tenofovir 136 MG Oral Tablet
DRUG INTERACTIONS
7 This section describes clinically relevant drug interactions with VIREAD.
Drug interactions trials are described elsewhere in the labeling [See ].
Clinical Pharmacology (12.3) Didanosine: Coadministration increases didanosine concentrations.
Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy).
Consider dose reductions or discontinuations of didanosine if warranted.
( ) 7.1 HIV-1 protease inhibitors: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations.
When coadministered with VIREAD, use atazanavir given with ritonavir.
Coadministration of VIREAD with atazanavir and ritonavir, darunavir and ritonavir, or lopinavir/ritonavir increases tenofovir concentrations.
Monitor for evidence of tenofovir toxicity.
( ) 7.2 7.1 Didanosine Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions.
Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.
When administered with VIREAD, C and AUC of didanosine increased significantly .
The mechanism of this interaction is unknown.
Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy.
Suppression of CD4 cell counts has been observed in patients receiving VIREAD with didanosine 400 mg daily.
max [See ] Clinical Pharmacology (12.3) + In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD.
In patients weighing less than 60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with VIREAD.
When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat).
For additional information on coadministration of VIREAD and didanosine, please refer to the full prescribing information for didanosine.
7.2 HIV-1 Protease Inhibitors VIREAD decreases the AUC and C of atazanavir .
When coadministered with VIREAD, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg.
VIREAD should not be coadministered with atazanavir without ritonavir.
min [See ] Clinical Pharmacology (12.3) Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations .
Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters.
When tenofovir disoproxil fumarate is coadministered with an inhibitor of these transporters, an increase in absorption may be observed.
Patients receiving VIREAD concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for VIREAD-associated adverse reactions.
VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions.
[See ] Clinical Pharmacology (12.3) 7.3 Hepatitis C Antiviral Agents Coadministration of tenofovir disoproxil fumarate and HARVONI (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure .
[See ] Clinical Pharmacology (12.3) In patients receiving VIREAD concomitantly with HARVONI without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir disoproxil fumarate.
In patients receiving VIREAD concomitantly with HARVONI and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established.
If coadministration is necessary, monitor for adverse reactions associated with tenofovir disoproxil fumarate.
7.4 Drugs Affecting Renal Function Since tenofovir is primarily eliminated by the kidneys , coadministration of VIREAD 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, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs .
[See ] Clinical Pharmacology (12.3) [See ] Warnings and Precautions (5.3) In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).
OVERDOSAGE
10 Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available.
In Study 901, 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28 days.
No severe adverse reactions were reported.
The effects of higher doses are not known.
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 VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
DESCRIPTION
11 VIREAD 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 to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.
Tenofovir exhibits activity against HIV-1 reverse transcriptase.
In vivo The chemical name of tenofovir disoproxil fumarate is 9-[( )-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1).
It has a molecular formula of C H N O P • C H O and a molecular weight of 635.52.
It has the following structural formula: R 19 30 5 10 4 4 4 Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C.
It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.
VIREAD is available as tablets or as an oral powder.
VIREAD tablets are for oral administration in strengths of 150, 200, 250, and 300 mg of tenofovir disoproxil fumarate, which are equivalent to 123, 163, 204 and 245 mg of tenofovir disoproxil, respectively.
Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
The 300 mg tablets are coated with Opadry II Y-30-10671-A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.
The 150, 200, and 250 mg tablets are coated with Opadry II 32K-18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.
VIREAD oral powder is available for oral administration as white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate per gram of oral powder, which is equivalent to 33 mg of tenofovir disoproxil.
The oral powder contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide.
In this insert, all dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.
Chemical Structure Figure
CLINICAL STUDIES
14 14.1 Clinical Efficacy in Adults with HIV-1 Infection Treatment-Naïve Adult Patients Study 903 Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing VIREAD (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects.
Subjects had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20% were Black.
The mean baseline CD4 cell count was 279 cells/mm (range 3–956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000).
Subjects were stratified by baseline HIV-1 RNA and CD4 cell count.
Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4 cell counts <200 cells/mm .
Treatment outcomes through 48 and 144 weeks are presented in Table 17.
