ALBENDAZOLE: 1,039 Adverse Event Reports & Safety Profile

Albendazole is an orally administered anthelmintic drug. Chemically, it is methyl 5-(propylthio)-2-benzimidazolecarbamate. Its molecular formula is C 12 H 15 N 3 O 2 S. Its molecular weight is 265.34. It has the following chemical structure: Albendazole USP is a white to slightly yellowish or faintly yellowish powder. It is practically insoluble in water, freely soluble in anhydrous formic acid, very slightly soluble in methylene chloride, practically insoluble in ethanol 96 %v/v. Each tablet is white to off white, film-coated, round biconvex with beveled edges is debossed with "452" on one side and plain other side Inactive ingredients consist of: corn starch, hypromellose 2910 (15 mPas), hypromellose 2910 (5 mPas), lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, saccharin sodium, sodium lauryl sulfate, and sodium starch glycolate. FDA approved dissolution test method differs from the USP dissolution test method.

AND USAGE Albendazole tablets are an anthelmintic drug indicated for: Treatment of parenchymal neurocysticercosis due to active lesions caused by larval forms of the pork tapeworm, Taenia solium . ( 1.1 ) Treatment of cystic hydatid disease of the liver, lung, and peritoneum, caused by the larval form of the dog tapeworm, Echinococcus granulosus . ( 1.2 )

1.1 Neurocysticercosis Albendazole tablets are indicated for the treatment of parenchymal neurocysticercosis due to active lesions caused by larval forms of the pork tapeworm, Taenia solium .

1.2 Hydatid Disease Albendazole tablets are indicated for the treatment of cystic hydatid disease of the liver, lung, and peritoneum, caused by the larval form of the dog tapeworm, Echinococcus granulosus .

2 DOSAGE & ADMINISTRATION Patients weighing 60 kg or greater, 400 mg twice daily; less than 60 kg, 15 mg/kg/day in divided doses twice daily (maximum total daily dose 800 mg).

Albendazole

Tablets should be taken with food. ( 2 ) Hydatid disease: 28‑day cycle followed by 14‑day albendazole‑free interval for a total of 3 cycles. ( 2 ) Neurocysticercosis: 8 to 30 days. ( 2 ) See additional important information in the Full Prescribing Information. ( 2 )

2.1 Dosage Dosing of Albendazole Tablets will vary depending upon the indication.

Albendazole

Tablets may be crushed or chewed and swallowed with a drink of water.

Albendazole

Tablets should be taken with food [ see Clinical Pharmacology ( 12.3 ) ].

Table

1: Albendazole Tablets Dosage Indication Patient Weight Dose Duration Hydatid Disease 60 kg or greater 400 mg twice daily, with meals 28‑day cycle followed by a 14‑day albendazole‑free interval, for a total of 3 cycles Less than 60 kg 15 mg/kg/day given in divided doses twice daily with meals (maximum total daily dose 800 mg)

Neurocysticercosis

60 kg or greater 400 mg twice daily, with meals 8 to 30 days Less than 60 kg 15 mg/kg/day given in divided doses twice daily with meals (maximum total daily dose 800 mg)

2.2 Concomitant Medication to Avoid Adverse Reactions Patients being treated for neurocysticercosis should receive appropriate steroid and anticonvulsant therapy as required. Oral or intravenous corticosteroids should be considered to prevent cerebral hypertensive episodes during the first week of treatment [ see Warnings and Precautions ( 5.3 ) ].

2.3 Monitoring for Safety Before and During Treatment Monitor blood counts at the beginning of each 28‑day cycle of therapy, and every 2 weeks while on therapy with Albendazole Tablets in all patients [ see Warnings and Precautions ( 5.1 ) ]. Monitor liver enzymes (transaminases) at the beginning of each 28‑day cycle of therapy, and at least every 2 weeks during treatment with Albendazole Tablets in all patients [ see Warnings and Precautions ( 5.5 ) ]. Obtain a pregnancy test in females of reproductive potential prior to therapy [ see Warnings and Precautions ( 5.2 ) ].

Albendazole Tablets are contraindicated in patients with known hypersensitivity to the benzimidazole class of compounds or any components of Albendazole Tablets. Patients with known hypersensitivity to the benzimidazole class of compounds or any components of Albendazole Tablets. ( 4 )

REACTIONS Adverse reactions 1% or greater in hydatid disease: abnormal liver function tests, abdominal pain, nausea/vomiting, reversible alopecia, headache, dizziness/vertigo, fever. ( 6.1 ) Adverse reactions 1% or greater in neurocysticercosis: headache, nausea/ vomiting, raised intracranial pressure, meningeal signs. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Edenbridge Pharmaceuticals, LLC at 1-877-381-3336 or FDA at 1-800-332-1088 or www.fda.gov/medwatch .

