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Logo TRUVADA* Tablets
SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

TRUVADA* Tablets

COMPOSITION:
Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg tenofovir disoproxil).

WARNING
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS).
THE COMBINATION TABLET IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND THE SAFETY AND EFFICACY OF THE COMBINATION TABLET HAVE NOT BEEN ESTABLISHED IN PATIENTS COINFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO HAVE DISCONTINUED EMTRICITABINE (200 MG) OR TENOFOVIR. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE THE COMBINATION TABLET AND ARE COINFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).

PHARMACOLOGICAL CLASSIFICATION
A 20.2.8 Antimicrobial (Chemotherapeutic) Agents. Antiviral Agents

PHARMACOLOGICAL ACTION
Mechanism of Action:
Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase alpha, beta, e and mitochondrial DNA polymerase y.
Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate also known as tenofovir DF 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.
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 y

Drug Resistance:
Emtricitabine and tenofovir disoproxil fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in vitro. Genotypic analysis of these isolates identified the M184I/V and/or K65R amino acid substitutions in the viral RT.
Emtricitabine: Emtricitabine-resistant isolates of HIV have been selected in vitro.
Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a mutation in the HIV RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).
Emtricitabine-resistant isolates of HIV have been recovered from some patients treated with emtricitabine alone or in combination with other antiretroviral agents. In a clinical study, viral isolates from 6/16 (37.5%) treatment-naïve patients with virologic failure showed > 20-fold reduced susceptibility to emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I mutations in the HIV RT gene.
Tenofovir disoproxil fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in RT and showed a 2 – 4 fold reduction in susceptibility to tenofovir.
Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with tenofovir in combination with certain antiretroviral agents. In treatment-naïve patients, 8/47 (17%) isolates from patients failing tenofovir + lamivudine + efavirenz through week 144 showed > 1.4 fold (median 3.7) reduced susceptibility in vitroto tenofovir. In treatment-experienced patients, 14/304 (5%, Studies 902 and 907) isolates from patients failing tenofovir through week 96 showed > 1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 RT gene resulting in the K65R amino acid substitution.

Cross-resistance:
Emtricitabine and tenofovir disoproxil fumarate: Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognized. The M184V/I and/or K65R substitutions selected in vitro by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.
Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in vitro to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). Isolates from heavily treatment-experienced patients containing the M184V/I amino acid substitution in the context of other NRTI resistance-associated substitutions may retain susceptibility to tenofovir. HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring mutations conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.
Tenofovir disoproxil fumarate: HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the RT showed reduced susceptibility to tenofovir.

Pharmacodynamics:
Antiviral Activity
Emtricitabine and tenofovir disoproxil fumarate: In combination studies evaluating the in vitro antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.
Emtricitabine: The in vitro antiviral activity of emtricitabine against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The IC50 values for emtricitabine were in the range of 0.0013-0.64 microM (0.0003-0.158 micrograms/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Most of these drug combinations have not been studied in humans. Emtricitabine displayed antiviral activity in vitroagainst HIV-1 clades A, B, C, D, E, F, and G (IC50 values ranged from 0.007-0.075 microM) and showed strain specific activity against HIV-2 (IC50 values ranged from 0.007-1.5 microM).
Tenofovir disoproxil fumarate: The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0.04-8.5 microM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G and O (IC50 values ranged from 0.5-2.2 microM). The IC50 values of tenofovir against HIV-2 ranged from 1.6 microM to 4.9 microM.

Pharmacokinetics:
Pharmacokinetics in Adults
TRUVADA: One combination tablet was bioequivalent to one emtricitabine capsule (200 mg) plus one tenofovir disoproxil fumarate tablet following single-dose administration to fasting healthy subjects (N=39).
Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table 1. Following oral administration of emtricitabine (200 mg), emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1 –2 hours post-dose. In vitrobinding of emtricitabine to human plasma proteins is < 4% and is independent of concentration over the range of 0.02 –200 micrograms/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of emtricitabine (200 mg), the plasma emtricitabine half-life is approximately 10 hours.
Tenofovir disoproxil fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 1. Following oral administration of tenofovir, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. In vitrobinding of tenofovir to human plasma proteins is < 0.7% and is independent of concentration over the range of 0.01 –25 micrograms/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 tenofovir, the terminal elimination half-life is approximately 17 hours.

