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NDC 61958-0405-01 Viread 200 mg/1 Details
Viread 200 mg/1
Viread is a ORAL TABLET, COATED in the HUMAN PRESCRIPTION DRUG category. It is labeled and distributed by Gilead Sciences, Inc.. The primary component is TENOFOVIR DISOPROXIL FUMARATE.
MedlinePlus Drug Summary
Tenofovir is used along with other medications to treat human immunodeficiency virus (HIV) infection in adults and children 2 years of age and older. Tenofovir is also used to treat chronic (long term) HBV in adults and children 2 years of age and older weighing 22 pounds (10 kilograms) or more. Tenofovir is in a class of medications called nucleoside reverse transcriptase inhibitors (NRTIs). It works by decreasing the amount of HIV and HBV in the blood. Although tenofovir will not cure HIV, it may decrease your chance of developing acquired immunodeficiency syndrome (AIDS) and HIV-related illnesses such as serious infections or cancer. Taking these medications along with practicing safer sex and making other lifestyle changes may decrease the risk of transmitting the HIV virus to other people. Tenofovir will not cure hepatitis B and may not prevent complications of chronic hepatitis B such as cirrhosis of the liver or liver cancer. Tenofovir may not prevent the spread of hepatitis B to other people.
Related Packages: 61958-0405-01Last Updated: 12/01/2022
MedLinePlus Full Drug Details: Tenofovir
Product Information
| NDC | 61958-0405 |
|---|---|
| Product ID | 61958-0405_741e31d6-533d-4da5-8a00-364d657ee3ab |
| Associated GPIs | 12108570100310 |
| GCN Sequence Number | 068451 |
| GCN Sequence Number Description | tenofovir disoproxil fumarate TABLET 200 MG ORAL |
| HIC3 | W5I |
| HIC3 Description | ANTIVIRALS, HIV-SPECIFIC, NUCLEOTIDE ANALOG, RTI |
| GCN | 31229 |
| HICL Sequence Number | 022937 |
| HICL Sequence Number Description | TENOFOVIR DISOPROXIL FUMARATE |
| Brand/Generic | Brand |
| Proprietary Name | Viread |
| Proprietary Name Suffix | n/a |
| Non-Proprietary Name | TENOFOVIR DISOPROXIL FUMARATE |
| Product Type | HUMAN PRESCRIPTION DRUG |
| Dosage Form | TABLET, COATED |
| Route | ORAL |
| Active Ingredient Strength | 200 |
| Active Ingredient Units | mg/1 |
| Substance Name | TENOFOVIR DISOPROXIL FUMARATE |
| Labeler Name | Gilead Sciences, Inc. |
| Pharmaceutical Class | Hepatitis B Virus Nucleoside Analog Reverse Transcriptase Inhibitor [EPC], Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor [EPC], Nucleoside Reverse Transcriptase Inhibitors [MoA], Nucleosides [CS] |
| DEA Schedule | n/a |
| Marketing Category | NDA |
| Application Number | NDA021356 |
| Listing Certified Through | 2024-12-31 |
Package
Package Images
NDC 61958-0405-01 (61958040501)
| NDC Package Code | 61958-0405-1 |
|---|---|
| Billing NDC | 61958040501 |
| Package | 30 TABLET, COATED in 1 BOTTLE, PLASTIC (61958-0405-1) |
| Marketing Start Date | 2012-01-18 |
| NDC Exclude Flag | N |
| Pricing Information | N/A |
Standard Product Labeling (SPL)/Prescribing Information SPL 33fd6418-fbdc-42ca-a50d-ce2a476a5418 Details
HIGHLIGHTS OF PRESCRIBING INFORMATION
VIREAD® (tenofovir disoproxil fumarate) tablets, for oral use
VIREAD® (tenofovir disoproxil fumarate) powder, for oral use
Initial U.S. Approval: 2001
WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B
See full prescribing information for complete boxed warning.
Severe acute exacerbations of hepatitis B virus (HBV) have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely in HBV-infected patients who discontinue VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted. (5.1)
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
VIREAD is a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor and is indicated:
DOSAGE AND ADMINISTRATION
- Testing: Prior to or when initiating VIREAD test for hepatitis B virus infection and HIV-1 infection. Prior to initiation and during use of VIREAD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorous. (2.1)
- Recommended tablet dosage in adults and pediatric patients weighing at least 35 kg: One VIREAD 300 mg tablet once daily taken orally without regard to food. (2.2)
- Recommended dosage in pediatric patients at least 2 years of age and adults:
- Tablets: For patients weighing at least 17 kg who can swallow an intact tablet, one VIREAD tablet (150 mg, 200 mg, 250 mg, or 300 mg based on body weight) once daily taken orally without regard to food. (2.2)
- Oral powder: For patients weighing at least 10 kg and unable to swallow a tablet, 8 mg per kg VIREAD oral powder (up to a maximum of 300 mg) taken once daily with food. (2.3)
- Recommended dosage in renally impaired adult patients:
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
- New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering VIREAD with concurrent or recent use of nephrotoxic drugs. (5.2)
- 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. (5.3)
- Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.4)
- 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. (5.5)
- Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.6)
ADVERSE REACTIONS
- In HIV-infected adult subjects: Most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) were rash, diarrhea, nausea, headache, pain, depression, and asthenia. (6.1)
- In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). (6.1)
- In HBV-infected subjects with decompensated liver disease: Most common adverse reactions (incidence greater than or equal to 10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia. (6.1)
- In pediatric subjects: Adverse reactions in pediatric subjects were consistent with those observed in adults. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
- Tenofovir disoproxil fumarate increases didanosine concentrations. Dose reduction and close monitoring for didanosine toxicity are warranted. (7.2)
- Coadministration decreases atazanavir concentrations. When coadministered with VIREAD, use atazanavir given with ritonavir. (7.2)
- Coadministration of VIREAD with certain HIV-1 protease inhibitors or certain drugs to treat HCV increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.2)
- Consult Full Prescribing Information prior to and during treatment for important drug interactions. (7.2)
USE IN SPECIFIC POPULATIONS
Lactation: Breastfeeding in HIV-1 infected mothers is not recommended due to the potential for HIV-1 transmission. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 4/2019
Table Of Contents
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B
1 INDICATIONS AND USAGE
1.1 HIV-1 Infection
1.2 Chronic Hepatitis B
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of VIREAD for Treatment of HIV-1 Infection or Chronic Hepatitis B
2.2 Recommended Tablet Dosage in Adults and Pediatric Patients 2 Years and Older Weighing at Least 17 kg
2.3 Recommended Oral Powder Dosage in Adults and Pediatric Patients 2 Years and Older Weighing at Least 10 kg
2.4 Dosage Adjustment in Patients with Renal Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection
5.2 New Onset or Worsening Renal Impairment
5.3 Patients Coinfected with HIV-1 and HBV
5.4 Immune Reconstitution Syndrome
5.5 Bone Loss and Mineralization Defects
5.6 Lactic Acidosis/Severe Hepatomegaly with Steatosis
5.7 Risk of Adverse Reactions Due to Drug Interactions
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Drugs Affecting Renal Function
7.2 Established and Significant Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Overview of Clinical Trials
14.2 Clinical Trial Results in Adults with HIV-1 Infection
14.3 Clinical Trial Results in Pediatric Subjects with HIV-1 Infection
14.4 Clinical Trial Results in Adults with Chronic Hepatitis B
14.5 Clinical Trial Results in Pediatric Subjects with Chronic Hepatitis B
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
- *
- Sections or subsections omitted from the full prescribing information are not listed.
WARNING
Severe acute exacerbations of hepatitis B virus (HBV) 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 HBV-infected patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of VIREAD for Treatment of HIV-1 Infection or Chronic Hepatitis B
Prior to or when initiating VIREAD, test patients for HBV infection and HIV-1 infection. VIREAD alone should not be used in patients with HIV-1 infection [see Warnings and Precautions (5.3)].
Prior to initiation and during use of VIREAD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.2)].
