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 previous trials (Table 8).

Table 8: Significant laboratory abnormalities reported in ≥1% of subjects in any treatment group in trial 934 (0–144 weeks)

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

^a From Weeks 96 to 144 of the trial, subjects received tenofovir disoproxil fumarate/emtricitabine with efavirenz in place of tenofovir disoproxil fumarate + emtricitabine with efavirenz.

Clinical Trials in Treatment-Experienced HIV-1-Infected Adult Subjects

In Trial 907, the adverse reactions seen in HIV-1-infected treatment-experienced subjects were generally consistent with those seen in treatment-naïve subjects, including mild-to-moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions. Table 9 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 3% of subjects treated in any treatment group.

Table 9: Selected treatment-emergent adverse reactionsa (grades 2–4) reported in ≥3% in any treatment group in trial 907 (0–48 weeks)

	Tenofovir Disoproxil Fumarate (N=368) (Week 0–24)	Placebo (N=182) (Week 0–24)	Tenofovir Disoproxil Fumarate (N=368) (Week 0–48)	Placebo Crossover to Tenofovir Disoproxil Fumarate (N=170) (Week 24–48)
Body as a Whole
Asthenia	7%	6%	11%	1%
Pain	7%	7%	12%	4%
Headache	5%	5%	8%	2%
Abdominal pain	4%	3%	7%	6%
Back pain	3%	3%	4%	2%
Chest pain	3%	1%	3%	2%
Fever	2%	2%	4%	2%
Digestive System
Diarrhea	11%	10%	16%	11%
Nausea	8%	5%	11%	7%
Vomiting	4%	1%	7%	5%
Anorexia	3%	2%	4%	1%
Dyspepsia	3%	2%	4%	2%
Flatulence	3%	1%	4%	1%
Respiratory
Pneumonia	2%	0%	3%	2%
Nervous System
Depression	4%	3%	8%	4%
Insomnia	3%	2%	4%	4%
Peripheral neuropathy^b	3%	3%	5%	2%
Dizziness	1%	3%	3%	1%
Skin and Appendage
Rash event^c	5%	4%	7%	1%
Sweating	3%	2%	3%	1%
Musculoskeletal
Myalgia	3%	3%	4%	1%
Metabolic
Weight loss	2%	1%	4%	2%

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

^b Peripheral neuropathy includes peripheral neuritis and neuropathy.

^c Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.

Laboratory Abnormalities

Table 10 provides a list of Grades 3−4 laboratory abnormalities observed in Trial 907. Laboratory abnormalities occurred with similar frequency in the tenofovir disoproxil fumarate and placebo groups.

Table 10: Grades 3–4 laboratory abnormalities reported in ≥1% of tenofovir disoproxil fumarate-treated subjects in trial 907 (0–48 Weeks)

	Tenofovir Disoproxil Fumarate (N=368) (Week 0–24)	Placebo (N=182) (Week 0–24)	Tenofovir Disoproxil Fumarate (N=368) (Week 0–48)	Placebo Crossover to Tenofovir Disoproxil Fumarate (N=170) (Week 24–48)
Any ≥Grade 3 Laboratory Abnormality	25%	38%	35%	34%
Triglycerides (>750 mg/dL)	8%	13%	11%	9%
Creatine Kinase (M: >990U/L; F: >845 U/L)	7%	14%	12%	12%
Serum Amylase (>175 U/L)	6%	7%	7%	6%
Glucosuria (≥3+)	3%	3%	3%	2%
AST (M: >180 U/L; F: >170 U/L)	3%	3%	4%	5%
ALT (M: >215 U/L; F: >170 U/L)	2%	2%	4%	5%
Serum Glucose (>250 U/L)	2%	4%	3%	3%
Neutrophils (<750 mm³)	1%	1%	2%	1%

Adverse Reactions from Clinical Trials Experience in HBV-Infected Adults

Clinical Trials In Adult Subjects With Chronic Hepatitis B And Compensated Liver Disease

In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with tenofovir disoproxil fumarate during the 48-week double-blind period experienced nausea: 9% with tenofovir versus 2% with adefovir dipivoxil. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with tenofovir disoproxil fumarate included abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.

In Trials 0102 and 0103, during the open-label phase of treatment with tenofovir disoproxil fumarate (Weeks 48–384), 2% of subjects (13/585) experienced a confirmed increase in serum creatinine of 0.5 mg/dL from baseline.. No significant change in the tolerability profile was observed with continued treatment for up to 384 weeks.

Laboratory Abnormalities

Table 11 provides a list of Grade 3–4 laboratory abnormalities through Week 48. Grades 3–4 laboratory abnormalities were similar in subjects continuing tenofovir disoproxil fumarate treatment for up to 384 weeks in these trials.