Table 1 Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in Adults1

                        Emtricitabine Tenofovir
Fasted Oral Bioavailability2(%) 92 (83.1 –106.4) 25 (NC –45.0)
Plasma Terminal Elimination Half-Life2 (hr) 10 (7.4 – 18.0) 17 (12.0 –25.7)
Cmax3(microg/mL) 1.8 +0.724 0.30 +0.09
AUC3 (microg·hr/mL) 10.0 +3.124 2.29 +0.69
CL/F3(mL/min) 302 +94 1043 +115
Clrenal3(mL/min) 213 +89 243 +33
1. NC = Not calculated
2. Median (range)
3. Mean (+SD)
4. Data presented as steady state values.

Effects of Food on Oral Absorption
The combination tablet may be administered with or without food. Administration of the combination tablet 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 Cmaxby approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy studies, tenofovir was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when the combination tablet was administered with either a high fat or a light meal.

Special Populations:
Race
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of emtricitabine (200 mg).
Tenofovir disoproxil fumarate: 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 tenofovir disoproxil fumarate.
Gender
Emtricitabine and tenofovir disoproxil fumarate: Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.
Paediatric and Geriatric Patients: Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in children (< 18 years) or in the elderly (> 65 years) (see Special Precautions, Paediatric Use, Geriatric Use).
Patients with Impaired Renal Function: The pharmacokinetics of emtricitabine and tenofovir are altered in patients with renal impairment (see WARNINGS, Renal Impairment). In patients with creatinine clearance < 50 mL/min, Cmax, and AUC0-8 of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for the combination tablet be modified in patients with creatinine clearance 30 –49 mL/min.
The combination tablet should not be used in patients with creatinine clearance < 30 mL/min and in patients with end-stage renal disease requiring dialysis (see WARNINGS, Renal Impairment).
Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir disoproxil fumarate have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. The pharmacokinetics of the combination tablet or emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

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

CONTRA-INDICATIONS
TRUVADA is contra-indicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
Moderate to severe uncontrolled renal failure.
Pregnancy and lactation.

WARNINGS
• There are no study results demonstrating the effect of TRUVADA on clinical progression of HIV-1.
• It is not recommended that TRUVADA be used as a component of a triple nucleoside regimen.
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 such as TRUVADA alone or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs such as TRUVADA to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TRUVADA 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).
Patients with HIV and Hepatitis B Virus Coinfection
It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. TRUVADA is not indicated for the treatment of chronic HBV infection and the safety and efficacy of TRUVADA have not been established in patients coinfected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients after the discontinuation of emtricitabine (200 mg) and tenofovir disoproxil fumarate. Hepatic function should be closely monitored with both clinical and laboratory follow-up for at least several months in patients who discontinue TRUVADA and are coinfected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Renal Impairment
Emtricitabine and tenofovir are principally eliminated by the kidney. Dosing interval adjustment of TRUVADA is recommended in all patients with creatinine clearance 30 –49 mL/min, (see Dosage and directions for use). TRUVADA should not be administered to patients with creatine clearance < 30 mL/min or patients requiring hemodialysis.
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of tenofovir (see Side-Effects, Post Marketing Experience). The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents, however, some cases occurred in patients without identified risk factors.
TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.