2.2 Recommended Tablet Dosage in Adults and Pediatric Patients 2 Years and Older Weighing at Least 17 kg
The recommended dosage of VIREAD in adults and pediatric patients weighing at least 35 kg is one 300 mg tablet taken orally once daily without regard to food. The dosage for VIREAD is the same for both HIV and HBV indications.
The recommended dosage of VIREAD tablet in adults and pediatric patients 2 years and older weighing at least 17 kg is 8 mg of tenofovir disoproxil fumarate (TDF) per kg of body weight (up to a maximum of 300 mg) once daily. Dosage for pediatric patients 2 years and older weighing between 17 kg and 35 kg and able to swallow an intact tablet is provided in Table 1. Weight should be monitored periodically and the VIREAD dose adjusted accordingly.
| Body Weight (kg) | Dosing of VIREAD Tablets |
|---|---|
| 17 to less than 22 | one 150 mg tablet once daily |
| 22 to less than 28 | one 200 mg tablet once daily |
| 28 to less than 35 | one 250 mg tablet once daily |
| at least 35 | one 300 mg tablet once daily |
2.3 Recommended Oral Powder Dosage in Adults and Pediatric Patients 2 Years and Older Weighing at Least 10 kg
The recommended dosage of VIREAD oral powder in adults and pediatric patients 2 years and older weighing at least 10 kg who are unable to swallow a tablet is 8 mg of TDF per kg of body weight (up to a maximum of 300 mg) once daily administered as oral powder (see Table 2). Weight should be monitored periodically and the VIREAD dose adjusted accordingly.
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 TDF. 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).
| Body Weight (kg) | Dosing of VIREAD Oral Powder | Total Daily Dosage (40 mg per scoop) |
|---|---|---|
| 10 to less than 12 | 2 scoops once daily | 80 mg |
| 12 to less than 14 | 2.5 scoops once daily | 100 mg |
| 14 to less than 17 | 3 scoops once daily | 120 mg |
| 17 to less than 19 | 3.5 scoops once daily | 140 mg |
| 19 to less than 22 | 4 scoops once daily | 160 mg |
| 22 to less than 24 | 4.5 scoops once daily | 180 mg |
| 24 to less than 27 | 5 scoops once daily | 200 mg |
| 27 to less than 29 | 5.5 scoops once daily | 220 mg |
| 29 to less than 32 | 6 scoops once daily | 240 mg |
| 32 to less than 34 | 6.5 scoops once daily | 260 mg |
| 34 to less than 35 | 7 scoops once daily | 280 mg |
| at least 35 | 7.5 scoops once daily | 300 mg |
2.4 Dosage Adjustment in Patients with Renal Impairment
Significant increase in drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment (creatinine clearance below 50 mL/min). Table 3 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min) [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
| Creatinine Clearance (mL/min)* | Hemodialysis Patients | |||
|---|---|---|---|---|
| 50 or greater | 30–49 | 10–29 | ||
| Recommended 300 mg Dosing Interval | Every 24 hours | Every 48 hours | Every 72 to 96 hours | Every 7 days or after a total of approximately 12 hours of dialysis† |
No data are available to make dosage recommendations in patients with creatinine clearance below 10 mL/min who are not on hemodialysis.
No data are available to make dosage recommendations in pediatric patients with renal impairment.
3 DOSAGE FORMS AND STRENGTHS
VIREAD is available as tablets in four dose strengths or as an oral powder.
- 150 mg Tablets: 150 mg of tenofovir disoproxil fumarate (TDF) (equivalent to 123 mg of tenofovir disoproxil): triangle shaped, white, film coated, debossed with "GSI" on one side and with "150" on the other side.
- 200 mg Tablets: 200 mg of TDF (equivalent to 163 mg of tenofovir disoproxil): round shaped, white, film coated, debossed with "GSI" on one side and with "200" on the other side.
- 250 mg Tablets: 250 mg of TDF (equivalent to 204 mg of tenofovir disoproxil): capsule shaped, white, film coated, debossed with "GSI" on one side and with "250" on the other side.
- 300 mg Tablets: 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil): almond shaped, light blue, film coated, debossed with "GILEAD" and "4331" on one side and with "300" on the other side.
- Oral Powder: white, taste-masked, coated granules containing 40 mg of TDF (equivalent to 33 mg of tenofovir disoproxil) per level scoop. Each level scoop contains 1 gram of oral powder.
5 WARNINGS AND PRECAUTIONS
5.1 Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection
All patients should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating VIREAD [see Dosage and Administration (2.1)].
Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis B. 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, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
5.2 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)].
Prior to initiation and during use of VIREAD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.
Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min [see Dosage and Administration (2.4)]. 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 (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.1)]. 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 TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.
Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction.
5.3 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.
5.4 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.5 Bone Loss and Mineralization Defects
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 [see Adverse Reactions (6.1)]. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD.
Clinical trials evaluating VIREAD in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects 2 years to less than 18 years of age, 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 HBV-infected pediatric subjects 2 years to less than 18 years of age. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials [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 in adults and pediatric subjects 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children is unknown.
Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. If bone abnormalities are suspected, appropriate consultation should be obtained.
Mineralization Defects
Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with VIREAD use [see Adverse Reactions (6.2)]. Arthralgia 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 TDF-containing products [see Warnings and Precautions (5.2)].
5.6 Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF, alone or in combination with other antiretrovirals. 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).
5.7 Risk of Adverse Reactions Due to Drug Interactions
The concomitant use of VIREAD and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs [see Drug Interactions (7.2)].
See Table 12 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with VIREAD; review concomitant medications during therapy with VIREAD; and monitor for adverse reactions associated with the concomitant drugs.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
- Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions (5.1)].
- New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.2)].
- Immune Reconstitution Syndrome [see Warnings and Precautions (5.4)].
- Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5)].
- Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.6)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Adults
More than 12,000 subjects 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 programs. A total of 1,544 subjects have received VIREAD 300 mg once daily in clinical trials; over 11,000 subjects have received VIREAD in expanded access programs.
The most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.
Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects
In Trial 903, 600 antiretroviral-naïve subjects received VIREAD (N=299) or stavudine (d4T) (N=301) administered in combination with lamivudine (3TC) and efavirenz (EFV) for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea. Table 4 provides the treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group.
| VIREAD+3TC+EFV | d4T+3TC+EFV | |
|---|---|---|
| N=299 | N=301 | |
|
||
| Rash event† | 18% | 12% |
| Headache | 14% | 17% |
| Pain | 13% | 12% |
| Diarrhea | 11% | 13% |
| Depression | 11% | 10% |
| Back pain | 9% | 8% |
| Nausea | 8% | 9% |
| Fever | 8% | 7% |
| Abdominal pain | 7% | 12% |
| Asthenia | 6% | 7% |
| Anxiety | 6% | 6% |
| Vomiting | 5% | 9% |
| Insomnia | 5% | 8% |
| Arthralgia | 5% | 7% |
| Pneumonia | 5% | 5% |
| Dyspepsia | 4% | 5% |
| Dizziness | 3% | 6% |
| Myalgia | 3% | 5% |
| Lipodystrophy‡ | 1% | 8% |
| Peripheral neuropathy§ | 1% | 5% |
Laboratory Abnormalities: Table 5 provides a list of laboratory abnormalities (Grades 3–4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the VIREAD group (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the VIREAD and d4T treatment arms.
| 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% |
Changes in Bone Mineral Density: In HIV-1 infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + 3TC + EFV (−2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (−1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (−2.8% ± 3.5 in the VIREAD group vs. −2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of VIREAD-treated subjects vs. 21% of d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the VIREAD group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions (5.5)].