+ 3 + + 3 Table 17 Outcomes of Randomized Treatment at Week 48 and 144 (Study 903) At Week 48 At Week 144 Outcomes VIREAD+3TC +EFV (N=299) d4T+3TC +EFV (N=301) VIREAD+3TC +EFV (N=299) d4T+3TC +EFV (N=301) Responder Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144.
79% 82% 68% 62% Virologic failure Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144.
6% 4% 10% 8% Rebound 5% 3% 8% 7% Never suppressed 0% 1% 0% 0% Added an antiretroviral agent 1% 1% 2% 1% Death <1% 1% <1% 2% Discontinued due to adverse event 6% 6% 8% 13% Discontinued for other reasons Includes lost to follow-up, subject's withdrawal, noncompliance, protocol violation and other reasons.
8% 7% 14% 15% Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4 cell count (< or ≥200 cells/mm ).
Through 144 weeks of therapy, 62% and 58% of subjects in the VIREAD and stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL.
The mean increase from baseline in CD4 cell count was 263 cells/mm for the VIREAD arm and 283 cells/mm for the stavudine arm.
+ 3 + 3 3 Through 144 weeks, 11 subjects in the VIREAD group and 9 subjects in the stavudine group experienced a new CDC Class C event.
Study 934 Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects.
From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + VIREAD with efavirenz.
Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black.
The mean baseline CD4 cell count was 245 cells/mm (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log copies/mL (range 3.56–6.54).
Subjects were stratified by baseline CD4 cell count (< or ≥200 cells/mm ); 41% had CD4 cell counts 100,000 copies/mL.
Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 18.
+ 3 10 + 3 + 3 Table 18 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934) Outcomes At Week 48 At Week 144 FTC +VIREAD +EFV (N=244) AZT/3TC +EFV (N=243) FTC +VIREAD +EFV (N=227) Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue the trial after Week 48 or Week 96 were excluded from analysis.
AZT/3TC +EFV (N=229) Responder Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.
84% 73% 71% 58% Virologic failure Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144.
2% 4% 3% 6% Rebound 1% 3% 2% 5% Never suppressed 0% 0% 0% 0% Change in antiretroviral regimen 1% 1% 1% 1% Death <1% 1% 1% 1% Discontinued due to adverse event 4% 9% 5% 12% Discontinued for other reasons Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.
10% 14% 20% 22% Through Week 48, 84% and 73% of subjects in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144).
The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial.
In addition, 80% and 70% of subjects in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144).
The mean increase from baseline in CD4 cell count was 190 cells/mm in the EMTRIVA + VIREAD group and 158 cells/mm in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm at Week 144).
+ 3 3 3 Through 48 weeks, 7 subjects in the emtricitabine + VIREAD group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
Treatment-Experienced Adult Patients Study 907 Study 907 was a 24-week, double-blind placebo-controlled multicenter trial of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects.
After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label VIREAD for an additional 24 weeks.
Subjects had a mean baseline CD4 cell count of 427 cells/mm (range 23–1385), median baseline plasma HIV-1 RNA of 2340 (range 50–75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years.
Mean age of the subjects was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.
+ 3 The percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks are summarized in Table 19.
Table 19 Outcomes of Randomized Treatment (Study 907) Outcomes 0–24 weeks 0–48 weeks 24–48 weeks VIREAD (N=368) Placebo (N=182) VIREAD (N=368) Placebo Crossover to VIREAD (N=170) HIV-1 RNA <400 copies/mL Subjects with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively.
40% 11% 28% 30% Virologic failure Subjects with HIV-1 RNA ≥400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively.
53% 84% 61% 64% Discontinued due to adverse event 3% 3% 5% 5% Discontinued for other reasons Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.
3% 3% 5% 1% At 24 weeks of therapy, there was a higher proportion of subjects in the VIREAD arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively).
Mean change in absolute CD4 cell counts by Week 24 was +11 cells/mm for the VIREAD group and -5 cells/mm for the placebo group.
Mean change in absolute CD4 cell counts by Week 48 was +4 cells/mm for the VIREAD group.
+ 3 3 + 3 Through Week 24, one subject in the VIREAD group and no subjects in the placebo arm experienced a new CDC Class C event.
14.2 Clinical Efficacy in Adults with Chronic Hepatitis B HBeAg-Negative Chronic Hepatitis B Study 0102 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe+) subjects with compensated liver function, the majority of whom were nucleoside-naïve.
