NDC 60505-3947 Adefovir Dipivoxil

Adefovir Dipivoxil

NDC Product Code 60505-3947

NDC CODE: 60505-3947

Proprietary Name: Adefovir Dipivoxil What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Adefovir Dipivoxil What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat a chronic viral infection of the liver (hepatitis B) in people 12 years of age and older. It works by slowing the growth of the virus, helping to lower the amount of virus in your body. It is not a cure for hepatitis B and does not prevent the passing of hepatitis B to others. This medication is a nucleotide analog.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE TO OFF WHITE)
Shape: ROUND (C48348)
Size(s):
7 MM
Imprint(s):
APO;A10
Score: 1

NDC Code Structure

  • 60505 - Apotex Corp.

NDC 60505-3947-3

Package Description: 1 BOTTLE in 1 CARTON > 30 TABLET in 1 BOTTLE

NDC Product Information

Adefovir Dipivoxil with NDC 60505-3947 is a a human prescription drug product labeled by Apotex Corp.. The generic name of Adefovir Dipivoxil is adefovir dipivoxil. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Apotex Corp.

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Adefovir Dipivoxil Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • ADEFOVIR DIPIVOXIL 10 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • STARCH, CORN (UNII: O8232NY3SJ)
  • CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • TALC (UNII: 7SEV7J4R1U)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Hepatitis B Virus Nucleoside Analog Reverse Transcriptase Inhibitor - [EPC] (Established Pharmacologic Class)
  • Nucleoside Analog - [EXT]
  • Nucleoside Reverse Transcriptase Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Apotex Corp.
Labeler Code: 60505
FDA Application Number: ANDA205459 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 09-25-2018 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Adefovir Dipivoxil Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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.

2.1 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 ImpairmentCreatinine Clearance (mL/min)Creatinine clearance calculated by Cockcroft-Gault method using lean or ideal body weight.Greater than or equal to 5030 to 49 10 to 29 Hemodialysis PatientsRecommended doseand dosing interval10 mg every24 hours10 mg every48 hours10 mg every72 hours10 mg every 7 days followingdialysisThe 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.

5.1 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.

5.3 Hiv Resistance

Prior to initiating adefovir dipivoxil therapy, HIV antibody testing should be offered to all patients. Treatment with anti-hepatitis B therapies, such as adefovir dipivoxil, that have activity against HIV in a chronic hepatitis B patient with unrecognized or untreated HIV infection may result in emergence of HIV resistance. Adefovir dipivoxil has not been shown to suppress HIV RNA in patients; however, there are limited data on the use of adefovir dipivoxil to treat patients with chronic hepatitis B co-infected with HIV.

5.4 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 alone or in combination with antiretrovirals.A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with adefovir dipivoxil 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).

5.5 Coadministration With Other Products

Adefovir dipivoxil should not be used concurrently with VIREAD (tenofovir disoproxil fumarate) or tenofovir disoproxil fumarate-containing products including ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate combination tablet), COMPLERA® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate combination tablet), STRIBILD™ (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate combination tablet), and TRUVADA® (emtricitabine/tenofovir disoproxil fumarate combination tablet).

5.6 Clinical Resistance

Resistance to adefovir dipivoxil can result in viral load rebound which may result in exacerbation of hepatitis B and, in the setting of diminished hepatic function, lead to liver decompensation and possible fatal outcome. In order to reduce the risk of resistance in patients with lamivudine resistant HBV, adefovir dipivoxil should be used in combination with lamivudine and not as adefovir dipivoxil monotherapy. In order to reduce the risk of resistance in all patients receiving adefovir dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains above 1000 copies/mL with continued treatment. Long-term (144 week) data from Study 438 (N=124) show that patients with HBV DNA levels greater than 1000 copies/mL at Week 48 of treatment with adefovir dipivoxil were at greater risk of developing resistance than patients with serum HBV DNA levels below 1000 copies/mL at Week 48 of therapy.