Table 11: Grades 3–4 laboratory abnormalities reported in ≥1% of tenofovir disoproxil fumarate-treated subjects in trials 0102 and 0103 (0–48 Weeks)

	Tenofovir Disoproxil Fumarate (N=426)	Adefovir Dipivoxil (N=215)
Any ≥Grade 3 Laboratory Abnormality	19%	13%
Creatine Kinase (M: >990U/L; F: >845 U/L)	2%	3%
Serum Amylase (>175 U/L)	4%	1%
Glycosuria (≥3+)	3%	<1%
AST (M: >180 U/L; F: >170 U/L)	4%	4%
ALT (M: >215 U/L; F: >170 U/L)	10%	6%

The overall incidence of on-treatment ALT elevations (defined as serum ALT greater than 2 × baseline and greater than 10 × ULN, with or without associated symptoms) was similar between tenofovir disoproxil fumarate (2.6%) and adefovir dipivoxil (2%). ALT flares generally occurred within the first 4–8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subjects had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication.

The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with tenofovir disoproxil fumarate were consistent with those observed in other hepatitis B clinical trials in adults.

Clinical Trial in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease

In Trial 0108, subjects with chronic HBV and decompensated liver disease received treatment with tenofovir disoproxil fumarate or other antiviral drugs for up to 48 weeks. Among the 45 subjects receiving tenofovir disoproxil fumarate, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus less than 2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure. Because both tenofovir and decompensated liver disease may have an impact on renal function, the contribution of tenofovir to renal impairment in this population is difficult to ascertain.

One of 45 subjects experienced an on-treatment hepatic flare during the 48-week trial.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tenofovir disoproxil fumarate. 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

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, Asthenia, myopathy, hypophosphatemia.

Reporting of Side Effects

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side effects, 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.

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

Pharmacological Properties

Mechanism of Action

Tenofovir disoproxil fumarate is an antiviral drug.

Pharmacodynamic Properties

Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase 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.

Pharmacokinetic Properties

The pharmacokinetics of tenofovir disoproxil fumarate has been evaluated in healthy volunteers and HIV-1-infected individuals. Tenofovir pharmacokinetics is similar between these populations.

Absorption

Tenofovir disoproxil fumarate is a water-soluble diester prodrug of the active ingredient, tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted subjects is approximately 25%. Following oral administration of a single dose of tenofovir disoproxil fumarate 300 mg to HIV-1-infected subjects in the fasted state, maximum serum concentrations (C_max) are achieved in 1.0 ± 0.4 hours. C_max and AUC values are 0.30 ± 0.09 μg/mL and 2.29 ± 0.69 μg*hr/mL, respectively.

The pharmacokinetics of tenofovir is dose-proportional over a tenofovir disoproxil fumarate dose range of 75 to 600 mg and is not affected by repeated dosing.

In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean C_max of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.

Distribution

In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. The volume of distribution at steady state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.

Metabolism and Elimination

In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes.

Following intravenous administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of tenofovir disoproxil fumarate, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir disoproxil fumarate 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.

Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

Effects of Food on Oral Absorption

Administration of tenofovir following a high-fat meal (~700 to 1,000 kcal containing 40–50% fat) increases the oral bioavailability, with an increase in tenofovir AUC_0-∞ of approximately 40% and an increase in C_max of approximately 14%. However, administration of tenofovir with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared with fasted administration of the drug. Food delays the time to tenofovir C_max by approximately 1 hour. C_max and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg·hr/mL, respectively, following multiple doses of tenofovir 300 mg once daily in the fed state, when meal content was not controlled.

Special Populations

Race

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

Gender

Tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients

Pharmacokinetics of TENVIR Tablets in pediatric patients has not been established.

Geriatric Patients

Pharmacokinetic trials have not been performed in the elderly (65 years of age and older).

Patients with Renal Impairment

The pharmacokinetics of tenofovir is altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, C_max, and AUC_0-∞ of tenofovir were increased (Table 12). It is recommended that the dosing interval for TENVIR Tablets be modified in patients with creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis.

Table 12: Pharmacokinetic parameters (mean ± sd) of tenofovir disoproxil fumaratea in subjects with varying degrees of renal function

Baseline Creatinine Clearance (mL/min)	>80 (N=3)	50–80 (N=10)	30–49 (N=8)	12–29 (N=11)
C_max (μg/mL)	0.34 ± 0.03	0.33 ± 0.06	0.37 ± 0.16	0.60 ± 0.19
AUC_0-∞ (μg·hr/mL)	2.18 ± 0.26	3.06 ± 0.93	6.01 ± 2.50	15.98 ± 7.22
CL/F (mL/min)	1,043.7 ± 115.4	807.7 ± 279.2	444.4 ± 209.8	177.0 ± 97.1
CL_renal (mL/min)	243.5 ± 33.3	168.6 ± 27.5	100.6 ± 27.5	43.0 ± 31.2

^a 300 mg, single dose of tenofovir disoproxil fumarate

Patients with Hepatic Impairment

The pharmacokinetics of tenofovir following a 300 mg single dose of tenofovir disoproxil fumarate has 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. No change in TENVIR Tablets dosing is required in patients with hepatic impairment.

Non-Clinical Properties

Animal Toxicology and/or Pharmacology

Tenofovir and tenofovir disoproxil fumarate 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 BMD. 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, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate 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.

Mutagenesis

Tenofovir disoproxil fumarate 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 disoproxil fumarate was negative when administered to male mice.