The mean age of subjects was 44 years, 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy and 18% were nucleoside-experienced (16% had prior lamivudine experience).
At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log copies/mL; and mean serum ALT was 140 U/L.
10 HBeAg-Positive Chronic Hepatitis B Study 0103 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naïve subjects with compensated liver function.
The mean age of subjects was 34 years, 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced.
At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log copies /mL; and mean serum ALT was 147 U/L.
10 The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.
The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA <400 copies/mL (69 IU/mL) and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 20).
Table 20 Histological, Virological, Biochemical, and Serological Response at Week 48 0102 (HBeAg-) 0103 (HBeAg+) VIREAD (N=250) HEPSERA (N=125) VIREAD (N=176) HEPSERA (N=90) Complete Response 71% 49% 67% 12% Histology Histological Response Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis.
72% 69% 74% 68% <400 copies/mL (<69 IU/mL) HBV DNA 93% 63% 76% 13% Normalized ALT ALT The population used for analysis of ALT normalization included only subjects with ALT above ULN at baseline.
76% 77% 68% 54% HBeAg Loss/Seroconversion Serology NA NA = Not Applicable NA 20%/19% 16%/16% HBsAg Loss/Seroconversion 0/0 0/0 3%/1% 0/0 Treatment Beyond 48 Weeks In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to VIREAD and HEPSERA, respectively) were eligible to roll over to open-label VIREAD with no interruption in treatment.
In Study 0102, 266 of 347 subjects who entered the open-label period (77%) continued in the study through Week 384.
Among subjects randomized to VIREAD followed by open-label treatment with VIREAD, 73% had HBV DNA <400 copies/ml (69 IU/ml), and 63% had ALT normalization at Week 384.
Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 80% had HBV DNA <400 copies/mL (69 IU/mL) and 70% had ALT normalization through Week 384.
At Week 384, both HBsAg loss and seroconversion were approximately 1% in both treatment groups.
In Study 0103, 146 of 238 subjects who entered the open-label period (61%) continued in the study through Week 384.
Among subjects randomized to VIREAD, 49% had HBV DNA <400 copies/mL (69 IU/mL), 42% had ALT normalization, and 20% had HBeAg loss (13% seroconversion to anti-HBe antibody) through Week 384.
Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 56% had HBV DNA <400 copies/mL (69 IU/mL), 50% had ALT normalization, and 28% had HBeAg loss (19% seroconversion to anti-HBe antibody) through Week 384.
At Week 384, HBsAg loss and seroconversion were 11% and 8% respectively, in subjects initially randomized to VIREAD and 12% and 10%, respectively, in subjects initially randomized to HEPSERA.
Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with VIREAD monotherapy were available for analysis at baseline, Week 48 and Week 240.
There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label VIREAD without biopsy data that would be expected to affect histological outcomes at Week 240.
Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively.
In the subjects without cirrhosis at baseline (Ishak fibrosis score 0-4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively.
In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively.
Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points.
No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.
Patients with Lamivudine-Resistant Chronic Hepatitis B Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of VIREAD compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥ 1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M).
One hundred forty-one adult subjects were randomized to the VIREAD treatment arm.
The mean age of subjects randomized to VIREAD was 47 years (range 18–73), 74% were male, 59% were Caucasian, and 37% were Asian.
At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT.
Subjects had a mean HBV DNA of 6.4 log copies/mL and mean serum ALT of 71 U/L at baseline.
10 After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to VIREAD had HBV DNA < 400 copies/mL (69 IU/mL), and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization.
Among the HBeAg-positive subjects randomized to VIREAD, 10 of 65 subjects (15%) experienced HBeAg loss, and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96.
The proportion of subjects with HBV DNA concentrations below 400 copies/mL (69 IU/mL) at Week 96 was similar between the VIREAD monotherapy and the comparator arms.
Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.
Patients with Chronic Hepatitis B and Decompensated Liver Disease VIREAD was studied in a small randomized, double-blind, active-controlled trial evaluating the safety of VIREAD compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks (Study 0108).
Forty-five adult subjects (37 males and 8 females) were randomized to the VIREAD treatment arm.
At baseline, 69% subjects were HBeAg-negative, and 31% were HBeAg-positive.
Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log copies/mL and mean serum ALT of 61 U/L at baseline.
Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphorus of < 2 mg/dL .
10 [See ] Adverse Reactions (6.1) At 48 weeks, 31/44 (70%) and 12/26 (46%) Viread-treated subjects achieved an HBV DNA < 400 copies/mL (69 IU/mL), and normalized ALT, respectively.
The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.
HOW SUPPLIED
16 /STORAGE AND HANDLING NDC:54569-5334-0 in a BOTTLE of 30 TABLET, COATEDS Tablets VIREAD tablets, 150 mg, are triangle-shaped, white, film-coated tablets containing 150 mg of tenofovir disoproxil fumarate, which is equivalent to 123 mg of tenofovir disoproxil, are debossed with “GSI” on one side and with “150” on the other side.
Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure.
(NDC 61958-0404-1) VIREAD tablets, 200 mg, are round-shaped, white, film-coated tablets containing 200 mg of tenofovir disoproxil fumarate, which is equivalent to 163 mg of tenofovir disoproxil, are debossed with “GSI” on one side and with “200” on the other side.
Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure.
(NDC 61958-0405-1) VIREAD tablets, 250 mg, are capsule-shaped, white, film-coated tablets containing 250 mg of tenofovir disoproxil fumarate, which is equivalent to 204 mg of tenofovir disoproxil, are debossed with “GSI” on one side and with “250” on the other side.
Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure.
(NDC 61958-0406-1) VIREAD tablets, 300 mg, are almond-shaped, light blue, film-coated tablets containing 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, are debossed with “GILEAD” and “4331” on one side and with “300” on the other side.
Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure.
(NDC 61958-0401-1) Oral Powder VIREAD oral powder consists of white, coated granules containing 40 mg of tenofovir disoproxil fumarate, which is equivalent to 33 mg of tenofovir disoproxil, per gram of powder and is available in multi-use bottles containing 60 grams of oral powder, closed with a child-resistant closure, and co-packaged with a dosing scoop.
(NDC 61958-0403-1) Store VIREAD tablets and oral powder at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature).
Keep the bottle tightly closed.
Dispense only in original container.
Do not use if seal over bottle opening is broken or missing.
GERIATRIC USE
8.5 Geriatric Use Clinical trials of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
In general, dose selection for the elderly 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.
DOSAGE FORMS AND STRENGTHS
3 VIREAD is available as tablets or as an oral powder.
VIREAD tablets 150 mg contain 150 mg of tenofovir disoproxil fumarate, which is equivalent to 123 mg of tenofovir disoproxil.
The tablets are triangle-shaped, white, film-coated, and debossed with “GSI” on one side and “150” on the other side.
VIREAD tablets 200 mg contain 200 mg of tenofovir disoproxil fumarate, which is equivalent to 163 mg of tenofovir disoproxil.
The tablets are round-shaped, white, film-coated, and debossed with “GSI” on one side and “200” on the other side.
VIREAD tablets 250 mg contain 250 mg of tenofovir disoproxil fumarate, which is equivalent to 204 mg of tenofovir disoproxil.
The tablets are capsule-shaped, white, film-coated, and debossed with “GSI” on one side and “250” on the other side.
VIREAD tablets 300 mg contain 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil.
The tablets are almond-shaped, light blue, film-coated, and debossed with “GILEAD” and “4331” on one side and with “300” on the other side.
The oral powder consists of white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate, which is equivalent to 33 mg of tenofovir disoproxil, per level scoop.
Each level scoop contains 1 gram of oral powder.
Tablets: 150, 200, 250 and 300 mg ( ) 3 Oral Powder: 40 mg per 1 g of oral powder ( ) 3
MECHANISM OF ACTION
12.1 Mechanism of Action Tenofovir disoproxil fumarate is an antiviral drug [See ].
Microbiology (12.4)
INDICATIONS AND USAGE
1 VIREAD is a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor.
VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.
( ) 1 VIREAD is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.
( ) 1 1.1 HIV-1 Infection VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.
The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection: VIREAD should not be used in combination with ATRIPLA , COMPLERA , STRIBILD , or TRUVADA .
® ® ® ® [See ] Warnings and Precautions (5.4) 1.2 Chronic Hepatitis B VIREAD is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older .