In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either emtricitabine (FTC) + VIREAD (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 6 provides the treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group.
| VIREAD†+FTC+EFV | AZT/3TC+EFV | |
|---|---|---|
| N=257 | N=254 | |
|
||
| Fatigue | 9% | 8% |
| Depression | 9% | 7% |
| Nausea | 9% | 7% |
| Diarrhea | 9% | 5% |
| Dizziness | 8% | 7% |
| Upper respiratory tract infections | 8% | 5% |
| Sinusitis | 8% | 4% |
| Rash event‡ | 7% | 9% |
| Headache | 6% | 5% |
| Insomnia | 5% | 7% |
| Nasopharyngitis | 5% | 3% |
| Vomiting | 2% | 5% |
Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7).
| VIREAD+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% |
Clinical Trials in Treatment-Experienced HIV-1 Infected Adult Subjects
In Trial 907, the adverse reactions seen in HIV-1 infected treatment-experienced subjects were generally consistent with those seen in treatment-naïve subjects, including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions. Table 8 provides the treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 3% of subjects treated in any treatment group.
| 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 neuropathy† | 3% | 3% | 5% | 2% |
| Dizziness | 1% | 3% | 3% | 1% |
| Skin and Appendage | ||||
| Rash event‡ | 5% | 4% | 7% | 1% |
| Sweating | 3% | 2% | 3% | 1% |
| Musculoskeletal | ||||
| Myalgia | 3% | 3% | 4% | 1% |
| Metabolic | ||||
| Weight loss | 2% | 1% | 4% | 2% |
Laboratory Abnormalities: Table 9 provides a list of Grade 3–4 laboratory abnormalities observed in Trial 907. Laboratory abnormalities occurred with similar frequency in the VIREAD and placebo groups.
| 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: >990 U/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% |
Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Pediatric Subjects 2 Years and Older
Assessment of adverse reactions is based on two randomized trials (Trials 352 and 321) in 184 HIV-1 infected pediatric subjects (2 years to less than 18 years of age) who received treatment with VIREAD (N=93) or placebo/active comparator (N=91) in combination with other antiretroviral agents for 48 weeks [see Clinical Studies (14.3)]. The adverse reactions observed in subjects who received treatment with VIREAD were consistent with those observed in clinical trials in adults.
In Trial 352, 89 pediatric subjects (2 years to less than 12 years of age) received VIREAD for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z-score [see Warnings and Precautions (5.5)].
Changes in Bone Mineral Density: In Trial 321 (12 years to less than 18 years of age), the mean rate of BMD gain at Week 48 was less in the VIREAD group compared to the placebo group. Six VIREAD-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were −0.341 for lumbar spine and −0.458 for total body in the 28 subjects who were treated with VIREAD for 96 weeks. In Trial 352 (2 years to less than 12 years of age), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the VIREAD and the d4T or AZT treatment groups. Total body BMD gain was less in the VIREAD group compared to the d4T or AZT treatment group. One VIREAD-treated subject and none of the d4T- or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z-scores were −0.012 for lumbar spine and −0.338 for total body in the 64 subjects who were treated with VIREAD for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected for the duration of the clinical trials [see Warnings and Precautions (5.5)].
Adverse Reactions from Clinical Trials Experience in HBV-Infected Adults
Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease
In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48-week double-blind period experienced nausea: 9% with VIREAD versus 2% with HEPSERA®. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash.
In Trials 0102 and 0103, during the open-label phase of treatment with VIREAD (weeks 48–384), 2% of subjects (13/585) experienced a confirmed increase in serum creatinine of 0.5 mg/dL from baseline. No significant change in the tolerability profile was observed with continued treatment for up to 384 weeks.
Laboratory Abnormalities: Table 10 provides a list of Grade 3–4 laboratory abnormalities through Week 48. Grades 3–4 laboratory abnormalities were similar in subjects continuing VIREAD treatment for up to 384 weeks in these trials.
| VIREAD N=426 | HEPSERA N=215 |
|
|---|---|---|
| Any ≥ Grade 3 Laboratory Abnormality | 19% | 13% |
| Creatine Kinase (M: >990 U/L; F: >845 U/L) | 2% | 3% |
| Serum Amylase (>175 U/L) | 4% | 1% |
| Glycosuria (≥3+) | 3% | <1% |
| AST (M: >180 U/L; F: >170 U/L) | 4% | 4% |
| ALT (M: >215 U/L; F: >170 U/L) | 10% | 6% |
The overall incidence of on-treatment ALT flares (defined as serum ALT greater than 2 × baseline and greater than 10 × ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and HEPSERA (2%). ALT flares generally occurred within the first 4 to 8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication.
The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with VIREAD were consistent with those observed in other HBV clinical trials in adults.
Clinical Trials in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease
In Trial 0108, a small randomized, double-blind, active-controlled trial, subjects with chronic HBV and decompensated liver disease received treatment with VIREAD or other antiviral drugs for up to 48 weeks [see Clinical Studies (14.4)]. Among the 45 subjects receiving VIREAD, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus less than 2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure. Because both VIREAD and decompensated liver disease may have an impact on renal function, the contribution of VIREAD to renal impairment in this population is difficult to ascertain.
One of 45 subjects experienced an on-treatment hepatic flare during the 48-week trial.
Adverse Reactions from Clinical Trials Experience in HBV-Infected Pediatric Subjects 2 Years and Older
Assessment of adverse reactions in pediatric subjects infected with chronic HBV is based on two randomized trials: Trial GS-US-174-0115 in 106 subjects (12 years to less than 18 years of age) receiving treatment with VIREAD (N=52) or placebo (N=54) for 72 weeks and Trial GS-US-174-0144 in 89 subjects (2 years to less than 12 years of age) receiving treatment with VIREAD (N=60) or placebo (N=29) for 48 weeks [see Clinical Studies (14.5)]. The adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults.
In Trial 115 (12 years to less than 18 years of age) and Trial 144 (2 years to less than 12 years of age), both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine and total body BMD over 72 and 48 weeks, respectively, as expected for a pediatric population (Table 11). In Trial 115, the mean percentage BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects (Table 11).Three subjects (6%) in the VIREAD group and two subjects (4%) in the placebo group had significant (greater than or equal to 4%) lumbar spine BMD loss at Week 72. In Trial 144 (2 years to less than 12 years of age), mean percentage BMD gains from baseline to Week 48 in lumbar spine and total body BMD in VIREAD-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects. At Week 48, the cumulative percentage of subjects with greater than or equal to 4% decreases in spine or whole body BMD was numerically higher for subjects in the TDF group compared with the placebo group (Table 11). As observed in pediatric studies of HIV-infected subjects, normal skeletal growth (height) was not affected for the duration of the clinical trial [see Warnings and Precautions (5.5)].
| Trial 115 (Week 72) | Trial 144 (Week 48) |
|||
|---|---|---|---|---|
| VIREAD (N=52) | Placebo (N=54) | VIREAD (N=60) | Placebo (N=29) |
|
| Mean percentage change in BMD | ||||
| Lumbar spine | +5% | +8% | +4% | +8% |
| Total body | +3% | +5% | +5% | +9% |
| Cumulative incidence of ≥4% decrease in BMD | ||||
| Lumbar spine | 6% | 4% | 18% | 7% |
| Total body | 0% | 2% | 7% | 0% |
| Baseline BMD Z-score (mean) | ||||
| Lumbar spine | −0.43 | −0.28 | +0.02 | −0.29 |
| Total body | −0.20 | −0.26 | +0.11 | −0.05 |
| Mean change in BMD Z-score | ||||
| Lumbar spine | -0.05 | +0.07 | −0.12 | +0.14 |
| Total body | -0.15 | +0.06 | −0.18 | +0.22 |
The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in pediatric patients 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown [see Warnings and Precautions (5.5)].
6.2 Postmarketing Experience
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
allergic reaction, including angioedema
Metabolism and Nutrition Disorders
lactic acidosis, hypokalemia, hypophosphatemia
Respiratory, Thoracic, and Mediastinal Disorders
dyspnea
Gastrointestinal Disorders
pancreatitis, increased amylase, abdominal pain
Hepatobiliary Disorders
hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
Skin and Subcutaneous Tissue Disorders
rash
Musculoskeletal and Connective Tissue Disorders
rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy
Renal and Urinary Disorders
acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria
General Disorders and Administration Site Conditions
asthenia
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
7 DRUG INTERACTIONS
7.1 Drugs Affecting Renal Function
Tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3)]. Coadministration of VIREAD with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.2)]. Drugs that decrease renal function may increase concentrations of tenofovir.