6 Adverse Reactions

  • The following adverse reactions are discussed in other sections of the labeling:Severe acute exacerbations of Hepatitis [See Boxed Warning, Warnings and Precautions (5.1)] Nephrotoxicity [See Boxed Warning, Warnings and Precautions (5.2)]

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.Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with adefovir dipivoxil.Adverse reactions to adefovir dipivoxil identified from placebo-controlled and open label studies include the following: asthenia, headache, abdominal pain, diarrhea, nausea, dyspepsia, flatulence, increased creatinine, and hypophosphatemia.The incidence of these adverse reactions in studies 437 and 438, where 522 patients with chronic hepatitis B and compensated liver disease received double-blind treatment with adefovir dipivoxil (N=294) or placebo (N=228) for 48 weeks is presented in Table 2. Patients who received open-label adefovir dipivoxil for up to 240 weeks in Study 438 reported adverse reactions similar in nature and severity to those reported in the first 48 weeks.Table 2 Adverse Reactions (Grades 1 to 4) Reported in ≥3% of All Adefovir Dipivoxil-Treated Patients in Pooled Studies 437 to 438 Studies (0 to 48 Weeks)In these studies, the overall incidence of adverse reactions with adefovir dipivoxil was similar to that reported with placebo. The incidence of adverse reactions is derived from treatment-related events as identified by the study investigators.Adverse ReactionAdefovir Dipivoxil 10 mg(N=294)Placebo(N=228)Asthenia13%14%Headache9%10%Abdominal Pain9%11%Nausea5%8%Flatulence4%4%Diarrhea3%4%Dyspepsia3%2%No patients treated with adefovir dipivoxil developed a confirmed serum creatinine increase greater than or equal to 0.5 mg/dL from baseline or a confirmed phosphorus decrease to 2 mg/dL or less by Week 48. By Week 96, 2% of adefovir dipivoxil-treated patients, by Kaplan-Meier estimate, had increases in serum creatinine greater than or equal to 0.5 mg/dL from baseline (no placebo-controlled results were available for comparison beyond Week 48). For patients who chose to continue adefovir dipivoxil for up to 240 weeks in Study 438, 4 of 125 patients (3%) had a confirmed increase of 0.5 mg/dL from baseline. The creatinine elevation resolved in 1 patient who permanently discontinued treatment and remained stable in 3 patients who continued treatment. For 65 patients who chose to continue adefovir dipivoxil for up to 240 weeks in Study 437, 6 had a confirmed increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration. See Adverse Reactions (6.2) for changes in serum creatinine in patients with underlying renal insufficiency at baseline.

6.3 Pediatric Patients

Assessment of adverse reactions is based on a placebo-controlled study (Study 518) in which 173 pediatric patients aged 2 to less than 18 years with chronic hepatitis B and compensated liver disease received double-blind treatment with adefovir dipivoxil (N=115), or placebo (N=58) for 48 weeks [See Clinical Studies (14.4) and Use In Specific Populations (8.4)]. The safety profile of adefovir dipivoxil in patients 12 to less than 18 years of age (N=56) was similar to that observed in adults. No pediatric patients treated with adefovir dipivoxil developed a confirmed serum creatinine increase greater than or equal to 0.5 mg/dL from baseline or a confirmed phosphorus decrease to less than 2 mg/dL by Week 48.

6.4 Post-Marketing Experience

In addition to adverse reaction reports from clinical trials, the following possible adverse reactions have also been identified during post-approval use of adefovir dipivoxil. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Metabolism and Nutrition Disorders: hypophosphatemiaGastrointestinal Disorders: pancreatitisMusculoskeletal System and Connective Tissue Disorders: myopathy, osteomalacia (manifested as bone pain and may contribute to fractures), both associated with proximal renal tubulopathy. Renal and Urinary Disorders: renal failure, Fanconi syndrome, proximal renal tubulopathy

7 Drug Interactions

Since adefovir is eliminated by the kidney, coadministration of adefovir dipivoxil with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these coadministered drugs [See Clinical Pharmacology (12.3)].Patients should be monitored closely for adverse events when adefovir dipivoxil is coadministered with drugs that are excreted renally or with other drugs known to affect renal function [See Warnings and Precautions (5.2)]. Adefovir dipivoxil should not be administered in combination with VIREAD [See Warnings and Precautions (5.5)].