INTERACTIONS
TRUVADA: No drug interaction studies have been conducted using TRUVADA Tablets.
Emtricitabine and tenofovir disoproxil fumarate: The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent dosed alone.
In vitroand clinical pharmacokinetic drug-drug interaction studies have shown the potential for CYP450 mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug.
Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, and tenofovir disoproxil fumarate (see Tables 2 and 3).
Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, adefovir dipivoxil, ribavirin, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone and oral contraceptives in studies conducted in healthy volunteers (see Tables 4 and 5).

Table 2 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug1

Co-administered Drug Dose of Co- administered
Drug (mg)		 Emtricitabine
Dose (mg)		 N % Change of Emtricitabine
Pharmacokinetic
Parameters2(90% CI)
        Cmax AUC Cmin
Tenofovir DF 300 once daily x 7 days 200 once daily x 7 days
 17
 —
 — ^20
(^12 to^29)
Indinavir 800 x 1 200 x 1 12 — — NA
Famciclovir 500 x 1 200 x 1 12 — — NA
Stavudine 40 x 1 200 x 1 6 — — NA
1. All interaction studies conducted in healthy volunteers.
2. ^= Increase; v= Decrease; —= No Effect; NA = Not Applicable

Table 3 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Emtricitabine1

Co-administered Drug Dose of Co- administered
Drug (mg)		 Emtricitabine
Dose (mg)		 N % Change of Emtricitabine
Pharmacokinetic
Parameters2(90% CI)
        Cmax AUC Cmin
Tenofovir DF 300 once daily x 7 days 200 once daily x 7 days
 17
 —
 —
 —
Indinavir 800 x 1 200 x 1 12 — — NA
Famciclovir 500 x 1 200 x 1 12 — — NA
Stavudine 40 x 1 200 x 1 6 — — NA
1. All interaction studies conducted in healthy volunteers.
2.^= Increase; v= Decrease; —= No Effect; NA = Not Applicable

Table 4 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir1in the Presence of the Coadministered Drug

Co-administered
Drug 		Dose of Co-
administered
Drug (mg)		 N % Change of Tenofovir
Pharmacokinetic
Parameters2
(90% CI)
      Cmax AUC Cmin
Abacavir 300 once 8 — — NC
Adefovir dipivoxil 10 once 22 — — NC
Atazanavir3 400 once daily x 14 days 33 ^14
(^8 to ^20)		 ^24
(^21 to ^28) 		^22
(^15 to ^30)
Didanosine (enteric-coated) 400 once 25 — — —
Didanosine (buffered) 250 or 400 once daily x 7 days 14 — — —
Efavirenz 600 once daily x 14 days 29 — — —
Emtricitabine 200 once daily x 7 days 17 — — —
Indinavir 800 three times daily x 7 days 13 ^14
(v3 to ^33)		 — —
Lamivudine 150 twice daily x 7 days 15 — — —
Lopinavir/Ritonavir 400/100 twice daily x 14 days 24 — ^32
(^25 to ^38)		 ^51
(^37 to ^66)
1. Patients received VIREAD 300 mg once daily.
2. Increase = ^; Decrease = v; No Effect = —; NC = Not Calculated
3. REYATAZ® US Prescribing Information (Bristol-Myers Squibb)

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir

Co-
administered
Drug		 Dose of
Co-administered
Drug (mg)

 N % Change of Coadministered
Drug Pharmacokinetic Parameters1
(90% CI)
                        Cmax AUC Cmin
Abacavir 300 once 8 ^12
(v1 to ^26)
 —
 NA
Adefovir dipivoxil 10 once 22 — — NA
Atazanavir2 400 once daily x 14 days 34 v21
(v27 to v14) 		v25
(v30 to v19)		 v40
(v48 to v32)
Atazanavir2 Atazanavir/Ritonavir
300/100 once daily x 42 days
10
 v28
(v50 to ^5)
 v253
(v42 to v3)
 v233
(v46 to ^10)
Efavirenz 600 once daily x 14 days 30 — — —
Emtricitabine 200 once daily x 7 days 17 — — ^20
(^12 to ^29)
Indinavir 800 three times daily x 7 days 12 v11
(v30 to^12)		 — —
Lamivudine 150 twice daily x 7 days 15 v24
(v34 to v12)		 — —
Lopinavir Lopinavir/Ritonavir 400/100 twice daily x 14 days 24 — — —
Methadone4 40 –110 once daily x 14 days5 13 — — —
Oral Contraceptives6 Ethinyl Estradiol/ Norgestimate (Ortho-Tricyclen®) Once daily x 7 days 20 — — —
Ribavirin 600 once 22 — — NA
Ritonavir Lopinavir/Ritonavir 400/100 twice daily x 14 days 24 — — —