In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).
7.2 Established and Significant Interactions
Table 12 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with TDF [see Clinical Pharmacology (12.3)].
| Concomitant Drug Class: Drug Name | Effect on Concentration† | Clinical Comment |
|---|---|---|
| NRTI:
didanosine | ↑ didanosine | Patients receiving VIREAD and didanosine should be monitored closely for didanosine-associated adverse reactions. Discontinue didanosine in patients who develop didanosine-associated adverse reactions. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving VIREAD with didanosine 400 mg daily. In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with VIREAD. In patients weighing less than 60 kg, reduce the didanosine dose to 200 mg when it is coadministered with VIREAD. When coadministered, VIREAD and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). |
| HIV-1 Protease Inhibitors: atazanavir | ↓ atazanavir | When coadministered with VIREAD, atazanavir 300 mg should be given with ritonavir 100 mg. |
| lopinavir/ritonavir atazanavir/ritonavir darunavir/ritonavir | ↑ tenofovir | Monitor patients receiving VIREAD concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir for TDF-associated adverse reactions. Discontinue VIREAD in patients who develop TDF-associated adverse reactions. |
| Hepatitis C Antiviral Agents:
sofosbuvir/velpatasvir sofosbuvir/velpatasvir/voxilaprevir | ↑ tenofovir | Monitor patients receiving VIREAD concomitantly with EPCLUSA® (sofosbuvir/velpatasvir) for adverse reactions associated with TDF. |
| ledipasvir/sofosbuvir | Monitor patients receiving VIREAD concomitantly with HARVONI® (ledipasvir/sofosbuvir) without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, for adverse reactions associated with TDF. In patients receiving 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 TDF. | |
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VIREAD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for tenofovir disoproxil fumarate (TDF) (2.1%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%.
Published studies in HBV-infected subjects do not report an increased risk of adverse pregnancy-related outcomes with the use of VIREAD during the third trimester of pregnancy (see Data).
In animal reproduction studies, no adverse developmental effects were observed when TDF was administered at doses/exposures ≥ 14 (TDF) and 2.7 (tenofovir) times those of the recommended daily dose of VIREAD (see Data).
Data
Human Data
Based on prospective reports from the APR exposures to TDF-containing regimens during pregnancy resulting in live births (including 3,342 exposed in the first trimester and 1,475 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.8%) with first trimester exposure to TDF-containing regimens, and 2.1% (95% CI: 1.4% to 3.0%) with the second/third trimester exposure to TDF-containing regimens.
Prospective reports from the APR of overall major birth defects in pregnancies exposed to TDF are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.
In published data from three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were administered VIREAD from 28 to 32 weeks gestation through 1 to 2 months postpartum and followed for up to 12 months after delivery. There were no new safety findings in pregnant women compared with the known safety profile of VIREAD in HBV-infected adults. An increased risk of adverse pregnancy-related outcomes was not observed; 2 stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in VIREAD-exposed infants. Infants were followed for up to 12 months after delivery; there were no clinically relevant drug-related safety findings in infants exposed to VIREAD during late gestation.
Animal Data
TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of VIREAD.
8.2 Lactation
Risk Summary
Based on published data, tenofovir has been shown to be present in human breast milk (see Data). It is not known if tenofovir affects milk production or has effects on the breastfed child.
Treatment of HIV-1 infection:
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.
Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking VIREAD for the treatment of HIV-1.
Data
In a study of 50 HIV-uninfected, breastfeeding women on a tenofovir-containing regimen initiated between 1 and 24 weeks postpartum (median 13 weeks), tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers. There were no serious adverse events in mothers or infants.
8.4 Pediatric Use
Pediatric Patients 2 Years and Older with HIV-1 Infection
The safety and effectiveness of VIREAD in pediatric patients 2 years to less than 18 years of age is supported by data from two randomized trials. Trial 352 was a randomized controlled trial in 92 HIV-1 treatment experienced subjects 2 years to less than 12 years of age who were virologically suppressed on a stavudine- or zidovudine-containing regimen and were randomized to either switch to a VIREAD-containing regimen (N=44) or stay on their original regimen (N=48) for 48 weeks. At Week 48, 89% of subjects in the VIREAD treatment group and 90% of subjects in the d4T or AZT treatment group had HIV-1 RNA concentrations <400 copies/mL. Trial 321 was a placebo-controlled trial in 87 HIV-1 treatment experienced subjects 12 years to less than 18 years of age who were treated with VIREAD (N=45) or placebo (N=42) in combination with an optimized background regimen for 48 weeks. Overall, the trial failed to show a difference in virologic response between the VIREAD and placebo 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 [see Adverse Reactions (6.1) and Clinical Studies (14.3)].
Although changes in HIV-1 RNA in these highly treatment-experienced subjects in Trial 321 were less than anticipated, the pharmacokinetic profile of tenofovir in patients 2 years 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)].
The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in HIV-1 pediatric patients 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].
Safety and effectiveness of VIREAD in pediatric patients younger than 2 years of age and weighing less than 10 kg with HIV-1 infection have not been established.
Pediatric Patients 2 Years of Age and Older with Chronic Hepatitis B
The safety and effectiveness of VIREAD in pediatric patients 2 years to less than 18 years of age is supported by data from two randomized trials (Trial 115 and Trial 144) in which VIREAD was administered to HBV-infected treatment-experienced subjects.
In Trial 115, 106 HBeAg negative (9%) and positive (91%) subjects 12 years to less than 18 years of age with chronic HBV infection were randomized to receive blinded treatment with VIREAD or placebo for 72 weeks. At Week 72, 88% of subjects in the VIREAD group and 0% of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL). In Trial 144, 89 HBeAg positive (96%) and negative (4%) subjects 2 years to less than 12 years of age were treated with VIREAD 8 mg/kg up to maximum dose of 300 mg or placebo once daily for 48 weeks. At Week 48, 77% of subjects in the VIREAD group and 7% of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL).
The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in chronic HBV-infected pediatric patients 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].
Safety and effectiveness of VIREAD in chronic HBV-infected pediatric patients younger than 2 years of age and weighing less than 10 kg have not been established.
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.
8.6 Renal Impairment
The dosing interval for VIREAD should be modified in adult patients with estimated creatinine clearance below 50 mL/min or in patients with end stage renal disease requiring dialysis [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
10 OVERDOSAGE
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.
11 DESCRIPTION
VIREAD is the brand name for tenofovir disoproxil fumarate (TDF) (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.
The chemical name of TDF is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P ∙ C4H4O4 and a molecular weight of 635.52. It has the following structural formula:
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 and are available in the following strengths: 150 mg, 200 mg, 250 mg, and 300 mg of TDF (equivalent to 123 mg, 163 mg, 204 mg, and 245 mg of tenofovir disoproxil, respectively).
All strengths of VIREAD tablets contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The 300 mg strength 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 mg, 200 mg, and 250 mg strength 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 TDF per gram of oral powder (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 TDF except where otherwise noted.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tenofovir disoproxil fumarate is an antiviral drug [see Microbiology (12.4)].
12.3 Pharmacokinetics
The pharmacokinetics of TDF have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Absorption
VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from VIREAD in fasted subjects is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 µg/mL and 2.29 ± 0.69 µg∙hr/mL, respectively.
The pharmacokinetics of tenofovir are dose proportional over a VIREAD dose range of 75 to 600 mg and are not affected by repeated dosing.
In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.
Distribution
In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination
In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes.
Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of VIREAD 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Effects of Food on Oral Absorption
Administration of VIREAD 300 mg tablets following a high-fat meal (~700 to 1,000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0–∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of VIREAD with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 µg/mL and 3.32 ± 1.37 µg∙hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.
Specific Populations
Race
There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.