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. The adverse reaction profile of Albendazole Tablets differs between hydatid disease and neurocysticercosis. Adverse reactions occurring with a frequency of 1% or greater in either disease are described in Table 2 below. These symptoms were usually mild and resolved without treatment. Treatment discontinuations were predominantly due to leukopenia (0.7%) or hepatic abnormalities (3.8% in hydatid disease). The following incidence reflects adverse reactions that were reported to be at least possibly or probably related to Albendazole Tablets.

Table

2 : Adverse Reaction Incidence 1% or Greater in Hydatid Disease and Neurocysticercosis Adverse Reaction Hydatid Disease Neurocysticercosis Gastrointestinal Abdominal Pain 6 0 Nausea 4 6 Vomiting 4 6 General disorders and administration site conditions Fever 1 0 Investigations Elevated Hepatic Enzymes 16 less than 1 Nervous system disorders Dizziness 1 less than 1 Headache 1 11 Meningeal Signs 0 1 Raised Intracranial Pressure 0 2 Vertigo 1 less than 1 Skin and subcutaneous tissue disorders Reversible Alopecia 2 less than 1 The following adverse events were observed at an incidence of less than 1%: Blood and Lymphatic System Disorders: There have been reports of leukopenia, granulocytopenia, pancytopenia, agranulocytosis, or thrombocytopenia [see Warnings and Precautions ( 5.1 ) ].

Immune System

Disorders: Hypersensitivity reactions, including rash and urticaria.

6.2 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Albendazole Tablets. Because these 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. Blood and Lymphatic System Disorders: Aplastic anemia, bone marrow suppression, neutropenia.

Eye

Disorders: Vision blurred.

Gastrointestinal

Disorders: Diarrhea.

General System

Disorders: Asthenia.

Hepatobiliary

Disorders: Elevations of hepatic enzymes, hepatitis, acute liver failure. Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.

Nervous System

Disorders: Somnolence, convulsion. Renal and Urinary Disorders: Acute renal failure. Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens‑Johnson syndrome

AND PRECAUTIONS Bone Marrow Suppression: Fatalities have been reported due to bone marrow suppression; monitor blood counts in all patients at the beginning of each 28‑day cycle of therapy, and every 2 weeks while on therapy.

Discontinue Albendazole

Tablets if clinically significant changes in blood counts occur. ( 5.1 , 5.4 ) Embryo-Fetal Toxicity: May cause fetal harm. Pregnancy testing is recommended for females of reproductive potential prior to therapy. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception. ( 2.3 , 5.2 , 8.1 , 8.3 ) Risk of Neurologic Symptoms: Neurocysticercosis patients may experience cerebral hypertensive episodes, seizures or focal neurologic deficits after initiation of therapy; begin appropriate steroid and anticonvulsant therapy. ( 5.3 ) Risk of Retinal Damage in Retinal Cysticercosis: Cases of retinal involvement have been reported; examine the patient for the presence of retinal lesions before initiating therapy for neurocysticercosis. ( 5.4 )

Hepatic

Effects. Elevations of liver enzymes may occur. Monitor liver enzymes before the start of each treatment cycle and at least every 2 weeks while on Albendazole Tablets therapy and discontinue if clinically significant elevations occur. ( 5.5 )

5.1 Bone Marrow Suppression Fatalities associated with the use of Albendazole Tablets have been reported due to granulocytopenia or pancytopenia.

Albendazole

Tablets may cause bone marrow suppression, aplastic anemia, and agranulocytosis. Monitor blood counts at the beginning of each 28‑day cycle of therapy, and every 2 weeks while on therapy with Albendazole Tablets in all patients. Patients with liver disease and patients with hepatic echinococcosis are at increased risk for bone marrow suppression and warrant more frequent monitoring of blood counts.

Discontinue Albendazole

Tablets if clinically significant decreases in blood cell counts occur.

5.2 Embryo-Fetal Toxicity Based on findings from animal reproduction studies, Albendazole Tablets may cause fetal harm when administered to a pregnant woman. Embryotoxicity and skeletal malformations were reported in rats and rabbits when treated during the period of organogenesis (at oral doses approximately 0.1 to 0.6 times the recommended human dose normalized for total body surface area). Advise pregnant women of the potential risk to a fetus. Pregnancy testing is recommended for females of reproductive potential prior to initiating Albendazole Tablets [ see Dosage and Administration ( 2.3 ) ]. Advise females of reproductive potential to use an effective method of contraception during treatment with Albendazole Tablets and for 3 days after the final dose [ see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.3 ) ].