1. Increase = ­^Decrease = v; No Effect = —; NA = Not Applicable
2. REYATAZ® US Prescribing Information (Bristol-Myers Squibb)
3. In HIV-infected patients, addition of tenofovir DF to atazanavir 300 mg plus ritonavir
100 mg, resulted in AUC and Cmin values of atazanavir that were 2,3 and 4-fold higher
than the respective values observed for atazanavir 400 mg when given alone.
4. R-(active), S-and total methadone exposures were equivalent when dosed alone or with VIREAD.
5. Individual subjects were maintained on their stable methadone dose.
No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported.
6. Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD.
Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy or oral contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating lack of clinically significant drug interactions between these agents and tenofovir.
Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 6 summarizes the effects of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir disoproxil fumarate with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine.
When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil fumarate, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown.

Table 6 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of Tenofovir

Didanosine1
Dose (mg)/
Method of Administration2		 Tenofovir Method
of Administration2		 N % Difference (90% CI) vs.
Didanosine 400 mg Alone,
Fasted3
      Cmax AUC
Buffered tablets 
400 once daily4 x 7 days Fasted 1 hour after didanosine 14 ^28
(^11 to ^48)		 ^44
(^31 to ^59)
Enteric-coated capsules 
400 once,
fasted		 With food,
2 hrs after didanosine		 26 ^48
(^25 to ^76)		 ^48
(^31 to ^67)
400 once,
with food		 Simultaneously
with didanosine		 26 ^64
(^41 to ^89)		 ^60
(^44 to ^79)
250 once,
fasted		 With food,
2 hrs after
didanosine		 28 v10
(v22 to ^3)		 —
250 once,
fasted		 Simultaneously with didanosine 28 — ^14
(0 to ^31)
250 once,
with food		 Simultaneously with didanosine 28 v29
(v39 to v18)		 v11
(v23 to ^2)
1. See Precautions regarding use of didanosine with tenofovir.
2. Administration with food was with a light meal (~373 kcal, 20% fat).
3. Increase = ^; Decrease = v; No Difference = —
4. Includes 4 subjects weighing < 60 kg receiving ddI 250 mg.

PREGNANCY AND LACTATION
Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose.
Tenofovir disoproxil fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, TRUVADA should not be used during pregnancy (See CONTRA-INDICATIONS).
Nursing Mothers: HIV-infected mothers should not breast-feed their infants, to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk.
It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TRUVADA.

Dosage and directions for use
The dose of TRUVADA is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.
Dose Adjustment for Renal Impairment:
Significantly increased exposure occurred when emtricitabine (200 mg) or tenofovir were administered to patients with moderate to severe renal impairment (see CONTRAINDICATIONS).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-Effects:
Clinical Trials
TRUVADA: Safety and efficacy studies using TRUVADA Tablets or using emtricitabine (200 mg) and tenofovir in combination are ongoing. Two hundred eighty three HIV-1 infected patients have received combination therapy with emtricitabine (200 mg) and tenofovir with either a non-nucleoside reverse transcriptase inhibitor or protease inhibitor for 24 to 48 weeks in ongoing clinical studies. Based on these limited data, no new patterns of adverse events were identified and there was no increased frequency of established toxicities.