Pediatric Patients
2 Years and Older: Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-1 infected pediatric subjects 2 years to less than 18 years of age (Table 13). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of VIREAD 300 mg (tablet) or 8 mg/kg of body weight (powder) up to a maximum dose of 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.
| Dose and Formulation | 300 mg Tablet | 8 mg/kg Oral Powder |
|---|---|---|
| 12 Years to <18 Years (N=8) | 2 Years to <12 Years (N=23) | |
| Cmax (µg/mL) | 0.38 ± 0.13 | 0.24 ± 0.13 |
| AUCtau (µg∙hr/mL) | 3.39 ± 1.22 | 2.59 ± 1.06 |
Tenofovir exposures in HBV-infected pediatric subjects (12 years to less than 18 years of age) receiving oral once-daily doses of VIREAD 300 mg tablet and pediatric subjects 2 years to less than 12 years of age receiving VIREAD 8 mg/kg of body weight (tablet or powder) up to a maximum dose of 300 mg were comparable to exposures achieved in HIV-1 infected adult subjects receiving identical doses.
Geriatric Patients
Pharmacokinetic trials have not been performed in the elderly (65 years and older).
Patients with Renal Impairment
The pharmacokinetics of tenofovir are altered in subjects with renal impairment [see Warnings and Precautions (5.2)]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0–∞ of tenofovir were increased (Table 14).
| Baseline Creatinine Clearance (mL/min) | >80 N=3 | 50–80 N=10 | 30–49 N=8 | 12–29 N=11 |
|---|---|---|---|---|
|
||||
| Cmax (µg/mL) | 0.34 ± 0.03 | 0.33 ± 0.06 | 0.37 ± 0.16 | 0.60 ± 0.19 |
| AUC0–∞ (µg∙hr/mL) | 2.18 ± 0.26 | 3.06 ± 0.93 | 6.01 ± 2.50 | 15.98 ± 7.22 |
| CL/F (mL/min) | 1043.7 ± 115.4 | 807.7 ± 279.2 | 444.4 ± 209.8 | 177.0 ± 97.1 |
| CLrenal (mL/min) | 243.5 ± 33.3 | 168.6 ± 27.5 | 100.6 ± 27.5 | 43.0 ± 31.2 |
Patients with Hepatic Impairment
The pharmacokinetics of tenofovir following a 300 mg single dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in VIREAD dosing is required in patients with hepatic impairment.
Assessment of Drug Interactions
At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low.
VIREAD has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 15 and 16 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of VIREAD on the pharmacokinetics of coadministered drug.
TDF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed.
No clinically significant drug interactions have been observed between VIREAD and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.
| Coadministered Drug | Dose of Coadministered Drug (mg) | N | % Change of Tenofovir Pharmacokinetic Parameters†
(90% CI) |
||
|---|---|---|---|---|---|
| Cmax | AUC | Cmin | |||
|
|||||
| Atazanavir‡ | 400 once daily × 14 days | 33 | ↑ 14 (↑ 8 to ↑ 20) | ↑ 24 (↑ 21 to ↑ 28) | ↑ 22 (↑ 15 to ↑ 30) |
| Atazanavir/ Ritonavir‡ | 300/100 once daily | 12 | ↑ 34 (↑ 20 to ↑ 51) | ↑ 37 (↑ 30 to ↑ 45) | ↑ 29 (↑ 21 to ↑ 36) |
| Darunavir/ Ritonavir§ | 300/100 twice daily | 12 | ↑ 24 (↑ 8 to ↑ 42) | ↑ 22 (↑ 10 to ↑ 35) | ↑ 37 (↑ 19 to ↑ 57) |
| Indinavir | 800 three times daily × 7 days | 13 | ↑ 14 (↓ 3 to ↑ 33) | ⇔ | ⇔ |
| Ledipasvir/ Sofosbuvir¶,# | 90/400 once daily × 10 days | 24 | ↑ 47 (↑ 37 to ↑ 58) | ↑ 35 (↑ 29 to ↑ 42 ) | ↑ 47 (↑ 38 to ↑ 57) |
| Ledipasvir/ Sofosbuvir¶,Þ | 23 | ↑ 64 (↑ 54 to ↑ 74) | ↑ 50 (↑ 42 to ↑ 59) | ↑ 59 (↑ 49 to ↑ 70) |
|
| Ledipasvir/ Sofosbuvirß | 90/400 once daily × 14 days | 15 | ↑ 79 (↑ 56 to ↑ 104) | ↑ 98 (↑ 77 to ↑ 123) | ↑ 163 (↑ 132 to↑ 197) |
| Lopinavir/ Ritonavir | 400/100 twice daily × 14 days | 24 | ⇔ | ↑ 32 (↑ 25 to ↑ 38) | ↑ 51 (↑ 37 to ↑ 66) |
| Saquinavir/ Ritonavir | 1000/100 twice daily × 14 days | 35 | ⇔ | ⇔ | ↑ 23 (↑ 16 to ↑ 30) |
| Sofosbuvirà | 400 single dose | 16 | ↑ 25 (↑ 8 to ↑ 45) | ⇔ | ⇔ |
| Sofosbuvir/ Velpatasvirè | 400/100 once daily | 24 | ↑ 44 (↑ 33 to ↑ 55) | ↑ 40 (↑ 34 to ↑ 46) | ↑ 84 (↑ 76 to ↑ 92) |
| Sofosbuvir/ Velpatasvirð | 400/100 once daily | 30 | ↑ 46 (↑ 39 to ↑ 54) | ↑ 40 (↑ 34 to ↑ 45) | ↑ 70 (↑ 61 to ↑ 79) |
| Sofosbuvir/ Velpatasvir/ Voxilaprevirø | 400/100/100 + Voxilaprevirý 100 once daily | 29 | ↑ 48 (↑ 36 to ↑ 61) | ↑ 39 (↑ 32 to ↑ 46) | ↑ 47 (↑ 38 to ↑ 56) |
| Tacrolimus | 0.05 mg/kg twice daily × 7 days | 21 | ↑ 13 (↑ 1 to ↑ 27) | ⇔ | ⇔ |
| Tipranavir/ Ritonavir£ | 500/100 twice daily | 22 | ↓ 23 (↓ 32 to ↓ 13) | ↓ 2 (↓ 9 to ↑ 5) | ↑ 7 (↓ 2 to ↑ 17) |
| 750/200 twice daily (23 doses) | 20 | ↓ 38 (↓ 46 to ↓ 29) | ↑ 2 (↓ 6 to ↑ 10) | ↑ 14 (↑ 1 to ↑ 27) |
|
No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with VIREAD: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.