8.2 Labor And Delivery

There are no studies in pregnant women and no data on the effect of adefovir dipivoxil on transmission of HBV from mother to infant. Therefore, appropriate infant immunizations should be used to prevent neonatal acquisition of hepatitis B virus.

8.3 Nursing Mothers

It is not known whether adefovir is excreted in human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from adefovir dipivoxil, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Pediatric patients 12 to less than 18 years: The safety, efficacy, and pharmacokinetics of adefovir dipivoxil in pediatric patients (aged 12 to less than 18 years) were evaluated in a double-blind, randomized, placebo-controlled study (GS-US-103-518, Study 518) in 83 pediatric patients with chronic hepatitis B and compensated liver disease. The proportion of patients treated with adefovir dipivoxil who achieved the primary efficacy endpoint of serum HBV DNA less than 1,000 copies/mL and normal ALT levels at the end of 48 weeks blinded treatment was significantly greater (23%) when compared to placebo-treated patients (0%). [See Clinical Studies (14.4), Dosage and Administration (2) and Adverse Reactions (6.3)]. Pediatric patients 2 to less than 12 years: Patients 2 to less than 12 years of age were also evaluated in Study 518. The efficacy of adefovir dipivoxil was not significantly different from placebo in patients less than 12 years of age.Adefovir dipivoxil tablets are not recommended for use in children below 12 years of age.

8.5 Geriatric Use

Clinical studies of adefovir dipivoxil did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised when prescribing to elderly patients since they have greater frequency of decreased renal or cardiac function due to concomitant disease or other drug therapy.

8.6 Patients With Impaired Renal Function

It is recommended that the dosing interval for adefovir dipivoxil be modified in adult patients with baseline creatinine clearance less than 50 mL per minute. The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute or in adolescent patients with renal insufficiency; therefore, no dosing recommendations are available for these patients. [See Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

10 Overdosage

Doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks have been associated with gastrointestinal side effects. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.Following a 10 mg single dose of adefovir dipivoxil, a four hour hemodialysis session removed approximately 35% of the adefovir dose.

11 Description

Adefovir dipivoxil is a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV). The chemical name of adefovir dipivoxil is 9-[2-[[bis[(pivaloyloxy)methoxy]-phosphinyl]-methoxy]ethyl]adenine. It has a molecular formula of C20H32N5O8P, a molecular weight of 501.47 and the following structural formula:Adefovir dipivoxil is a white to off-white powder with an aqueous solubility of 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. It has an octanol/aqueous phosphate buffer (pH 7) partition coefficient (log p) of 1.91.Adefovir dipivoxil tablets are for oral administration. Each tablet contains 10 mg of adefovir dipivoxil and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, starch and talc.

12.1 Mechanism Of Action

Adefovir is an antiviral drug. [See Clinical Pharmacology (12.4)].

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term oral carcinogenicity studies of adefovir dipivoxil in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for HBV infection. In both mouse and rat studies, adefovir dipivoxil was negative for carcinogenic findings. Adefovir dipivoxil was mutagenic in the in vitro mouse lymphoma cell assay (with or without metabolic activation). Adefovir induced chromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolic activation. Adefovir dipivoxil was not clastogenic in the in vivo mouse micronucleus assay and adefovir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation. In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposure approximately 19 times that achieved in humans at the therapeutic dose.

