These highlights do not include all the information needed to use VIREAD safely and effectively. See full prescribing information for VIREAD.VIREAD (tenofovir disoproxil fumarate) tablet, coated for oral useInitial U.S. Approval: 2001
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)].
VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection:
VIREAD is indicated for the treatment of chronic hepatitis B in adults.
The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection:
For the treatment of HIV-1 or chronic hepatitis B: The dose of VIREAD is 300 mg once daily taken orally, without regard to food.
In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.
Significantly increased drug exposures occurred when VIREAD was administered to patients with moderate to severe renal impairment [See Clinical Pharmacology (12.3)]. Therefore, the dosing interval of VIREAD should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 1. 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 eva luated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.3)].
No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment [See Warnings and Precautions (5.3)].
The pharmacokinetics of tenofovir have not been eva luated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients.
Table 1 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 dialysisGenerally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis. |
VIREAD is available as tablets. Each tablet contains 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.
None.
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).
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.
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 creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment.
Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min [See Dosage and Administration (2.2)]. 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.
VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent.
VIREAD should not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA 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)].
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.
Bone mineral density (BMD) monitoring should be considered for 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.
In HIV-infected patients treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in 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 VIREAD + 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 VIREAD 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 VIREAD-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 VIREAD 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 VIREAD 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 VIREAD group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.
Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].
The bone effects of VIREAD have not been studied in patients with chronic HBV infection.
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.
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 Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further eva luation and treatment.
Clinical studies in HIV-infected patients have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance 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.
The following adverse reactions are discussed in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials in Patients with HIV Infection
More than 12,000 patients have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access studies. A total of 1,544 patients have received VIREAD 300 mg once daily in clinical trials; over 11,000 patients have received VIREAD in expanded access studies.
The most common adverse reactions (incidence ≥10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.
Treatment-Naïve Patients
Study 903 - Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve patients received VIREAD (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.
Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 2.
Table 2 Selected Treatment-Emergent Adverse ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 903 (0–144 Weeks)
|
|
VIREAD + 3TC + EFV |
d4T + 3TC + EFV |
|
|
N=299 |
N=301 |
|
Body as a Whole |
|
|
|
Headache |
14% |
17% |
|
Pain |
13% |
12% |
|
Fever |
8% |
7% |
|
Abdominal pain |
7% |
12% |
|
Back pain |
9% |
8% |
|
Asthenia |
6% |
7% |
|
Digestive System |
|
|
|
Diarrhea |
11% |
13% |
|
Nausea |
8% |
9% |
|
Dyspepsia |
4% |
5% |
|
Vomiting |
5% |
9% |
|
Metabolic Disorders |
|
|
|
LipodystrophyLipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. |
1% |
8% |
|
Musculoskeletal |
|
|
|
Arthralgia |
5% |
7% |
|
Myalgia |
3% |
5% |
|
Nervous System |
|
|
|
Depression |
11% |
10% |
|
Insomnia |
5% |
8% |
|
Dizziness |
3% |
6% |
|
Peripheral neuropathyPeripheral neuropathy includes peripheral neuritis and neuropathy. |
1% |
5% |
|
Anxiety |
6% |
6% |
|
Respiratory |
|
|
|
Pneumonia |
5% |
5% |
|
Skin and Appendages |
|
|
|
Rash eventRash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. |
18% |
12% |
Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with VIREAD (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the VIREAD and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 3.
Table 3 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Patients in Study 903 (0–144 Weeks)
|
|
VIREAD + 3TC + EFV |
d4T + 3TC + EFV |
|
|
N=299 |
N=301 |
|
Any ≥ Grade 3 Laboratory Abnormality |
36% |
42% |
Fasting Cholesterol
(>240 mg/dL) |
19% |
40% |
Creatine Kinase
(M: >990 U/L)
(F: >845 U/L) |
12% |
12% |
|
Serum Amylase (>175 U/L) |
9% |
8% |
AST
(M: >180 U/L)
(F: >170 U/L) |
5% |
7% |
ALT
(M: >215 U/L)
(F: >170 U/L) |
4% |
5% |
|
Hematuria (>100 RBC/HPF) |
7% |
7% |
|
Neutrophils (<750/mm3) |
3% |
1% |
|
Fasting Triglycerides (>750 mg/dL) |
1% |
9% |
Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve patients received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve patients (Table 4).