The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-naïve and subjects who were treatment-experienced with documented resistance to lamivudine.
Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease [See ].
Clinical Studies (14.2) VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease .
[See , ] Adverse Reactions (6.1) Clinical Studies (14.2) The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy [See , ].
Microbiology (12.4) Clinical Studies (14.2)
PEDIATRIC USE
8.4 Pediatric Use Pediatric Patients 2 Years of Age and Older with HIV-1 infection The safety of VIREAD in pediatric patients aged 2 to less than 18 years is supported by data from two randomized trials in which VIREAD was administered to HIV-1 infected treatment-experienced subjects.
In addition, the pharmacokinetic profile of tenofovir in patients 2 to less than 18 years of age at the recommended doses was similar to that found to be safe and effective in adult clinical trials .
[See ] Clinical Pharmacology (12.3) In Study 352, 92 treatment-experienced subjects 2 to less than 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimen were randomized to either replace stavudine or zidovudine with VIREAD (N = 44) or continue their original regimen (N = 48) for 48 weeks.
Five additional subjects over the age of 12 were enrolled and randomized (VIREAD N=4, original regimen N=1) but are not included in the efficacy analysis.
After 48 weeks, all eligible subjects were allowed to continue in the study receiving open-label VIREAD.
At Week 48, 89% of subjects in the VIREAD treatment group and 90% of subjects in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations less than 400 copies/mL.
During the 48 week randomized phase of the study, 1 subject in the VIREAD group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the VIREAD group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons.
In Study 321, 87 treatment-experienced subjects 12 to less than 18 years of age were treated with VIREAD (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks.
The mean baseline CD4 cell count was 374 cells/mm and the mean baseline plasma HIV-1 RNA was 4.6 log copies/mL.
At baseline, 90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates.
Overall, the trial failed to show a difference in virologic response between the VIREAD and placebo treatment groups.
Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to VIREAD and OBR.
3 10 Although changes in HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of VIREAD in pediatric patients 12 years of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to VIREAD.
[See , , and ].
Warnings and Precautions (5.6) Adverse Reactions (6.1) Clinical Pharmacology (12.3) Safety and effectiveness of VIREAD in pediatric patients younger than 2 years of age with HIV-1 infection have not been established.
Pediatric Patients 12 Years of Age and Older with Chronic Hepatitis B In Study 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with VIREAD 300 mg (N = 52) or placebo (N = 54) for 72 weeks.
At study entry, the mean HBV DNA was 8.1 log copies/mL and mean ALT was 101 U/L.
Of 52 subjects treated with VIREAD, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced.
Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience.
At Week 72, 88% (46/52) of subjects in the VIREAD group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL).
Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving VIREAD had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group.
One VIREAD-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation.
10 Safety and effectiveness of VIREAD in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, VIREAD should be used during pregnancy only if clearly needed.
: To monitor fetal outcomes of pregnant women exposed to VIREAD, an Antiretroviral Pregnancy Registry has been established.
Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Antiretroviral Pregnancy Registry Risk Summary Animal Data 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.
NUSRING MOTHERS
8.3 Nursing Mothers Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk.
The impact of this exposure in breastfed infants is unknown.
Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.
mothers should be instructed not to breastfeed if they are receiving VIREAD.
BOXED WARNING
WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals .
[See ] Warnings and Precautions (5.1) Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD.
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 VIREAD.
If appropriate, resumption of anti-hepatitis B therapy may be warranted .
[See ] Warnings and Precautions (5.2) WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS See full prescribing information for complete boxed warning.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD.
( ) 5.1 Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD.
Hepatic function should be monitored closely in these patients.
If appropriate, resumption of anti-hepatitis B therapy may be warranted.
( ) 5.2
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome.
Assess estimated creatinine clearance before initiating treatment with VIREAD.
In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine protein before initiating treatment with VIREAD and periodically during treatment.
Avoid administering VIREAD with concurrent or recent use of nephrotoxic drugs.
( ) 5.3 Coadministration with Other Products: Do not use with other tenofovir-containing products (e.g., ATRIPLA, COMPLERA, STRIBILD and TRUVADA).
Do not administer in combination with HEPSERA.
( ) 5.4 HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD.