14.2 Study 435 (Pre- And Post-Liver Transplantation Patients)

Adefovir dipivoxil was also evaluated in an open-label, uncontrolled study of 467 chronic hepatitis B patients pre- (N=226) and post- (N=241) liver transplantation with clinical evidence of lamivudine-resistant hepatitis B virus (Study 435). At baseline, 60% of pre-liver transplantation patients were classified as Child-Pugh-Turcotte score of Class B or C. The median baseline HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.4 and 8.2 log10 copies/mL, and the median baseline ALT was 1.8 and 2.0 times the upper limit of normal in pre- and post-liver transplantation patients, respectively. Results of this study are displayed in Table 7. Treatment with adefovir dipivoxil resulted in a similar reduction in serum HBV DNA regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at baseline. The significance of the efficacy results listed in Table 7 as they relate to clinical outcomes is not known.Table 7 Efficacy in Pre- and Post-Liver Transplantation Patients at Week 48Efficacy ParameterData are missing for 29% (HBV DNA) and 37% to 45% (CPT Score, Normalization of ALT, Albumin, Bilirubin, and PT) of total patients enrolled in the study.Pre-Liver Transplantation(N=226)Post-Liver Transplantation(N=241)Mean change ± SD in HBV DNA from baseline (log10 copies/mL)–3.7 ± 1.6(N=117)–4.0 ± 1.6(N=164)Proportion with undetectable HBV DNA (< 1000 copies/mL)Denominator is the number of patients with serum HBV DNA ≥1000 copies/mL at baseline using the Roche Amplicor Monitor PCR Assay (LLOQ = 1000 copies/mL) and non-missing value at Week 48.77/109 (71%)64/159 (40%)Stable or improved Child-Pugh-Turcotte score86/90 (96%)107/115 (93%)Normalization of: Denominator is patients with abnormal values at baseline and non-missing value at Week 48.  ALT61/82 (74%)56/110 (51%)  Albumin43/54 (80%)21/26 (81%)  Bilirubin38/68 (58%)29/38 (76%)  Prothrombin time39/46 (85%)5/9 (56%)

14.3 Study 461 (Clinical Evidence Of Lamivudine Resistance)

In Study 461, a double-blind, active controlled study in 59 chronic hepatitis B patients with clinical evidence of lamivudine-resistant hepatitis B virus, patients were randomized to receive either adefovir dipivoxil monotherapy or adefovir dipivoxil in combination with lamivudine 100 mg or lamivudine 100 mg alone. At Week 48, the mean ± SD decrease in serum HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 4.00 ± 1.41 log10 copies/mL for patients treated with adefovir dipivoxil and 3.46 ± 1.10 log10 copies/mL for patients treated with adefovir dipivoxil in combination with lamivudine. There was a mean decrease in serum HBV DNA of 0.31 ± 0.93 log10 copies/mL in patients receiving lamivudine alone. ALT normalized in 47% of patients treated with adefovir dipivoxil, in 53% of patients treated with adefovir dipivoxil in combination with lamivudine, and 5% of patients treated with lamivudine alone. The significance of these findings as they relate to clinical outcomes is not known.

14.4 Study 518 (Pediatric Study)

Study 518 was a double-blind, placebo-controlled, study in which 173 pediatric patients (ages 2 to less than 18 years) with chronic hepatitis B (CHB) infection and elevated ALT were randomized 2:1 (115 receiving adefovir dipivoxil and 58 receiving placebo). Randomization was stratified by prior treatment and age 2 to less than 7 years old (cohort 1), 7 to less than 12 years old (cohort 2), and 12 to less than 18 years old (cohort 3). All patients in cohort 3 received 10 mg tablet formulation; all patients in cohorts 1 and 2 received an investigational suspension formulation (0.3 mg/kg/day cohort 1, 0.25 mg/kg/day cohort 2) once daily. The primary efficacy endpoint was HBV DNA less than 1000 copies/mL plus normalization of ALT at the end of Week 48.In cohort 3 (N=83), significantly more patients treated with adefovir dipivoxil achieved the primary efficacy endpoint at the end of 48 weeks of blinded treatment (23%) when compared to placebo-treated patients (0%). The proportion of patients from cohorts 1 and 2 who responded to treatment with adefovir dipivoxil was not statistically significant when compared to the placebo arm, although the adefovir plasma concentrations in these patients were comparable to those observed in older patients. Overall, 22 of 115 (19%) of pediatric patients who received adefovir dipivoxil versus 1 of 58 (2%) of placebo treated patients responded to treatment by Week 48 [See Adverse Reactions (6.3), Use In Specific Populations (8.4) and Clinical Pharmacology (12.3, 12.4)].