EMTRICITABINE (200 mg):
Neurological disorders:
Frequent: Headache.
The following side-effects have been reported and frequencies are unknown: Asthenia, dizziness.
Sleep disturbances (abnormal dreams, insomnia), depressive disorder.
Neuropathy, peripheral neuritis, paraesthesia.
Gastrointestinal disorders:
Frequent: Nausea, vomiting, diarrhoea.
The following side-effect has been reported and frequency is unknown: Abdominal pain.
Dyspepsia.
Dermatological disorders:
Frequent: Rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).
The following side-effects have been reported and frequencies are unknown: Skin discolouration, manifested by hyperpigmentation on the palms and/or soles, but is generally mild.
Musculoskeletal disorders:
The following side-effects have been reported and frequencies are unknown: Arthralgia, myalgia.
Haematological disorders:
The following side-effects have been reported and frequencies are unknown:
Neutropenia, anaemia.
Genito-urinary disorders:
Frequent: Elevation of creatinine kinase.
Respiratory disorders:
The following side-effects have been reported and frequencies are unknown: Increased cough and rhinitis.
Hepato-biliary disorders:
The following side-effects have been reported and frequencies are unknown: Raised liver enzyme concentrations and hyperbilirubinaemia.
Metabolic disorders:
The following side-effect has been reported and frequency is unknown: Lactic acidosis, usually associated with severe hepatomegaly and steatosis, has been associated with nucleoside reverse transcriptase inhibitors.
Hypertriglyceridaemia.
Hyperglycaemia.

TENOFOVIR (300 mg):
Gastrointestinal disorders:
Frequent: Nausea, vomiting, diarrhoea, abdominal pain, flatulence, dyspepsia and anorexia.
Less frequent: Serum-amylase concentrations may be raised.
Pancreatitis.
The following side-effect has been reported and frequency is unknown: Abdominal pain. Dyspepsia.
Neurological disorders:
The following side-effects have been reported and frequencies are unknown: Depression.
Headache.
Asthenia, dizziness.
Insomnia.
Peripheral neuropathy (including peripheral neuritis and neuropathy).
Anxiety.
Dermatological disorders:
The following side-effects have been reported and frequencies are unknown: Skin rashes (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash and pustular rash).
Musculoskeletal disorders:
The following side-effects have been reported and frequencies are unknown: Back pain. Myalgia, arthralgia.
Respiratory disorders:
The following side-effects have been reported and frequencies are unknown: Chest pain, pneumonia, dyspnoea.
Haematological disorders:
The following side-effects have been reported and frequencies are unknown:
Neutropenia. Haematuria.
Hepato-biliary disorders:
The following side-effects have been reported and frequencies are unknown: Raised liver enzyme and hepatitis.
Metabolic disorders:
Frequent: Hypophosphataemia.
The following side-effects have been reported and frequencies are unknown: Lactic acidosis, usually associated with severe hepatomegaly and steatosis, has been associated with nucleoside reverse transcriptase inhibitors.
Hypertriglyceridaemia.
Hyperglycaemia.
Genito-urinary disorders:
The following side-effect has been reported and frequency is unknown: Increased creatinine kinase levels.
Nephritis, nephrogenic diabetes insipidus, renal impairment, acute renal failure, and effects on the renal proximal tubules, including Fanconi syndrome.
Immune system disorders:
The following side-effect has been reported and frequency is unknown: Allergy.
Other:
The following side-effects have been reported and frequencies are unknown: Fever, sweating, weight loss.
Post Marketing Experience
EMTRICITABINE (200 mg):No additional events have been identified for inclusion in this section.
TENOFOVIR (300 mg):In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of tenofovir.
Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting or potential causal connection to tenofovir.