VIREAD should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection.
( ) 5.5 Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss.
( ) 5.6 Redistribution/accumulation of body fat: Observed in HIV-infected patients receiving antiretroviral combination therapy.
( ) 5.7 Immune reconstitution syndrome: Observed in HIV-infected patients.
May necessitate further evaluation and treatment.
( ) 5.8 Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients.
Monitor carefully and consider treatment modification.
( ) 5.9 5.1 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 VIREAD, 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 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 VIREAD 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).
5.2 Exacerbation of Hepatitis after Discontinuation of Treatment Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis.
Patients infected with HBV who discontinue VIREAD 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.
5.3 New Onset or Worsening Renal Impairment Tenofovir is principally eliminated by the kidney.
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD .
[See ] Adverse Reactions (6.2) It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD.
In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA , it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of VIREAD, and periodically during VIREAD therapy.
® Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min .
No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity.
[See ] Dosage and Administration (2.3) VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) .
Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF.
Some patients required hospitalization and renal replacement therapy.
Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.
[See ] Drug Interactions (7.4) 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.
5.4 Coadministration with Other Products VIREAD should not be used in combination with the fixed-dose combination products ATRIPLA, COMPLERA, STRIBILD, or TRUVADA since tenofovir disoproxil fumarate is a component of these products.
VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil) [See ].
Drug Interactions (7.4) 5.5 Patients Coinfected with HIV-1 and HBV Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected 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 VIREAD.
It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD.
5.6 Bone Effects Bone Mineral Density: In clinical trials in HIV-1 infected adults, VIREAD 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 VIREAD .
[See ] Adverse Reactions (6.1) Clinical trials evaluating VIREAD in pediatric and adolescent subjects were conducted.
Under normal circumstances, BMD increases rapidly in pediatric patients.
In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover.
Total body BMD gain was less in the VIREAD-treated HIV-1 infected pediatric subjects as compared to the control groups.
Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years.
In all pediatric trials, skeletal growth (height) appeared to be unaffected .
[See ] Adverse Reactions (6.1) The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.
Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.
If bone abnormalities are suspected then appropriate consultation should be obtained.
Mineralization Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of VIREAD .
Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy.
Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF .
[See ] Adverse Reactions (6.2) [See ] Warnings and Precautions (5.3) 5.7 Fat Redistribution In HIV-infected patients 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 combination antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown.
A causal relationship has not been established.
5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including VIREAD.
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 infection, cytomegalovirus, pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.
Mycobacterium avium Pneumocystis jirovecii Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.9 Early Virologic Failure Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor.
In particular, early virological failure and high rates of resistance substitutions have been reported.
Triple nucleoside regimens should therefore be used with caution.
Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
VIREAD is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.
Patients should remain under the care of a physician when using VIREAD.
Patients should avoid doing things that can spread HIV or HBV to others.
Do not share needles or other injection equipment.
Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
Do not have any kind of sex without protection.
Tenofovir is excreted in breast milk and it is not known whether it can harm the baby.
Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Do not breastfeed.
The long-term effects of VIREAD are unknown.
VIREAD tablets and oral powder are for oral ingestion only.
VIREAD should not be discontinued without first informing their physician.
If you have HIV-1 infection, with or without HBV coinfection, it is important to take VIREAD with combination therapy.
It is important to take VIREAD on a regular dosing schedule and to avoid missing doses.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported.
Treatment with VIREAD should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) .
[See ] Warnings and Precautions (5.1) Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued VIREAD .
[See ] Warnings and Precautions (5.2) Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported.
VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) .
Dosing interval of VIREAD may need adjustment in patients with renal impairment .
[See ] Warnings and Precautions (5.3) [See ] Dosage and Administration (2.3) VIREAD should not be coadministered with the fixed-dose combination products ATRIPLA, COMPLERA, STRIBILD, and TRUVADA since it is a component of these products .
[See ] Warnings and Precautions (5.4) VIREAD should not be administered in combination with HEPSERA .
[See ] Warnings and Precautions (5.4) Patients with HIV-1 should be tested for Hepatitis B virus (HBV) before initiating antiretroviral therapy .
[See ] Warnings and Precautions (5.5) In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating VIREAD [See ].
Warnings and Precautions (5.5) Decreases in bone mineral density have been observed with the use of VIREAD.
Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia .
[See ] Warnings and Precautions (5.6) In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.
The relationship between response and long-term prevention of outcomes such as hepatocellular carcinoma is not known.
DOSAGE AND ADMINISTRATION
2 Recommended dose for the treatment of HIV-1 or chronic hepatitis B in adults and pediatric patients 12 years of age and older (35 kg or more): 300 mg once daily taken orally without regard to food.
( ) 2.1 Recommended dose for the treatment of HIV-1 in pediatric patients (2 to less than 12 years of age): Tablets: for pediatric patients weighing greater than or equal to 17 kg who can swallow an intact tablet, one VIREAD tablet (150, 200, 250 or 300 mg based on body weight) once daily taken orally without regard to food.
( ) Oral powder: 8 mg/kg VIREAD oral powder (up to a maximum of 300 mg) once daily with food.
( ) 2.2 2.2 Dose recommended in renal impairment in adults: Creatinine clearance 30–49 mL/min: 300 mg every 48 hours.
( ) Creatinine clearance 10–29 mL/min: 300 mg every 72 to 96 hours.
( ) Hemodialysis: 300 mg every 7 days or after approximately 12 hours of dialysis.
( ) 2.3 2.3 2.3 2.1 Recommended Dose in Adults and Pediatric Patients 12 Years of Age and Older (35 kg or more) For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.
For patients unable to swallow VIREAD tablets, the oral powder formulation (7.5 scoops) may be used.
In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.
Safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg have not been established.
2.2 Recommended Dose in Pediatric Patients 2 Years to Less than 12 Years of Age HIV-1 Infection For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of VIREAD is 8 mg of tenofovir disoproxil fumarate per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets.
VIREAD oral powder should be measured only with the supplied dosing scoop.
One level scoop delivers 1 g of powder which contains 40 mg of tenofovir disoproxil fumarate.
VIREAD oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt).
The entire mixture should be ingested immediately to avoid a bitter taste.
Do not administer VIREAD oral powder in a liquid as the powder may float on top of the liquid even after stirring.
Further patient instructions on how to administer VIREAD oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling (Patient Information).
VIREAD is also available as tablets in 150, 200, 250 and 300 mg strengths for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets.
The dose is one tablet once daily taken orally, without regard to food.
Tables 1 and 2 contain dosing recommendations for VIREAD oral powder and tablets based on body weight.
Weight should be monitored periodically and the VIREAD dose adjusted accordingly.
Table 1 Dosing Recommendations for Pediatric Patients ≥2 Years of Age Using VIREAD Oral Powder Body Weight Kilogram (kg) Oral Powder Once Daily Scoops of Powder 10 to <12 2 12 to <14 2.5 14 to <17 3 17 to <19 3.5 19 to <22 4 22 to <24 4.5 24 to <27 5 27 to <29 5.5 29 to <32 6 32 to <34 6.5 34 to <35 7 ≥35 7.5 Table 2 Dosing Recommendations for Pediatric Patients ≥2 Years of Age and Weighing ≥17 kg Using VIREAD Tablets Body Weight Kilogram (kg) Tablets Once Daily 17 to <22 150 mg 22 to <28 200 mg 28 to <35 250 mg ≥35 300 mg Chronic Hepatitis B Safety and efficacy of VIREAD in patients younger than 12 years of age have not been established.
2.3 Dose Adjustment for Renal Impairment in Adults Significantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment .
Therefore, the dosing interval of VIREAD tablets 300 mg should be adjusted in patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 3.
These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis.
The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients .
There are no data to recommend use of VIREAD tablets 150, 200 or 250 mg or VIREAD oral powder in patients with renal impairment.
[See ] Clinical Pharmacology (12.3) [See ] Warnings and Precautions (5.3) No dose adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min).
Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in patients with mild renal impairment .
[See ] Warnings and Precautions (5.3) Table 3 Dosage Adjustment for Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) Calculated using ideal (lean) body weight.
≥50 30–49 10–29 Hemodialysis Patients 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 Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration.
VIREAD should be administered following completion of dialysis.
The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance below 10 mL/min; therefore, no dosing recommendation is available for these patients.
No data are available to make dose recommendations in pediatric patients with renal impairment.