| Coadministered Drug | Dose of Coadministered Drug (mg) | N | % Change of Coadministered Drug Pharmacokinetic Parameters*
(90% CI) |
||
|---|---|---|---|---|---|
| Cmax | AUC | Cmin | |||
|
|||||
| Abacavir | 300 once | 8 | ↑ 12 (↓ 1 to ↑ 26) | ⇔ | NA |
| Atazanavir† | 400 once daily × 14 days | 34 | ↓ 21 (↓ 27 to ↓ 14) | ↓ 25 (↓ 30 to ↓ 19) | ↓ 40 (↓ 48 to ↓ 32) |
| Atazanavir† | Atazanavir/ Ritonavir 300/100 once daily × 42 days | 10 | ↓ 28 (↓ 50 to ↑ 5) | ↓ 25‡
(↓ 42 to ↓ 3) | ↓ 23‡
(↓ 46 to ↑ 10) |
| Darunavir§ | Darunavir/Ritonavir 300/100 once daily | 12 | ↑ 16 (↓ 6 to ↑ 42) | ↑ 21 (↓ 5 to ↑ 54) | ↑ 24 (↓ 10 to ↑ 69) |
| Didanosine¶ | 250 once, simultaneously with VIREAD and a light meal# | 33 | ↓ 20Þ
(↓ 32 to ↓ 7) | ⇔Þ | NA |
| Emtricitabine | 200 once daily × 7 days | 17 | ⇔ | ⇔ | ↑ 20 (↑ 12 to ↑ 29) |
| Entecavir | 1 mg once daily × 10 days | 28 | ⇔ | ↑ 13 (↑ 11 to ↑ 15) | ⇔ |
| Indinavir | 800 three times daily × 7 days | 12 | ↓ 11 (↓ 30 to ↑ 12) | ⇔ | ⇔ |
| Lamivudine | 150 twice daily × 7 days | 15 | ↓ 24 (↓ 34 to ↓ 12) | ⇔ | ⇔ |
| Lopinavir | Lopinavir/Ritonavir 400/100 twice daily × 14 days | 24 | ⇔ | ⇔ | ⇔ |
| Ritonavir | ⇔ | ⇔ | ⇔ | ||
| Saquinavir | Saquinavir/Ritonavir 1000/100 twice daily × 14 days | 32 | ↑ 22 (↑ 6 to ↑ 41) | ↑ 29ß
(↑ 12 to ↑ 48) | ↑ 47ß
(↑ 23 to ↑ 76) |
| Ritonavir | ⇔ | ⇔ | ↑ 23 (↑ 3 to ↑ 46) |
||
| Tacrolimus | 0.05 mg/kg twice daily × 7 days | 21 | ⇔ | ⇔ | ⇔ |
| Tipranavirà | Tipranavir/Ritonavir 500/100 twice daily | 22 | ↓ 17 (↓ 26 to ↓ 6) | ↓ 18 (↓ 25 to ↓ 9) | ↓ 21 (↓ 30 to ↓ 10) |
| Tipranavir/Ritonavir 750/200 twice daily (23 doses) | 20 | ↓ 11 (↓ 16 to ↓ 4) | ↓ 9 (↓ 15 to ↓ 3) | ↓ 12 (↓ 22 to 0) |
|
12.4 Microbiology
Mechanism of Action
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate (TFV-DP), an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) and HBV 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 α, β, and mitochondrial DNA polymerase γ.
Activity against HIV
Antiviral Activity
The 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 EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 µM to 8.5 µM. In drug combination studies, tenofovir was not antagonistic with HIV-1 NRTIs (abacavir, didanosine, lamivudine, stavudine, zidovudine), NNRTIs (efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir). Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 µM to 2.2 µM) and strain-specific activity against HIV-2 (EC50 values ranged from 1.6 µM to 5.5 µM).
Resistance
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2- to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir.
In Trial 903 of treatment-naïve subjects (VIREAD+3TC+EFV versus d4T+3TC+EFV) [see Clinical Studies (14.2)], genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of EFV and 3TC resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) of analyzed patient isolates in the VIREAD arm and in 2/49 (4%) of analyzed patient isolates in the d4T arm. Of the 8 subjects whose virus developed K65R in the VIREAD arm through 144 weeks, 7 occurred in the first 48 weeks of treatment and one at Week 96. One patient in the VIREAD arm developed the K70E substitution in the virus. Other substitutions resulting in resistance to VIREAD were not identified in this trial.
In Trial 934 of treatment-naïve subjects (VIREAD+FTC+EFV versus AZT/3TC+EFV) [see Clinical Studies (14.2)], genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of EFV resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to FTC and 3TC, was observed in 2/19 of analyzed subject isolates in the VIREAD+FTC group and in 10/29 of analyzed subject isolates in the AZT/3TC group. Through 144 weeks of Trial 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
Cross Resistance
Cross resistance among certain HIV-1 NRTIs has been recognized. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected subjects treated with abacavir or didanosine. HIV-1 isolates with this substitution also show reduced susceptibility to FTC and 3TC. Therefore, cross resistance among these drugs may occur in patients whose virus harbors the K65R or K70E substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of three AZT-associated RT substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.
In Trials 902 and 907 conducted in treatment-experienced subjects (VIREAD + Standard Background Therapy (SBT) compared to placebo + SBT) [see Clinical Studies (14.2)], 14/304 (5%) of the VIREAD-treated subjects with virologic failure through Week 96 had >1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 RT gene.
The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Trials 902 and 907. In these clinical trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial results.
Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross resistance of VIREAD to pre-existing AZT resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. VIREAD-treated subjects whose HIV-1 expressed 3 or more AZT resistance-associated substitutions that included either the M41L or L210W RT substitution showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to VIREAD therapy. Subjects whose virus expressed an L74V substitution without AZT resistance-associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
In the protocol defined analyses, virologic response to VIREAD was not reduced in subjects with HIV-1 that expressed the abacavir/FTC/3TC resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.
Trials 902 and 907 Phenotypic Analyses
Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 17 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.
Activity against HBV
Antiviral Activity
The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir ranged from 0.14 to 1.5 µM, with CC50 (50% cytotoxicity concentration) values >100 µM. In cell culture combination antiviral activity studies of tenofovir with HBV NrtIs entecavir, lamivudine, and telbivudine, and with the HIV-1 NRTI emtricitabine, no antagonistic activity was observed.
Resistance
Cumulative VIREAD genotypic resistance has been evaluated annually for up to 384 weeks in Trials 0102, 0103, 0106, 0108, and 0121 [see Clinical Studies (14.4)] with the paired HBV rt amino acid sequences of the pretreatment and on-treatment isolates from subjects who received at least 24 weeks of VIREAD monotherapy and remained viremic with HBV DNA ≥400 copies/mL (69 IU/mL) at the end of each study year (or at discontinuation of VIREAD monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Trials 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on VIREAD monotherapy (15% versus 5%, respectively).
HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 18); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to VIREAD (genotypic and phenotypic analyses).
| Compensated Liver Disease | ||||
|---|---|---|---|---|
| Nucleotide-Naïve (N=417)* | HEPSERA-Experienced (N=247)† | Lamivudine- Resistant (N=136)‡ | Decompensated Liver Disease (N=39)§ |
|
|
||||
| Viremic at Last Time Point on VIREAD | 38/417 (9%) | 37/247 (15%) | 9/136 (7%) | 7/39 (18%) |
| Treatment-Emergent Amino Acid Substitutions¶ | 18#/32 (56%) | 11Þ/31 (35%) | 6ß/8 (75%) | 3/5 (60%) |
Cross Resistance
Cross resistance has been observed between HBV NrtIs.
In cell-based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine (3TC) and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.
HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild type virus.
HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9- to 1.5-fold that of wild type virus.
One hundred fifty-two subjects initiating VIREAD therapy in Trials 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV NrtIs: 14 with adefovir resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 with 3TC resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and 3TC resistance-associated substitutions. Following up to 384 weeks of VIREAD treatment, 10 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with 3TC-resistant HBV, and 2 of the 3 subjects with both adefovir- and 3TC-resistant HBV achieved and maintained virologic suppression (HBV DNA <400 copies/mL [69 IU/mL]). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.
Mutagenesis
Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice.
Impairment of Fertility
There were no effects on fertility, mating performance or early embryonic development when TDF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.
13.2 Animal Toxicology and/or Pharmacology
Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
14 CLINICAL STUDIES
14.1 Overview of Clinical Trials
The efficacy and safety of VIREAD in adults and pediatric subjects were evaluated in the trials summarized in Table 19.