Table 4 Selected Treatment-Emergent Adverse ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks)
|
|
VIREADFrom Weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. + FTC + EFV |
AZT/3TC + EFV |
|
|
N=257 |
N=254 |
|
Gastrointestinal Disorder |
|
|
|
Diarrhea |
9% |
5% |
|
Nausea |
9% |
7% |
|
Vomiting |
2% |
5% |
|
General Disorders and Administration Site Condition |
|
|
|
Fatigue |
9% |
8% |
|
Infections and Infestations |
|
|
|
Sinusitis |
8% |
4% |
|
Upper respiratory tract infections |
8% |
5% |
|
Nasopharyngitis |
5% |
3% |
|
Nervous System Disorders |
|
|
|
Headache |
6% |
5% |
|
Dizziness |
8% |
7% |
|
Psychiatric Disorders |
|
|
|
Depression |
9% |
7% |
|
Insomnia |
5% |
7% |
|
Skin and Subcutaneous Tissue Disorders |
|
|
|
Rash eventRash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. |
7% |
9% |
Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 5).
Table 5 Significant Laboratory Abnormalities Reported in ≥1% of Patients in Any Treatment Group in Study 934 (0–144 Weeks)
|
|
VIREADFrom Weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. + FTC + EFV |
AZT/3TC + EFV |
|
|
N=257 |
N=254 |
|
Any ≥ Grade 3 Laboratory Abnormality |
30% |
26% |
|
Fasting Cholesterol (>240 mg/dL) |
22% |
24% |
Creatine Kinase
(M: >990 U/L)
(F: >845 U/L) |
9% |
7% |
|
Serum Amylase (>175 U/L) |
8% |
4% |
|
Alkaline Phosphatase (>550 U/L) |
1% |
0% |
AST
(M: >180 U/L)
(F: >170 U/L) |
3% |
3% |
ALT
(M: >215 U/L)
(F: >170 U/L) |
2% |
3% |
|
Hemoglobin (<8.0 mg/dL) |
0% |
4% |
|
Hyperglycemia (>250 mg/dL) |
2% |
1% |
|
Hematuria (>75 RBC/HPF) |
3% |
2% |
|
Glycosuria (≥3+) |
<1% |
1% |
|
Neutrophils (<750/mm3) |
3% |
5% |
|
Fasting Triglycerides (>750 mg/dL) |
4% |
2% |
Treatment-Experienced Patients
Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment experienced patients were generally consistent with those seen in treatment naïve patients including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of patients discontinued participation in the clinical studies due to gastrointestinal adverse reactions (Study 907).
A summary of moderate to severe, treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 6.