IMMUNE SYSTEM DISORDERS
Allergic reaction
METABOLISM AND NUTRITION DISORDERS
Hypophosphataemia, Lactic acidosis
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
Dyspnoea
GASTROINTESTINAL DISORDERS
Abdominal pain, Increased amylase, Pancreatitis
HEPATOBILIARY DISORDERS
Increased liver enzymes, Hepatitis
RENAL AND URINARY DISORDERS
Renal insufficiency, Renal failure, Acute renal failure, Fanconi syndrome, Proximal tubulopathy, Proteinuria, Increased creatinine, Acute tubular necrosis, Nephrogenic diabetes insipidus

SPECIAL PRECAUTIONS:
Drug Interactions
Tenofovir disoproxil fumarate: When tenofovir disoproxil fumarate was administered with didanosine the Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly (see Table 6). The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis, and neuropathy.
In adults weighing > 60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with TRUVADA. Data are not available to recommend a dose adjustment of didanosine for patients weighing < 60 kg. When coadministered, TRUVADA and didanosine may be taken under fasted conditions or with a light meal (< 400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with TRUVADA should be under fasted conditions. Coadministration of TRUVADA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosineassociated adverse events.
Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and lopinavir/ritonavir and TRUVADA should be monitored for TRUVADA-associated adverse events. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse events.
Tenofovir decreases the AUC and Cminof atazanavir. When coadministered with TRUVADA, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg.
Atazanavir without ritonavir should not be coadministered with TRUVADA.
Emtricitabine and tenofovir disoproxil fumarate: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of TRUVADA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir and valganciclovir.
TRUVADA is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. TRUVADA should not be coadministered with emtricitabine (200 mg) or tenofovir. Due to similarities between emtricitabine and lamivudine, TRUVADA should not be coadministered with other drugs containing lamivudine, including lamivudine and zidovudine coformulation, lamivudine for HIV, lamivudine for HBV, abacavir sulfate and lamivudine coformulation or abacavir sulfate, lamivudine and zidovudine coformulation.
Bone Effects
Tenofovir disoproxil fumarate: In study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving tenofovir + lamivudine + efavirenz (-2.2% ± 3.9) compared with patients receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24 –48 weeks of the study and this reduction was sustained through week 144. Twenty-eight percent of tenofovir-treated patients vs. 21% of the stavudine-treated patients lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients in the tenofovir group and 6 patients in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide and urinary N-telopeptide) in the tenofovir group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the tenofovir group relative to the stavudine group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of tenofovir associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.
Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance”have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including tenofovir. 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.
Paediatric Use
Safety and effectiveness in paediatric patients have not been established.
Geriatric Use
Clinical studies of emtricitabine (200 mg) or tenofovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine (200 mg). In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported.
Haemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.
Tenofovir disoproxil fumarate: Limited clinical experience at doses higher than the therapeutic dose of tenofovir 300 mg is available. In one study, 600 mg tenofovir disoproxil fumarate was administered to 8 patients orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known. Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir, a four-hour haemodialysis session removed approximately 10% of the administered tenofovir dose.

IDENTIFICATION
TRUVADA tablets are light blue, capsule-shaped, film-coated, debossed with “GILEAD”on one side.

PRESENTATION
TRUVADA Tablets are supplied as follows:
A 75 mL, white, high density polyethylene (HDPE) bottle, a white polypropylene continuous-thread, child-resistant cap lined with an induction activated aluminum foil liner and silica gel desiccant. The container/closure system is child-resistant.
Each HDPE bottle contains 30 tablets. Bottles are sealed with an aluminum induction seal.

STORAGE INSTRUCTIONS
Store below 30ºC.
Do not use if seal over bottle opening is broken or missing.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
41/20.2.8/0171

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
PHARMACARE LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Sandton
2148

Manufactured by Aspen under licence from Gilead.

DATE OF PUBLICATION OF THE PACKAGE INSERT
23 February 2007

575192/070205
03/2007
BRITEPAK

* = TM

New product: October 2007
Source: Pharmaceutical Industry

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