| Trial | Population | Study Arms (N)* | Timepoint (Week) |
|---|---|---|---|
| Trial 903†
(NCT00158821) | HIV-1 treatment-naïve adults | VIREAD+lamivudine+efavirenz (299) stavudine+lamivudine+efavirenz (301) | 144 |
| Trial 934‡
(NCT00112047) | emtricitabine+VIREAD+efavirenz (257) zidovudine/lamivudine+efavirenz (254) | 144 | |
| Trial 907§
(NCT00002450) | HIV-1 treatment-experienced adults | VIREAD (368) Placebo (182) | 24 |
| Trial 0102†
(NCT00117676) | HBeAg-negative adults with chronic HBV | VIREAD (250) HEPSERA (125) | 48 |
| Trial 0103†
(NCT00116805) | HBeAg-positive adults with chronic HBV | VIREAD (176) HEPSERA (90) | 48 |
| Trial 121†
(NCT00737568) | Adults with lamivudine-resistant chronic HBV | VIREAD (141) | 96 |
| Trial 0108†
(NCT00298363) | Adults with chronic HBV and decompensated liver disease | VIREAD (45) | 48 |
| Trial 352‡
(NCT00528957) | HIV-1 treatment experienced pediatric subjects 2 years to <12 years | VIREAD (44) stavudine or zidovudine (48) | 48 |
| Trial 321§
(NCT00352053) | HIV-1 treatment-experienced pediatric subjects 12 years to <18 years | VIREAD (45) Placebo (42) | 48 |
| Trial 115§
(NCT00734162) | Pediatric subjects 12 years to <18 years with chronic HBV | VIREAD (52) Placebo (54) | 72 |
| Trial 144§
(NCT01651403) | Pediatric subjects 2 years to <12 years with chronic HBV | VIREAD (60) Placebo (29) | 48 |
14.2 Clinical Trial Results in Adults with HIV-1 Infection
Treatment-Naïve Subjects: Trial 903
Data through 144 weeks are reported for Trial 903, a double-blind, active-controlled multicenter trial comparing VIREAD (300 mg once daily) administered in combination with lamivudine (3TC) and efavirenz (EFV) versus stavudine (d4T), 3TC, and EFV 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/mm3 (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/mm3. Table 20 provides treatment outcomes through 48 and 144 weeks.
| 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* | 79% | 82% | 68% | 62% |
| Virologic failure† | 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‡ | 8% | 7% | 14% | 15% |
Achievement of plasma HIV-1 RNA concentrations of <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/mm3). Through 144 weeks of therapy, 62% and 58% of subjects in the VIREAD and d4T arms, respectively, achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm3 for the VIREAD arm and 283 cells/mm3 for the d4T arm.
Through 144 weeks, 11 subjects in the VIREAD group and 9 subjects in the d4T group experienced a new CDC Class C event.
Treatment-Naïve Subjects: Trial 934
Data through 144 weeks are reported for Trial 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine (FTC) + VIREAD administered in combination with efavirenz (EFV) versus zidovudine (AZT)/lamivudine (3TC) fixed-dose combination administered in combination with EFV in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of FTC and TDF with EFV in place of FTC + VIREAD with EFV. 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/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Table 21 provides treatment outcomes through 48 and 144 weeks for those subjects who did not have EFV resistance at baseline.
| Outcomes | At Week 48 | At Week 144 | ||
|---|---|---|---|---|
| FTC+VIREAD+EFV (N=244) | AZT/3TC+EFV (N=243) | FTC+VIREAD+EFV (N=227)* | AZT/3TC+EFV (N=229)* |
|
|
||||
| Responder† | 84% | 73% | 71% | 58% |
| Virologic failure‡ | 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§ | 10% | 14% | 20% | 22% |
Through Week 48, 84% and 73% of subjects in the FTC + VIREAD group and the AZT/3TC 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 AZT/3TC group in this open-label trial. In addition, 80% and 70% of subjects in the FTC + VIREAD group and the AZT/3TC 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/mm3 in the FTC + VIREAD group and 158 cells/mm3 in the AZT/3TC group at Week 48 (312 and 271 cells/mm3 at Week 144).
Through 48 weeks, 7 subjects in the FTC + VIREAD group and 5 subjects in the AZT/3TC group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
Treatment-Experienced Subjects: Trial 907
Trial 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/mm3 (range 23–1,385), median baseline plasma HIV-1 RNA of 2,340 (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, 69% Caucasian, 17% Black, and 12% Hispanic.
Table 22 provides the percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks.
| 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 * | 40% | 11% | 28% | 30% |
| Virologic failure† | 53% | 84% | 61% | 64% |
| Discontinued due to adverse event | 3% | 3% | 5% | 5% |
| Discontinued for 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/mm3 for the VIREAD group and −5 cells/mm3 for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm3 for the VIREAD group.
Through Week 24, one subject in the VIREAD group and no subjects in the placebo group experienced a new CDC Class C event.
14.3 Clinical Trial Results in Pediatric Subjects with HIV-1 Infection
In Trial 352, 92 treatment-experienced subjects 2 years to less than 12 years of age with stable, virologic suppression on a stavudine (d4T)- or zidovudine (AZT)-containing regimen were randomized to either replace d4T or AZT with VIREAD (N=44) or continue their original regimen (N=48) for 48 weeks. Five additional subjects over the age of 12 years 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 trial receiving open-label VIREAD. At Week 48, 89% of subjects in the VIREAD treatment group and 90% of subjects in the d4T or AZT treatment group had HIV-1 RNA concentrations <400 copies/mL. During the 48-week randomized phase of the trial, 1 subject in the VIREAD group discontinued the trial prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the VIREAD group and 1 subject in the d4T or AZT group) discontinued for other reasons.
In Trial 321, 87 treatment-experienced subjects 12 years 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/mm3 and the mean baseline plasma HIV-1 RNA was 4.6 log10 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 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.
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 and older who weigh at least 35 kg and whose HIV-1 isolate is expected to be sensitive to VIREAD [see Warnings and Precautions (5.5), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].
14.4 Clinical Trial Results in Adults with Chronic Hepatitis B
HBeAg-Negative Chronic HBV Subjects: Trial 0102
Trial 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 log10 copies/mL; and mean serum ALT was 140 U/L.
HBeAg-Positive Chronic HBV Subjects: Trial 0103
Trial 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 log10 copies /mL; and mean serum ALT was 147 U/L.
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 (see Table 23).
| 0102 (HBeAg-) | 0103 (HBeAg+) | |||
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| Complete Response | 71% | 49% | 67% | 12% |
| Histology
Histological Response* | 72% | 69% | 74% | 68% |
| HBV DNA
<400 copies/mL (<69 IU/mL) | 93% | 63% | 76% | 13% |
| ALT
Normalized ALT† | 76% | 77% | 68% | 54% |
| Serology
HBeAg Loss/ Seroconversion | NA‡ | NA‡ | 20%/19% | 16%/16% |
| HBsAg Loss/ Seroconversion | 0/0 | 0/0 | 3%/1% | 0/0 |
Treatment Beyond 48 Weeks: Trials 0102 and 0103
In Trials 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 Trial 0102, 266 of 347 subjects who entered the open-label period (77%) continued in the trial 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 Trial 0103, 146 of 238 subjects who entered the open-label period (61%) continued in the trial 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 trials, 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.
Lamivudine-Resistant Chronic HBV Subjects: Trial 121
Trial 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 log10 copies/mL and mean serum ALT of 71 U/L at baseline.
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.
Chronic HBV and Decompensated Liver Disease Subjects: Trial 0108
Trial 0108 was 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.
Forty-five adult subjects (37 males and 8 females) were randomized to the VIREAD treatment arm. At baseline, 69% of 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 log10 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 [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.
14.5 Clinical Trial Results in Pediatric Subjects with Chronic Hepatitis B
Pediatric Subjects 12 Years to less than 18 Years of Age with Chronic HBV
In Trial 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 trial entry, the mean HBV DNA was 8.1 log10 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 trial participation.
Pediatric Subjects 2 Years to less than 12 Years of Age with Chronic HBV
In Trial 144, 89 HBeAg positive (96%) and negative (4%) subjects 2 years to less than 12 years of age with chronic HBV infection were treated with VIREAD 8 mg/kg up to a maximum dose of 300 mg (N=60) or placebo (N=29) once daily for 48 weeks. At trial entry, the mean HBV DNA was 8.1 log10 IU/mL and mean ALT was 123 U/L. There was an overall higher proportion in the VIREAD group with HBV DNA <400 copies/mL (69 IU/mL) and ALT normalization rate at Week 48 compared to the placebo group (Table 24). There was no difference between treatment groups in those who achieved HBeAg loss or HBeAg seroconversion.
| Endpoint at Week 48 | VIREAD N=60 | Placebo N=29 |
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| HBV DNA <400 copies/mL (69 IU/ml) | 46/60 (77%) | 2/29 (7%) |
| ALT Normalization* | 38/58 (66%) | 4/27 (15%) |
| HBeAg loss† | 17/56 (30%) | 8/29 (28%) |
| HBeAg seroconversion† | 14/56 (25%) | 7/29 (24%) |
In Trials 115 and 144, sequencing data from paired baseline and on treatment HBV isolates from subjects who received VIREAD were available for 14 of 15 subjects who had plasma HBV DNA ≥400 copies/mL. No amino acid substitutions associated with resistance to VIREAD were identified in these isolates by Week 72 (Trial 115) or Week 48 (Trial 144).
