Hepsera Side Effects

Generic Name: adefovir

Please note - some side effects for Hepsera may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Hepsera - for the Consumer

Hepsera

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Hepsera:

Diarrhea; fever; gas; headache; increased cough; indigestion; nausea; sore throat; upset stomach; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Hepsera:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); change in the amount of urine you produce; cold arms and legs; dark urine; dizziness; fast or irregular heartbeat; loss of appetite; muscle pain; pale stools; severe or persistent stomach or back pain, nausea, or vomiting; unusual drowsiness; unusual weakness or fatigue; or yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Hepsera Side Effects - for the Professional

Hepsera

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)]

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 Hepsera.

Adverse reactions to Hepsera 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 Hepsera (n=294) or placebo (n=228) for 48 weeks is presented in Table 2. Patients who received open-label Hepsera 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 1–4) Reported in ≥3% of All Hepsera-Treated Patients in Pooled Studies 437–438 Studies (0–48 Weeks)*

Adverse Reaction	Hepsera 10mg (N=294)	Placebo (N=228)
* In these studies, the overall incidence of adverse reactions with Hepsera was similar to that reported with placebo. The incidence of adverse reactions is derived from treatment-related events as identified by the study investigators.
Asthenia	13%	14%
Headache	9%	10%
Abdominal Pain	9%	11%
Nausea	5%	8%
Flatulence	4%	4%
Diarrhea	3%	4%
Dyspepsia	3%	2%

No patients treated with Hepsera developed a confirmed serum creatinine increase ≥0.5 mg/dL or confirmed phosphorus decrease ≤2 mg/dL from baseline by Week 48. By Week 96, 2% of Hepsera-treated patients, by Kaplan-Meier estimate, had increases in serum creatinine ≥0.5 mg/dL from baseline (no placebo-controlled results were available for comparison beyond Week 48). For patients who chose to continue Hepsera 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 Hepsera for up to 240 weeks in Study 437, 6 had a confirmed increase in serum creatinine of ≥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.

Special Risk Patients

Pre- and Post-Liver Transplantation Patients

Additional adverse reactions observed from an open-label study (Study 435) in pre- and post- liver transplantation patients with chronic hepatitis B and lamivudine-resistant hepatitis B administered Hepsera once daily for up to 203 weeks include: abnormal renal function, renal failure, vomiting, rash, and pruritus.

Changes in renal function occurred in pre-and post-liver transplantation patients with risk factors for renal dysfunction, including concomitant use of cyclosporine and tacrolimus, renal insufficiency at baseline, hypertension, diabetes, and on-study transplantation. Therefore, the contributory role of Hepsera to these changes in renal function is difficult to assess.

Increases in serum creatinine ≥0.3 mg/dL from baseline were observed in 37% and 53% of pre-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Increases in serum creatinine ≥0.3 mg/dL from baseline were observed in 32% and 51% of post-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Serum phosphorus values <2 mg/dL were observed in 3/226 (1.3%) of pre-liver transplantation patients and in 6/241 (2.5%) of post-liver transplantation patients by last study visit. Four percent (19 of 467) of patients discontinued treatment with Hepsera due to renal adverse events.

Pediatric Patients

Assessment of adverse reactions is based on a placebo-controlled study (Study 518) in which 173 pediatric patients aged 2 to <18 years with chronic hepatitis B and compensated liver disease received double-blind treatment with Hepsera (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 Hepsera in patients ≥12 to <18 years of age (n=56) was similar to that observed in adults. No pediatric patients treated with Hepsera developed a confirmed serum creatinine increase ≥ 0.5 mg/dL or confirmed phosphorus decrease to <2 mg/dL from baseline by Week 48.

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: hypophosphatemia

Gastrointestinal Disorders: pancreatitis

Musculoskeletal System and Connective Tissue Disorders: myopathy, osteomalacia (both associated with proximal renal tubulopathy)

Renal and Urinary Disorders: renal failure, Fanconi syndrome, proximal renal tubulopathy

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Side Effects by Body System - for Healthcare Professionals

General

In patients with chronic hepatitis B, the incidence of side effects increased slightly with increased duration of treatment.

Other

Other side effects have included asthenia (13%), abdominal pain (9%), fever (greater than or equal to 2%), weight loss, influenza-like syndrome, infection, back pain, pain, and accidental injury.

Renal

Renal side effects have included hematuria (greater than or equal to 3+, 11% ), increases in serum creatinine (greater than or equal to 0.3 mg/dL, 4% to 37%; greater than or equal to 0.5 mg/dL, 2% to 31%), decreases in serum phosphorus (4% to 6%), renal failure (greater than or equal to 2%), renal insufficiency (greater than or equal to 2%), glycosuria (greater than or equal to 3+, 1%), renal calculus, and renal pain. Adefovir was discontinued due to renal side effects in 1% of pre- and post-liver transplant patients. Causality could not be definitely determined because of the presence of multiple risk factors for renal dysfunction. A rare potential risk of adefovir includes nephrotoxicity. Fanconi-like syndrome and overall renal function deterioration have been reported at high doses. Renal failure, proximal renal tubulopathy, and Fanconi syndrome have been reported during postmarketing experience.

Nervous system

Nervous system side effects have included headache (9%), dizziness, and insomnia.

Gastrointestinal

Gastrointestinal side effects have included abdominal pain (9%), nausea (5%), flatulence (4%), diarrhea (3%), dyspepsia (3%), vomiting (2%), and anorexia. Pancreatitis has been reported during postmarketing experience.

Hepatic

Hepatic side effects have included hepatic failure (greater than or equal to 2%), and laboratory abnormalities with increases in ALT (greater than 5 times ULN), AST (greater than 5 times ULN), creatine kinase (greater than 4 times ULN), and amylase (greater than 2 times ULN). Nucleoside analogs alone or in combination with antiretrovirals have been associated with lactic acidosis and severe hepatomegaly with steatosis.

Severe acute exacerbations of hepatitis have been reported in patients who have discontinued adefovir dipivoxil. Although most events appear to have been self-limited, fatalities have been reported. Patients who discontinue adefovir dipivoxil should have close monitoring of hepatic function at repeated intervals over a period of time. If appropriate, resumption of antihepatitis B therapy may be warranted.

Dermatologic

Dermatologic side effects reported in pre- and post-liver transplantation patients have included pruritus and rash in greater than or equal to 2% of patients.

Respiratory

Respiratory side effects reported in pre- and post-liver transplantation patients have included increased cough, pharyngitis, and sinusitis in greater than or equal to 2% of patients. Bronchitis and rhinitis have also been reported.

Cardiovascular

Cardiovascular side effects have included myocardial infarction at high doses.

Musculoskeletal

Musculoskeletal side effects have included arthralgia. Hypophosphatemic osteomalacia (in the context of Fanconi syndrome) has been reported. Myopathy and osteomalacia, both associated with proximal renal tubulopathy, have been reported during postmarketing experience.

Metabolic

Metabolic side effects have included hypophosphatemia during postmarketing experience.

Ocular

Ocular side effects have included amblyopia at high doses.

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