Table 6 Selected Treatment-Emergent Adverse ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥3% in Any Treatment Group in Study 907 (0–48 Weeks)
|
|
VIREAD
(N=368)
(Week 0–24) |
Placebo
(N=182)
(Week 0–24) |
VIREAD
(N=368)
(Week 0–48) |
Placebo Crossover to VIREAD
(N=170)
(Week 24–48) |
|
Body as a Whole |
|
|
|
|
|
Asthenia |
7% |
6% |
11% |
1% |
|
Pain |
7% |
7% |
12% |
4% |
|
Headache |
5% |
5% |
8% |
2% |
|
Abdominal pain |
4% |
3% |
7% |
6% |
|
Back pain |
3% |
3% |
4% |
2% |
|
Chest pain |
3% |
1% |
3% |
2% |
|
Fever |
2% |
2% |
4% |
2% |
|
Digestive System |
|
|
|
|
|
Diarrhea |
11% |
10% |
16% |
11% |
|
Nausea |
8% |
5% |
11% |
7% |
|
Vomiting |
4% |
1% |
7% |
5% |
|
Anorexia |
3% |
2% |
4% |
1% |
|
Dyspepsia |
3% |
2% |
4% |
2% |
|
Flatulence |
3% |
1% |
4% |
1% |
|
Respiratory |
|
|
|
|
|
Pneumonia |
2% |
0% |
3% |
2% |
|
Nervous System |
|
|
|
|
|
Depression |
4% |
3% |
8% |
4% |
|
Insomnia |
3% |
2% |
4% |
4% |
|
Peripheral neuropathyPeripheral neuropathy includes peripheral neuritis and neuropathy. |
3% |
3% |
5% |
2% |
|
Dizziness |
1% |
3% |
3% |
1% |
|
Skin and Appendage |
|
|
|
|
|
Rash eventRash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. |
5% |
4% |
7% |
1% |
|
Sweating |
3% |
2% |
3% |
1% |
|
Musculoskeletal |
|
|
|
|
|
Myalgia |
3% |
3% |
4% |
1% |
|
Metabolic |
|
|
|
|
|
Weight loss |
2% |
1% |
4% |
2% |
Laboratory Abnormalities: Laboratory abnormalities observed in this study occurred with similar frequency in the VIREAD and placebo-treated groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 7.
Table 7 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Patients in Study 907 (0–48 Weeks)
|
|
VIREAD
(N=368)
(Week 0–24) |
Placebo
(N=182)
(Week 0–24) |
VIREAD
(N=368)
(Week 0–48) |
Placebo Crossover to VIREAD
(N=170)
(Week 24–48) |
|
Any ≥ Grade 3 Laboratory Abnormality |
25% |
38% |
35% |
34% |
|
Triglycerides (>750 mg/dL) |
8% |
13% |
11% |
9% |
Creatine Kinase
(M: >990U/L)
(F: >845 U/L) |
7% |
14% |
12% |
12% |
|
Serum Amylase (>175 U/L) |
6% |
7% |
7% |
6% |
|
Glycosuria (≥3+) |
3% |
3% |
3% |
2% |
AST
(M: >180 U/L)
(F: >170 U/L) |
3% |
3% |
4% |
5% |
ALT
(M: >215 U/L)
(F: >170 U/L) |
2% |
2% |
4% |
5% |
|
Serum Glucose (>250 U/L) |
2% |
4% |
3% |
3% |
|
Neutrophils (<750/mm3) |
1% |
1% |
2% |
1% |
Clinical Trials in Patients with Chronic Hepatitis B
Treatment-Emergent Adverse Reactions: In controlled clinical trials in patients with chronic hepatitis B, more patients treated with VIREAD experienced nausea: 9% with VIREAD versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in >5% of patients treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.
Laboratory Abnormalities: A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 8.
The overall incidence of on-treatment ALT elevations (defined as serum ALT >2 × baseline and >10 × ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and HEPSERA (2%). ALT elevations generally occurred within the first 4–8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No patient had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication.
Table 8. Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Patients in Studies 0102 and 0103 (0-48 Weeks)
|
|
VIREAD
(N=426) |
HEPSERA
(N=215) |
|
Any ≥ Grade 3 Laboratory Abnormality |
19% |
13% |
Creatine Kinase
(M: >990U/L)
(F: >845 U/L) |
2% |
3% |
|
Serum Amylase (>175 U/L) |
4% |
1% |
|
Glycosuria (≥3+) |
3% |
<1% |
AST
(M: >180 U/L)
(F: >170 U/L) |
4% |
4% |
ALT
(M: >215 U/L)
(F: >170 U/L) |
10% |
6% |
The following adverse reactions have been identified during postapproval use of VIREAD. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders
Manufacturer
State of Florida DOH Central Pharmacy
Active Ingredients
Source
-
U.S. National Library of Medicine
-
DailyMed
-
Last Updated: 2nd of March 2011