16 HOW SUPPLIED/STORAGE AND HANDLING
VIREAD tablets are available in bottles containing 30 tablets with child-resistant closure as follows:
- 150 mg of TDF (equivalent to 123 mg of tenofovir disoproxil): tablets are triangle-shaped, white, film-coated, and debossed with "GSI" on one side and with "150" on the other side. (NDC 61958-0404-1)
- 200 mg of TDF (equivalent to 163 mg of tenofovir disoproxil): tablets are round-shaped, white, film-coated, and debossed with "GSI" on one side and with "200" on the other side. (NDC 61958-0405-1)
- 250 mg of TDF (equivalent to 204 mg of tenofovir disoproxil): tablets are capsule-shaped, white, film-coated and debossed with "GSI" on one side and with "250" on the other side. (NDC 61958-0406-1)
- 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil): tablets are almond-shaped, light-blue, film-coated, and debossed with "GILEAD" and "4331" on one side and with "300" on the other side. (NDC 61958-0401-1)
VIREAD oral powder consists of white, coated granules containing 40 mg of TDF (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)
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Severe Acute Exacerbation of Hepatitis B in Patients Infected with HBV
Inform patients that severe acute exacerbations of hepatitis B have been reported in patients infected with hepatitis B virus (HBV) and have discontinued VIREAD. Advise patients not to discontinue VIREAD without first informing their healthcare provider. All patients should be tested for HBV infection before or when starting VIREAD and those who are infected with HBV need close medical follow-up for several months after stopping VIREAD to monitor for exacerbations of hepatitis [see Warnings and Precautions (5.1)].
New Onset or Worsening Renal Impairment
Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of VIREAD. Advise patients to avoid VIREAD with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Warnings and Precautions (5.2)]. The dosing interval of VIREAD may need adjustment in HIV-1 infected patients with renal impairment.
Immune Reconstitution Syndrome
Inform patients that in some patients with advanced HIV infection (AIDS) signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.4)].
Bone Loss and Mineralization Defects
Inform patients that decreases in bone mineral density have been observed with the use of VIREAD. Consider bone monitoring in patients who have a history of pathologic bone fracture or at risk for osteopenia [see Warnings and Precautions (5.5)].
Lactic Acidosis and Severe Hepatomegaly
Inform patients that 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 [see Warnings and Precautions (5.6)].
Drug Interactions
Advise patients that VIREAD may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other medication, including other HIV drugs and drugs for treatment of hepatitis C virus [see Warnings and Precautions (5.7) and Drug Interactions (7)].
Dosing Recommendations
Inform patients that it is important to take VIREAD on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance [see Dosage and Administration (2)].
Pregnancy Registry
Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to VIREAD [see Use in Specific Populations (8.1)].
Lactation
Instruct mothers not to breastfeed if they are taking VIREAD for the treatment of HIV-1 infection because of the risk of passing the HIV-1 virus to the baby [see Use in Specific Populations (8.2)].
SPL UNCLASSIFIED SECTION
Gilead Sciences, Inc.
Foster City, CA 94404
VIREAD, ATRIPLA, COMPLERA, EPCLUSA, HARVONI, HEPSERA, SOVALDI, STRIBILD, and TRUVADA are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.
© 2019 Gilead Sciences, Inc. All rights reserved.
21356-GS-041
SPL UNCLASSIFIED SECTION
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Revised: April 2019 |
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Patient Information |
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VIREAD® (VEER-ee-ad) | VIREAD® (VEER-ee-ad) (tenofovir disoproxil fumarate) oral powder |
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Read this Patient Information before you start taking VIREAD and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. |
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What is the most important information I should know about VIREAD? VIREAD can cause serious side effects, including:
For more information about side effects, see "What are the possible side effects of VIREAD?" |
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What is VIREAD? VIREAD is a prescription medicine that is used to:
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What should I tell my healthcare provider before taking VIREAD? Before you take VIREAD, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may interact with VIREAD. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
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How should I take VIREAD?
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What are the possible side effects of VIREAD? VIREAD may cause serious side effects, including:
The most common side effects in all people taking VIREAD are: |
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In some people with advanced HBV-infection, other common side effects may include: |
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These are not all the possible side effects of VIREAD. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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How should I store VIREAD?
Keep VIREAD and all medicines out of the reach of children. |
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General information about the safe and effective use of VIREAD. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VIREAD for a condition for which it was not prescribed. Do not give VIREAD to other people, even if they have the same condition you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VIREAD that is written for health professionals. A vaccine is available to protect people at risk for becoming infected with HBV. You can ask your healthcare provider for information about this vaccine. |
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What are the ingredients in VIREAD? Active ingredient: tenofovir disoproxil fumarate Inactive ingredients: VIREAD tablets: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. VIREAD powder: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide. Tablet coating: VIREAD tablets 300 mg: Opadry II Y-30-10671-A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. VIREAD tablets 150, 200, and 250 mg: Opadry II 32K-18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. Manufactured for and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 |
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Instructions for Use
VIREAD® (VEER-ee-ad)
(tenofovir disoproxil fumarate)
powder
for oral use
Read the Patient Information that comes with VIREAD powder for important information about VIREAD.
Read this Instructions for Use before you give VIREAD for the first time. Be sure you understand and follow the instructions. If you have any questions, ask your healthcare provider or pharmacist.
Important information
- VIREAD powder comes in a box that has a bottle of VIREAD and a dosing scoop (see Figure A).
- Only use the dosing scoop to measure VIREAD powder.
- Only mix VIREAD powder with soft foods that can be swallowed without chewing. Examples of soft foods you can use are: applesauce, baby food, or yogurt.
- Do not mix VIREAD powder with liquid. The powder may float to the top even after stirring.
- Give the entire dose right away after mixing to avoid a bad taste.
How do I prepare and give a dose of VIREAD powder?
- Wash your hands well with soap and water, and dry them.
- Measure ¼ to ½ cup of soft food such as applesauce, baby food, or yogurt into a cup or bowl.
- To open a new bottle of powder, press down on the bottle lid and turn to remove (see picture on the top of the bottle cap). Peel off the foil.
- Measure the number of scoops prescribed by your healthcare provider.
- Sprinkle the VIREAD powder on the soft food. Stir with a spoon until well mixed. Give the entire dose right away after mixing to avoid a bad taste.
- Close the bottle of VIREAD tightly.
- Wash and dry the dosing scoop. Do not store the dosing scoop in the bottle.
How should I store VIREAD powder?
- Store VIREAD powder at room temperature between 68 °F to 77 °F (20 °C to 25 °C).
- Keep VIREAD powder in the original container.
- Keep the bottle tightly closed.
- Do not use VIREAD powder if the seal over the bottle opening is broken or missing.
Keep VIREAD and all medicines out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
SPL UNCLASSIFIED SECTION
Manufactured for and distributed by: Gilead Sciences, Inc. Foster City, CA 94404
Revised: April 2019
VIREAD is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.
© 2019 Gilead Sciences, Inc. All rights reserved.
21356-GS-041
PRINICPAL DISPLAY PANEL - 150 mg Tablet Bottle Label
PRINICPAL DISPLAY PANEL - 200 mg Tablet Bottle Label
PRINICPAL DISPLAY PANEL - 250 mg Tablet Bottle Label
PRINICPAL DISPLAY PANEL - 300 mg Tablet Bottle Label
PRINICPAL DISPLAY PANEL - 40 mg/Scoop Bottle Label
INGREDIENTS AND APPEARANCE
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tenofovir disoproxil fumarate tablet, coated |
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| Labeler - Gilead Sciences, Inc. (185049848) |