16 How Supplied/Storage And Handling

Adefovir Dipivoxil Tablets are white to off-white, round, flat-faced bevelled edge tablets, engraved “APO” on one side, “A10” on the other side. They are supplied as follows: Bottles of 30s (NDC-60505-3947-3)

17.1 Instructions For Safe Use

  • See FDA-approved patient labeling (Patient Information)Physicians should inform patients of the potential risks and benefits of adefovir dipivoxil tablets and of alternative modes of therapy. Physicians should instruct their patients to: –Read the Patient Package Insert before starting adefovir dipivoxil therapy.–Follow a regular dosing schedule to avoid missing doses.–Immediately report any severe abdominal pain, muscle pain, yellowing of the eyes, dark urine, pale stools, and/or loss in appetite.–Inform their doctor or pharmacist if they develop any unusual symptom(s), or if any known symptom persists or worsens.Patients should remain under the care of a physician when using adefovir dipivoxil tablets.Patients should be advised that:–The optimal duration of adefovir dipivoxil tablets treatment and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.–Patients should not discontinue adefovir dipivoxil tablets without first informing their physician [See Warnings and Precautions (5.1)].–Routine laboratory monitoring and follow-up with a physician is important during adefovir dipivoxil therapy.–Obtaining HIV antibody testing prior to starting adefovir dipivoxil tablets is important [See Warnings and Precautions (5.3)].–Adefovir dipivoxil tablets should not be administered concurrently with ATRIPLA or COMPLERA or STRIBILD or TRUVADA or VIREAD [See Warnings and Precautions (5.5)].–Lamivudine-resistant patients should use adefovir dipivoxil tablets in combination with lamivudine and not as adefovir dipivoxil tablets monotherapy [See Warnings and Precautions. (5.6)].

17.2 Pregnancy And Breastfeeding

  • Physicians should inform women of childbearing age about the risks associated with exposure to adefovir dipivoxil during pregnancy.Patients should inform their physician if they become pregnant while using adefovir dipivoxil.Pregnant patients using adefovir dipivoxil tablets should be informed about the Antiretroviral Pregnancy Registry and offered the opportunity to enroll.Patients should be informed that it is not known whether adefovir dipivoxil is excreted into human milk or if it can harm a nursing infant. Therefore, a decision should be made whether to discontinue breastfeeding or drug.

