Fagol

Neurocysticercosis

FagolZA is indicated for the treatment of parenchymal neurocysticercosis due to active lesions caused by larval forms of the pork tapeworm, Taenia solium.

Hydatid Disease

FagolZA is 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.

Dosage

Dosing of FagolZA will vary depending upon the indication. FagolZA tablets may be crushed or chewed and swallowed with a drink of water. FagolZA tablets should be taken with food.

Table 1: FagolZA Dosage

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.

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 FagolZA in all patients.
• Monitor liver enzymes (transaminases) at the beginning of each 28-day cycle of therapy, and at least every 2 weeks during treatment with FagolZA in all patients.
• Obtain a pregnancy test in women of reproductive potential prior to therapy.

FagolZA is contraindicated in patients with known hypersensitivity to the benzimidazole class of compounds or any components of FagolZA.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Bone Marrow Suppression

Fatalities associated with the use of FagolZA have been reported due to granulocytopenia or pancytopenia FagolZA 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 FagolZA 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 FagolZA if clinically significant decreases in blood cell counts occur.

Teratogenic Effects

FagolZA may cause fetal harm and should not be used in pregnant women except in clinical circumstances where no alternative management is appropriate. Obtain pregnancy test prior to prescribing FagolZA to women of reproductive potential. Advise women of reproductive potential to use effective birth control for the duration of FagolZA therapy and for one month after end of therapy. Immediately discontinue FagolZA if a patient becomes pregnant and apprise the patient of the potential hazard to the fetus.

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.

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 FagolZA-induced death of the parasite.

Hepatic Effects

In clinical trials, treatment with FagolZA 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.

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 FagolZA therapy based on individual patient circumstances. Restarting FagolZA treatment in patients whose hepatic enzymes have normalized off treatment is an individual decision that should take into account the risk/benefit of further FagolZA usage. Perform laboratory tests frequently if FagolZA treatment is restarted.

Patients with elevated liver enzyme test results are at increased risk for hepatotoxicity and bone marrow suppression. Discontinue therapy if liver enzymes are significantly increased or if clinically significant decreases in blood cell counts occur.

Unmasking Of Neurocysticercosis In Hydatid Patients

Undiagnosed neurocysticercosis may be uncovered in patients treated with FagolZA for other conditions. Patients with epidemiologic factors who are at risk for neurocysticercosis should be evaluated prior to initiation of therapy.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies of FagolZA administration in pregnant women. FagolZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

FagolZA should not be used in pregnant women except in clinical circumstances where no alternative management is appropriate. Obtain pregnancy test prior to prescribing FagolZA to women of reproductive potential. Advise women of reproductive potential to use effective birth control for the duration of FagolZA therapy and for one month after end of therapy. If a patient becomes pregnant while taking this drug, FagolZA should be discontinued immediately. If pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.

FagolZA has been shown to be teratogenic (to cause embryotoxicity and skeletal malformations) in pregnant rats and rabbits. The teratogenic response in the rat was shown at oral doses of 10 and 30 mg/kg/day (0.10 times and 0.32 times the recommended human dose based on body surface area in mg/m², respectively) during gestation days 6 to 15 and in pregnant rabbits at oral doses of 30 mg/kg/day (0.60 times the recommended human dose based on body surface area in mg/m²) administered during gestation days 7 to 19. In the rabbit study, maternal toxicity (33% mortality) was noted at 30 mg/kg/day. In mice, no teratogenic effects were observed at oral doses up to 30 mg/kg/day (0.16 times the recommended human dose based on body surface area in mg/m²), administered during gestation days 6 to 15.

Nursing Mothers

FagolZA is excreted in animal milk. It is not known whether it is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FagolZA is administered to a nursing woman.

Pediatric Use

Hydatid disease is uncommon in infants and young children. In neurocysticercosis, the efficacy of FagolZA in children appears to be similar to that in adults.

Geriatric Use

In patients aged 65 and older with either hydatid disease or neurocysticercosis, there was insufficient data to determine whether the safety and effectiveness of FagolZA is different from that of younger patients.

Patients With Impaired Renal Function

The pharmacokinetics of FagolZA in patients with impaired renal function has not been studied.

Patients With Extra-Hepatic Obstruction

In patients with evidence of extrahepatic obstruction (n = 5), the systemic availability of Fagoldazole sulfoxide was increased, as indicated by a 2-fold increase in maximum serum concentration and a 7-fold increase in area under the curve. The rate of absorption/conversion and elimination of Fagoldazole sulfoxide appeared to be prolonged with mean Tmax and serum elimination half-life values of 10 hours and 31.7 hours, respectively. Plasma concentrations of parent FagolZA were measurable in only 1 of 5 patients.

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 FagolZA 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 FagolZA.

Table 2: Adverse Reaction Incidence 1% or Greater in Hydatid Disease and Neurocysticercosis

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.

Immune System Disorders : Hypersensitivity reactions, including rash and urticaria.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of FagolZA. 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.

In case of overdosage, symptomatic therapy and general supportive measures are recommended.

Absorption

Fagoldazole is poorly absorbed from the gastrointestinal tract due to its low aqueous solubility. Fagoldazole concentrations are negligible or undetectable in plasma as it is rapidly converted to the sulfoxide metabolite prior to reaching the systemic circulation. The systemic anthelmintic activity has been attributed to the primary metabolite, Fagoldazole sulfoxide. Oral bioavailability appears to be enhanced when Fagoldazole is coadministered with a fatty meal (estimated fat content 40 grams) as evidenced by higher (up to 5-fold on average) plasma concentrations of Fagoldazole sulfoxide as compared to the fasted state.

Maximal plasma concentrations of Fagoldazole sulfoxide were achieved 2 hours to 5 hours after dosing and were on average 1310 ng/mL (range 460 ng/mL to 1580 ng/mL) following oral doses of Fagoldazole (400 mg) in 6 hydatid disease patients, when administered with a fatty meal. Plasma concentrations of Fagoldazole sulfoxide increased in a dose-proportional manner over the therapeutic dose range following ingestion of a high-fat meal (fat content 43.1 grams). The mean apparent terminal elimination half-life of Fagoldazole sulfoxide ranged from 8 hours to 12 hours in 25 healthy subjects, as well as in 14 hydatid and 8 neurocysticercosis patients.

Following 4 weeks of treatment with Fagoldazole (200 mg three times daily), 12 patients' plasma concentrations of Fagoldazole sulfoxide were approximately 20% lower than those observed during the first half of the treatment period, suggesting that Fagoldazole may induce its own metabolism.

Distribution

Fagoldazole sulfoxide is 70% bound to plasma protein and is widely distributed throughout the body; it has been detected in urine, bile, liver, cyst wall, cyst fluid, and cerebrospinal fluid (CSF).

Concentrations in plasma were 3-fold to 10-fold and 2-fold to 4-fold higher than those simultaneously determined in cyst fluid and CSF, respectively.

Metabolism And Excretion

Fagoldazole is rapidly converted in the liver to the primary metabolite, Fagoldazole sulfoxide, which is further metabolized to Fagoldazole sulfone and other primary oxidative metabolites that have been identified in human urine. Following oral administration, Fagoldazole has not been detected in human urine. Urinary excretion of Fagoldazole sulfoxide is a minor elimination pathway with less than 1% of the dose recovered in the urine. Biliary elimination presumably accounts for a portion of the elimination as evidenced by biliary concentrations of Fagoldazole sulfoxide similar to those achieved in plasma.