Prescription Drug Information: TENOFOVIR DISOPROXIL FUMARATE

TENOFOVIR DISOPROXIL FUMARATE- tenofovir disoproxil fumarate tablet
Strides Pharma Science Limited

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B

Severe acute exacerbations of hepatitis B virus (HBV) have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in HBV-infected in patients who dis continue anti-hepatitis B therapy, including tenofovir disoproxil fumarate. If appropriate, resumption of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

1.1 HIV-1 Infection

Tenofovir disoproxil fumarate is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 2 years of age and older weighing at least 10 kg.

1.2 Chronic Hepatitis B

Tenofovir disoproxil fumarate is indicated for the treatment of chronic hepatitis B virus (HBV) in adults and pediatric patients 12 years of age and older

Pediatric use information is approved for Gilead Sciences, Inc.’s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Initiation of Tenofovir disoproxil fumarates for Treatment of HIV-1 Infection or Chronic Hepatitis B

Prior to or when initiating Tenofovir disoproxil fumarate, test patients for HBV infection and HIV-1 infection. Tenofovir disoproxil fumarate alone should not be used in patients with HIV-1 infection [see Warnings and Precautions (5.3)].

Prior to initiation and during use of Tenofovir disoproxil fumarate, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see 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 Tenofovir disoproxil fumarate 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 Tenofovir disoproxil fumarate is the same for both HIV and HBV indications.

The recommended dosage of Tenofovir disoproxil fumarate 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 Tenofovir disoproxil fumarate dose adjusted accordingly.

Table 1 Recommended Dosing for Patients 2 Years and Older and Weighing at Least 17 kg Using Tenofovir disoproxil fumarate

Body Weight (kg) Dosing of Tenofovir Disoproxil Fumarate 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

2.4 Dosage Adjustment in Patients with Renal Impairment

Significant increase in drug exposures occurred when tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate 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)].

Table 3 Dosage Interval Adjustment for Adult Patients with Altered Creatinine Clearance

*
Calculated using ideal (lean) body weight.
Generally once weekly assuming 3 hemodialysis sessions a week of approximately 4 hours’ duration. Tenofovir disoproxil fumarate should be administered following completion of dialysis.
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 dose recommendations in pediatric patients with renal impairment.

3 DOSAGE FORMS AND STRENGTHS

Tenofovir disoproxil fumarate is available as tablets.

Tenofovir disoproxil fumarate tablets 300 mg contain 300 mg of tenofovir disoproxil fumarate which is equivalent to 245 mg of tenofovir disoproxil. The tablets are white circular film coated, convex tablets engraved “TDF” on one side and plain on other side.

4 CONTRAINDICATIONS

None.

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 tenofovir disoproxil fumarate [see Dosage and Administration (2.1)].

Discontinuation of anti-HBV therapy, including tenofovir disoproxil fumarate, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate [see Adverse Reactions (6.2)].

Prior to initiation and during use of tenofovir disoproxil fumarate, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Dosing interval adjustment of tenofovir disoproxil fumarate and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 ml/min [See Dosage and Administration (2.4)]. No safety or efficacy data are available in patients with renal impairment who received tenofovir disoproxil fumarate using these dosing guidelines, so the potential benefit of tenofovir disoproxil fumarate therapy should be assessed against the potential risk of renal toxicity.

Tenofovir disoproxil fumarate 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, tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with tenofovir disoproxil fumarate.

5.4 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including tenofovir disoproxil fumarate. 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-Barre 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, tenofovir disoproxil fumarate was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [See Adverse Reactions (6.1)]. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir disoproxil fumarate.

Clinical trials evaluating tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic HBV-infected pediatric subjects 12 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 tenofovir disoproxil fumarate -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 tenofovir disoproxil fumarate 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 products containing TDF-containing products [See Warnings and Precautions (5.2)].

Pediatric use information is approved for Gilead Sciences, Inc.’s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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