Impairment of Fertility

There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate 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 is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir), which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. Tenofovir disoproxil fumarate is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C₁₉H₃₀N₅O₁₀P • C₄H₄O₄ and a molecular weight of 635.52. It has the following structural formula:

Pharmaceutical Particulars

Incompatibility

Not applicable.

Shelf-Life

3 years from the date of manufacture.

Packaging Information

TENVIR Tablets…………..Container pack of 30 tablets

Storage and Handling Instructions

Store in a cool and dry place.

Patient Counseling Information

Read this Patient Information before you start taking TENVIR Tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

1. What is TENVIR Tablet?

TENVIR Tablet is a prescription medicine that is used for the following:

• Treatment of HIV-1 infection in adults in combination with other antiretroviral agents (such as Non-nucleoside reverse transcriptase inhibitors [NNRTIs] or Protease inhibitor [PIs]).

• Treatment of chronic hepatitis B in adults.

2. What is the most important information I should know about TENVIR Tablets?

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

· Worsening of hepatitis B virus infection (HBV). Your healthcare provider will test you for HBV and HIV before starting treatment with TENVIR Tablets. If you have HBV infection and take TENVIR Tablets your HBV may get worse (flare-up) if you stop taking TENVIR Tablets. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.

· Do not run out of TENVIR Tablets. Refill your prescription or talk to your healthcare provider before your TENVIR Tablet is all gone.

· Do not stop taking TENVIR Tablets without first talking to your healthcare provider.

· If you stop taking TENVIR Tablets, your healthcare provider will need to check your health often and do blood tests regularly to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TENVIR Tablets.

3. What should I tell my healthcare provider before taking TENVIR Tablets?

Before you take TENVIR Tablets, tell your healthcare provider about all of your medical conditions, including if you have the following:

• Liver problems, including HBV infection

• Kidney problems or receiving kidney dialysis treatment

• Bone problems

• HIV infection

• Are pregnant or plan to become pregnant.

o Tell your healthcare provider if you become pregnant during treatment with TENVIR Tablets.

o Pregnancy Registry: There is a pregnancy registry for women who take TENVIR Tablets during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this Registry.

• Are breastfeeding or plan to breastfeed.

o Tenofovir disoproxil fumarate, the main ingredient in TENVIR Tablets, can pass on to your baby in your breast milk.

o Do not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.

o If you take TENVIR Tablets for treatment of HBV infection, 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 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 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 Tablets with other medicines.

4. How should I take TENVIR Tablets?

• Take TENVIR Tablets exactly as your healthcare provider tells you to take it.

• Do not change your dose or stop taking TENVIR Tablets without first talking with your healthcare provider. Stay under a healthcare provider’s care when taking TENVIR Tablets. Take TENVIR Tablets at the same time every day.

• Take TENVIR Tablets by mouth, with or without food.

• Do not miss a dose of TENVIR Tablets. Missing a dose lowers the amount of medicine in your blood. Refill your TENVIR Tablets prescription before you run out of medicine.

• If you take too much TENVIR Tablets, call your local poison control center or go right away to the nearest hospital emergency room.

5. What are the possible side effects of TENVIR Tablets?

TENVIR Tablets may cause serious side effects, including the following:

• See “What is the most important information I should know about TENVIR 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 Tablets. Your healthcare provider may tell you to take TENVIR Tablets less often, or to stop taking TENVIR Tablets if you get new or worse kidney problems.

• Changes in your immune system (Immune Reconstitution Syndrome) can happen when an HIV-1 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 new symptoms after starting your TENVIR Tablets for the treatment of HIV-1 infection.

• Bone problems can happen in some adults who take TENVIR Tablets. Bone problems include bone pain, or softening or thinning of bones, which may lead to fractures. Your healthcare provider may need to do tests to check your bones.

• 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 have rapid breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.

• Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark “tea-colored” urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.

The most common side effects in all people taking tenofovir disoproxil fumarate are as follows:

• Nausea

• Rash

• Diarrhea

• Headache

• Pain

• Depression

• Weakness

In some people with advanced HBV infection, other common side effects may include the following:

• Fever

• Itching

• Vomiting

• Stomach area pain

• Dizziness

• Sleeping problems

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 tenofovir disoproxil fumarate. For more information, ask your healthcare provider or pharmacist.

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 18002677779. By reporting side effects, you can help provide more information on the safety of this product.

6. How should I store TENVIR Tablets?

• Keep TENVIR Tablets in the original container.

• Store in a cool and dry place.

• Keep the bottle tightly closed.

• Do not use TENVIR Tablets if the seal over the bottle opening is broken or missing.

Keep TENVIR Tablets and all medicines out of the reach of children.

7. General information about the safe and effective use of TENVIR Tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TENVIR Tablets for a condition for which it was not prescribed. Do not give TENVIR Tablets to other people, even if they have the same condition you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TENVIR Tablets that is written for health professionals. A vaccine is available to protect people at risk for HBV infection. You can ask your healthcare provider for information about this vaccine.

Details of the Manufacturer

Mfd. by: Cipla Ltd.

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400 013, India.

Details of Permission or License Number with Date

MF--6095/05 dated: 17/08/2005

Date of Revision

29/04/2021