Spl Patient Package Insert

  • FDA-Approved Patient LabelingPATIENT INFORMATIONAdefovir Dipivoxil Tablets(a def’ oh vir dye" piv ox’ il)Read this information carefully before you start taking adefovir dipivoxil tablets. Read and check for new information each time you get more adefovir dipivoxil tablets. This information does not take the place of talking with your doctor about your medical condition or your treatment.What is the most important information I should know about adefovir dipivoxil tablets?1.Some people who stop taking adefovir dipivoxil tablets get a very serious hepatitis. This usually happens within 12 weeks after stopping. You will need to have regular blood tests to check for liver function and hepatitis B virus levels if you stop taking adefovir dipivoxil tablets.2.Adefovir dipivoxil tablets may cause a severe kidney problem called nephrotoxicity. It usually happens in people that already have a kidney problem, but it can happen to anyone that uses adefovir dipivoxil tablets. You will need to have regular blood tests to check for kidney function while you are taking adefovir dipivoxil tablets.3.If you get or have HIV that isn't being treated with medicines, adefovir dipivoxil tablets may increase the chances your HIV infection cannot be helped with usual HIV medicines. This can happen if you get or have HIV and don't know it, or if your HIV is not being treated while you are taking adefovir dipivoxil tablets. You should get an HIV test before you start taking adefovir dipivoxil tablets and anytime after that when there's a chance you were exposed to HIV.4.Some people who have taken medicines like adefovir dipivoxil tablets that are called nucleoside or nucleotide analogs have developed a serious condition called lactic acidosis (build up of an acid in the blood). Lactic acidosis is a medical emergency and must be treated in the hospital. Call your doctor right away if you get any of the following signs of lactic acidosis:You feel very weak or tired.You have unusual (not normal) muscle pain.You have trouble breathing.You have stomach pain with nausea and vomiting.You feel cold, especially in your arms and legs.You feel dizzy or lightheaded.You have a fast or irregular heartbeat.Some people who have taken medicines like adefovir dipivoxil tablets have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your doctor right away if you get any of the following signs of liver problems.Your skin or the white part of your eyes turns yellow (jaundice).Your urine turns dark.Your bowel movements (stools) turn light in color.You don't feel like eating food for several days or longer.You feel sick to your stomach (nausea).You have lower stomach pain.You may be more likely to get lactic acidosis or serious liver problems if you are very overweight (obese) or have been taking nucleoside analog medicines [ATRIPLA® (efavirenz plus emtricitabine plus tenofovir disoproxil fumarate), COMPLERA® (emtricitabine plus rilpivirine plus tenofovir disoproxil fumarate), Combivir (zidovudine plus lamivudine), EMTRIVA® (emtricitabine), Epivir, Epivir-HBV (lamivudine), Epzicom (abacavir plus lamivudine), Hivid (zalcitabine), Retrovir (zidovudine), STRIBILD™ (elvitegravir plus cobicistat plus emtricitabine plus tenofovir disoproxil fumarate), Trizivir (zidovudine plus lamivudine plus abacavir), TRUVADA® (emtricitabine plus tenofovir disoproxil fumarate), Videx (didanosine), VIREAD® (tenofovir disoproxil fumarate), Zerit (stavudine), and Ziagen (abacavir)] for a long time.What are adefovir dipivoxil tablets?Adefovir dipivoxil tablets are a medicine used to treat patients at least 12 years of age with continuing (chronic) infections with active hepatitis B virus. Adefovir dipivoxil tablets have not been studied in adults over the age of 65 and are not recommended for use in children less than 12 years of age.Adefovir dipivoxil tablets will not cure your chronic hepatitis B.Adefovir dipivoxil tablets may help lower the amount of hepatitis B virus in your body.Adefovir dipivoxil tablets may lower the ability of the virus to multiply and infect new liver cells.We do not know if adefovir dipivoxil tablets will reduce your chances of getting liver cancer or liver damage (cirrhosis) from chronic hepatitis B.We do not know how long adefovir dipivoxil tablets may help your hepatitis. Sometimes viruses change in your body and medicines no longer work. This is called drug resistance.Adefovir dipivoxil tablets do not stop you from spreading hepatitis B virus to others by sex or sharing needles. So practice safe sex and needle use.Who should not take adefovir dipivoxil tablets?Do not take adefovir dipivoxil tablets if you are allergic to any of the ingredients in adefovir dipivoxil tablets. The active ingredient in adefovir dipivoxil tablets is adefovir dipivoxil. See the end of this leaflet for a complete list of all the ingredients in adefovir dipivoxil tablets.Do not take adefovir dipivoxil tablets if you are already taking ATRIPLA, COMPLERA, STRIBILD, TRUVADA, or VIREAD.Tell your doctor if:You are pregnant. We do not know if adefovir dipivoxil can harm your unborn child. You and your doctor will need to decide if adefovir dipivoxil is right for you. If you take adefovir dipivoxil tablets and you are pregnant, talk to your doctor about how you can join the Antiretroviral Pregnancy Registry. You are breast-feeding. We do not know if adefovir dipivoxil can pass into your milk and if it can harm your baby. You will need to choose either to breast feed or take adefovir dipivoxil tablets, but not both.You have kidney problems now or had them before. Your dose and schedule of adefovir dipivoxil tablets may be reduced. Blood tests will need to be done regularly to see how your kidneys are working.Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how adefovir dipivoxil tablets work, especially medicines that affect how your kidneys work. Adefovir dipivoxil tablets can affect how your other medicines work. Your dose of adefovir dipivoxil tablets and the other medicines may be changed. Do not take any other medicines while you are taking adefovir dipivoxil tablets, unless your doctor has told you it is okay.How should I take adefovir dipivoxil tablets?Your doctor will tell you how much adefovir dipivoxil tablets to take.Your doctor will tell you when and how often to take adefovir dipivoxil tablets.Take adefovir dipivoxil tablets the same time each day that your doctor tells you. If you forget to take adefovir dipivoxil tablets, take it as soon as you remember that day. Do not take more than one dose of adefovir dipivoxil tablets in a day. Do not take two doses at the same time. Call your doctor or pharmacist if you are not sure what to do.Do not change your dose of adefovir dipivoxil tablets or stop adefovir dipivoxil tablets without talking to your doctor. Your hepatitis may get worse if you change doses or stop.You may take adefovir dipivoxil tablets with or without food.When your adefovir dipivoxil tablets supply gets low, call your doctor or pharmacy for a refill. Do not run out of adefovir dipivoxil tablets.If you take too much adefovir dipivoxil tablets, call your local poison control center or emergency room right away.Some patients get worse or very serious hepatitis B symptoms when they stop taking adefovir dipivoxil tablets (See, "What is the most important information I should know about adefovir dipivoxil tablets?"). We don't know how long you should use adefovir dipivoxil tablets. You and your doctor will need to decide when it is best for you to stop taking adefovir dipivoxil tablets. After you stop taking adefovir dipivoxil tablets, your doctor will still need to check your health and take blood tests to check your liver for a few months.What should I avoid while taking adefovir dipivoxil tablets?Avoid doing things that can spread hepatitis B virus since adefovir dipivoxil tablets do not stop you from passing the infection to others.Do not share needles or other injection equipment.Do not share personal items that can have blood or body fluids on them, like toothbrushes or razor blades.Do not have any kind of sex without protection. Practice "safe sex" using condoms and dental dams.What are the possible side effects of adefovir dipivoxil tablets?Adefovir dipivoxil tablets can cause the following serious side effects: (See, "What is the most important information I should know about adefovir dipivoxil tablets?")1.a very serious hepatitis if you stop taking it.2.a severe kidney problem called nephrotoxicity.3.increase your chance of developing a form of HIV that cannot be treated with usual HIV medicines.4.lactic acidosis and liver problems.The most common side effects of adefovir dipivoxil tablets are weakness, headache, stomach pain, nausea, flatulence (intestinal gas), diarrhea, indigestion and changes in the way the kidneys work. Additional side effects in liver transplant patients with chronic hepatitis B are vomiting, rash and itching. Some patients with liver transplants also had undesirable effects on their kidneys, including failure of the kidneys. Other side effects reported since adefovir dipivoxil tablets has been marketed include kidney failure, damage to kidney cells, muscle pain or weakness and weakening of the bones, which could cause them to break (both associated with kidney problems), and inflammation of the pancreas.These are not all of the possible side effects of adefovir dipivoxil tablets. For more information, ask your doctor or pharmacist.General information about the safe and effective use of adefovir dipivoxil tablets:Medicines are sometimes prescribed for conditions not mentioned in patient information leaflets. Do not use adefovir dipivoxil tablets for a condition for which it was not prescribed. Do not give adefovir dipivoxil tablets to other people, even if they have the same symptoms that you have.This leaflet summarizes the most important information about adefovir dipivoxil tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about adefovir dipivoxil tablets that is written for health professionals.Adefovir dipivoxil tablets should be stored at 20° to 25°C (68° to 77°F) and should be stored in their original container.What are the Ingredients of adefovir dipivoxil tablets?Active Ingredient: adefovir dipivoxilInactive Ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, starch and talc.

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