5.3 Risk of Neurologic Symptoms in Neurocysticercosis Patients being treated for neurocysticercosis should receive steroid and anticonvulsant therapy to prevent neurological symptoms (e.g. seizures, increased intracranial pressure and focal signs) as a result of an inflammatory reaction caused by death of the parasite within the brain.

5.4 Risk of Retinal Damage in Patients with Retinal Neurocysticercosis Cysticercosis may involve the retina. Before initiating therapy for neurocysticercosis, examine the patient for the presence of retinal lesions. If such lesions are visualized, weigh the need for anticysticeral therapy against the possibility of retinal damage resulting from inflammatory damage caused by albendazole‑induced death of the parasite.

5.5 Hepatic Effects In clinical trials, treatment with Albendazole Tablets has been associated with mild to moderate elevations of hepatic enzymes in approximately 16% of patients. These elevations have generally returned to normal upon discontinuation of therapy. There have also been case reports of acute liver failure of uncertain causality and hepatitis [ see Adverse Reactions ( 6 ) ]. Monitor liver enzymes (transaminases) before the start of each treatment cycle and at least every 2 weeks during treatment. If hepatic enzymes exceed twice the upper limit of normal, consideration should be given to discontinuing Albendazole Tablets therapy based on individual patient circumstances.

Restarting Albendazole

Tablets treatment in patients whose hepatic enzymes have normalized off treatment is an individual decision that should take into account the risk/benefit of further Albendazole Tablets usage. Perform laboratory tests frequently if Albendazole Tablets treatment is restarted. Patients with elevated liver enzyme test results are at increased risk for hepatotoxicity and bone marrow suppression [ see Warnings and Precautions ( 5.1 ) ]. Discontinue therapy if liver enzymes are significantly increased or if clinically significant decreases in blood cell counts occur.

5.6 Unmasking of Neurocysticercosis in Hydatid Patients Undiagnosed neurocysticercosis may be uncovered in patients treated with Albendazole Tablets for other conditions. Patients with epidemiologic factors who are at risk for neurocysticercosis should be evaluated prior to initiation of therapy.

INTERACTIONS

• Dexamethasone: Steady-state trough concentrations of albendazole sulfoxide were about 56% higher when dexamethasone was coadministered with each dose of albendazole. ( 7.1 )
• Praziquantel: In the fed state increased mean maximum plasma concentration and area under the curve of albendazole sulfoxide by about 50% in healthy subjects. ( 7.2 )
• Cimetidine: Increased albendazole sulfoxide concentrations in bile and cystic fluid by about 2-fold in hydatid cyst patients. ( 7.3 )
• Theophylline: Albendazole induces cytochrome P450 1A in human hepatoma cells; therefore, it is recommended that plasma concentrations of theophylline be monitored during and after treatment. ( 5.5 , 7.4 )

7.1 Dexamethasone Steady-state trough concentrations of albendazole sulfoxide were about 56% higher when 8 mg dexamethasone was co-administered with each dose of albendazole (15 mg/kg/day) in 8 neurocysticercosis patients.

7.2 Praziquantel In the fed state, praziquantel (40 mg/kg) increased mean maximum plasma concentration and area under the curve of albendazole sulfoxide by about 50% in healthy subjects (n = 10) compared with a separate group of subjects (n = 6) given albendazole alone. Mean T max and mean plasma elimination half-life of albendazole sulfoxide were unchanged. The pharmacokinetics of praziquantel were unchanged following co-administration with albendazole (400 mg).

7.3 Cimetidine Albendazole sulfoxide concentrations in bile and cystic fluid were increased (about 2-fold) in hydatid cyst patients treated with cimetidine (10 mg/kg/day) (n = 7) compared with albendazole (20 mg/kg/day) alone (n = 12). Albendazole sulfoxide plasma concentrations were unchanged 4 hours after dosing.

7.4 Theophylline Following a single dose of albendazole (400 mg), the pharmacokinetics of theophylline (aminophylline 5.8 mg/kg infused over 20 minutes) were unchanged. Albendazole induces cytochrome P450 1A in human hepatoma cells; therefore, it is recommended that plasma concentrations of theophylline be monitored during and after treatment.