Adefovir Dipivoxil

ADEFOVIR DIPIVOXIL- adefovir dipivoxil tablet
Apotex Corp.

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WARNING: SEVERE ACUTE EXACERBATIONS OF HEPATITIS, NEPHROTOXICITY, HIV RESISTANCE, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS

Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-Hepatitis B therapy including adefovir dipivoxil tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-Hepatitis B therapy. If appropriate, resumption of anti-Hepatitis B therapy may be warranted [See Warnings and Precautions (5. 1 )].

In patients at risk of or having underlying renal dysfunction, chronic administration of adefovir dipivoxil tablets may result in nephrotoxicity. These patients should be monitored closely for renal function and may require dose adjustment [See Warnings and Precautions (5. 2 ) and Dosage and Administration (2.2)] .

HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated Human Immunodeficiency Virus (HIV) infection treated with anti-hepatitis B therapies, such as therapy with adefovir dipivoxil tablets, that may have activity against HIV [See Warnings and Precautions (5. 3 )] .

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals [See Warnings and Precautions (5. 4 )] .

1 INDICATIONS AND USAGE

Adefovir dipivoxil tablets are indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

This indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.

For patients 12 to less than 18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus infection with compensated liver function.

2 DOSAGE AND ADMINISTRATION

2.1 Chronic Hepatitis B

The recommended dose of adefovir dipivoxil tablets in chronic hepatitis B patients for patients 12 years of age and older with adequate renal function is 10 mg, once daily, taken orally, without regard to food. The optimal duration of treatment is unknown.

Adefovir dipivoxil tablets are not recommended for use in children less than 12 years of age.

2.2 Dose Adjustment in Renal Impairment

Significantly increased drug exposures were seen when adefovir dipivoxil tablets were administered to adult patients with renal impairment [See Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Therefore, the dosing interval of adefovir dipivoxil tablets should be adjusted in adult patients with baseline creatinine clearance less than 50 mL per minute using the following suggested guidelines (See Table 1). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated.

Additionally, it is important to note that these guidelines were derived from data in patients with pre-existing renal impairment at baseline. They may not be appropriate for patients in whom renal insufficiency evolves during treatment with adefovir dipivoxil tablets. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Table 1 Dosing Interval Adjustment of Adefovir Dipivoxil Tablets in Adult Patients with Renal Impairment
Creatinine Clearance (mL/min)*
Greater than or equal to 50 30 to 49 10 to 29 Hemodialysis Patients
*
Creatinine clearance calculated by Cockcroft-Gault method using lean or ideal body weight.
Recommended doseand dosing interval 10 mg every24 hours 10 mg every48 hours 10 mg every72 hours 10 mg every 7 days followingdialysis

The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute; therefore, no dosing recommendation is available for these patients.

No clinical data are available to make dosing recommendations in adolescent patients with renal insufficiency [See Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHS

Adefovir Dipivoxil Tablets are white to off-white, round, flat-faced bevelled edge tablets, engraved “APO” on one side, “A10” on the other side.

4 CONTRAINDICATIONS

Adefovir dipivoxil tablets are contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

5 WARNINGS AND PRECAUTIONS

5.1 Exacerbation of Hepatitis after Discontinuation of Treatment

Severe acute exacerbation of hepatitis has been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with adefovir dipivoxil. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least several months in patients who discontinue adefovir dipivoxil. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

In clinical trials of adefovir dipivoxil, exacerbations of hepatitis (ALT elevations 10 times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation of adefovir dipivoxil. These events were identified in studies GS-98-437 and GS-98-438 (N=492). Most of these events occurred within 12 weeks of drug discontinuation. These exacerbations generally occurred in the absence of HBeAg seroconversion, and presented as serum ALT elevations in addition to re-emergence of viral replication. In the HBeAg-positive and HBeAg-negative studies in patients with compensated liver function, the exacerbations were not generally accompanied by hepatic decompensation. However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation. Although most events appear to have been self-limited or resolved with re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported. Therefore, patients should be closely monitored after stopping treatment.

5.2 Nephrotoxicity

Nephrotoxicity characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus was historically shown to be the treatment-limiting toxicity of adefovir dipivoxil therapy at substantially higher doses in HIV-infected patients (60 and 120 mg daily) and in chronic hepatitis B patients (30 mg daily). Chronic administration of adefovir dipivoxil (10 mg once daily) may result in delayed nephrotoxicity. The overall risk of nephrotoxicity in patients with adequate renal function is low. However, this is of special importance in patients at risk of or having underlying renal dysfunction and patients taking concomitant nephrotoxic agents such as cyclosporine, tacrolimus, aminoglycosides, vancomycin and non-steroidal anti-inflammatory drugs [See Adverse Reactions (6.2) and Clinical Pharmacology (12.3)]. It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with adefovir dipivoxil.

It is important to monitor renal function for all patients during treatment with adefovir dipivoxil, particularly for those with pre-existing or other risks for renal impairment. Patients with renal insufficiency at baseline or during treatment may require dose adjustment [See Dosage and Administration (2.2)]. The risks and benefits of adefovir dipivoxil treatment should be carefully evaluated prior to discontinuing adefovir dipivoxil in a patient with treatment-emergent nephrotoxicity.

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