Biltricide

1 INDICATIONS AND USAGE Biltricide is indicated in patients aged 1 year and older for the treatment of the following infections: • Schistosomiasis due to all species of schistosoma (for example, Schistosoma mekongi, Schistosoma japonicum, Schistosoma mansoni and Schistosoma hematobium ), and • Clonorchiasis and Opisthorchiasis due to the liver flukes, Clonorchis sinensis/Opisthorchis viverrini (approval of this indication was based on studies in which the two species were not differentiated) Biltricide is an anthelmintic indicated in patients aged one year and older for the treatment of the following infections: • Schistosomiasis due to all species of schistosoma (for example , Schistosoma mekongi , Schistosoma japonicum , Schistosoma mansoni and Schistosoma hematobium ), and, • Clonorchiasis and Opisthorchiasis due to the liver flukes, Clonorchis sinensis and Opisthorchis viverrini

2 DOSAGE AND ADMINISTRATION • Schistosomiasis : 20 mg/kg bodyweight 3 times a day separated by 4 to 6 hours for 1 day only. ( 2.1 ) • Clonorchiasis and Opisthorchiasis : 2 5 mg/kg 3 times a day separated by 4 to 6 hours for 1 day only. ( 2.1) • Take with water during meals. Do not chew or keep segments in the mouth. ( 2.2 ) • For pediatric patients under 6 years of age, the tablets may be crushed or disintegrated and mixed with semi-solid food or liquid. (2.2) • For additional administration instructions see the full prescribing information. 2.1 Recommended Dosage Schistosomiasis The recommended dosage for the treatment of schistosomiasis is 20 mg/kg bodyweight administered orally three times a day separated by 4 to 6 hours, for 1 day only. Clonorchiasis and Opisthorchiasis The recommended dosage for the treatment of clonorchiasis and opisthorchiasis is 25 mg/kg bodyweight administered orally three times a day separated by 4 to 6 hours for 1 day only. 2.2 Administration Take tablets with water during meals. Do not chew or keep the tablets (or parts of tablets) in the mouth; the bitter taste may cause gagging or vomiting. To prevent choking in pediatric patients under 6 years of age, the tablets may be crushed or disintegrated and mixed with semi-solid food or liquid. Use crushed or disintegrated tablets within 1 hour of mixing. Biltricide 600 mg tablets have three scores which can be split into four segments at the scores. When broken, each of the four segments contains 150 mg of praziquantel so that the dosage can be adjusted to the patient’s bodyweight. Segments are broken off by pressing the score (notch) with thumbnails. If one-quarter of a tablet is required, this is best achieved by breaking the segment from the outer end.

4 CONTRAINDICATIONS Biltricide is contraindicated in: • Patients who previously have shown hypersensitivity to praziquantel or any of the excipients in Biltricide. • Patients with ocular cysticercosis; since parasite destruction within the eye that occurs because of hypersensitivity reaction to the dead parasite after treatment may cause irreversible lesions, ocular cysticercosis must not be treated with Biltricide. • Patients taking strong Cytochrome P450 3A enzyme (CYP3A) inducers, such as rifampin, [see Warnings and Precautions ( 5.6 ) and Drug Interactions ( 7.1 , 7.2 )] . • Known hypersensitivity to Biltricide or any of its ingredients. ( 4.1 ) • Concomitant administration with strong Cytochrome P450 3A enzyme (CYP 3A) inducers such as rifampin. ( 4 , 5.6 7.1)

5 WARNINGS AND PRECAUTIONS • Clinical Deterioration : Potentially life threatening clinical deterioration can occur in patients treated during the acute phase of schistosomiasis. ( 5.1 ) • Central Nervous System (CNS) Effects : Biltricide can exacerbate central nervous system pathology due to schistosomiasis. Consider whether to administer to individuals reporting a history of epilepsy and/or other signs of potential central nervous systems involvement such as subcutaneous nodules suggestive of cysticercosis. ( 5.2) • Potential Lack of Efficacy for Acute Schistosomiasis : This has been reported in observational studies ( 5.3 ). • Cardiac Arrhythmias: Bradycardia, ectopic rhythms, ventricular fibrillation, and AV blocks has been observed with Biltricide administration. Monitor patients with cardiac arrhythmias during treatment ( 5.4). 5.1 Clinical Deterioration The use of Biltricide in patients with schistosomiasis may be associated with clinical deterioration (for example, paradoxical reactions, serum sickness Jarisch-Herxheimer like reactions: sudden inflammatory immune response suspected to be caused by the release of schistosomal antigens). These reactions predominantly occur in patients treated during the acute phase of schistosomiasis. They may lead to potentially life-threatening events, for example, respiratory failure, encephalopathy, papilledema, and/or cerebral vasculitis. 5.2 Central Nervous System (CNS) Effects Biltricide can exacerbate central nervous system pathology due to schistosomiasis, paragonimiasis, or Taenia solium cysticercosis. As a general rule, consider whether to administer Biltricide to individuals reporting a history of epilepsy and/or other signs of potential central nervous systems involvement such as subcutaneous nodules suggestive of cysticercosis unless the potential benefit justifies the potential risk. Hospitalize the patient for duration of treatment when schistosomiasis or fluke infection is found to be associated with cerebral cysticercosis. 5.3 Potential Lack of Efficacy During the Acute Phase of Schistosomiasis Data from two observational cohort studies in patients indicate that treatment with Biltricide in the acute phase of infection may not prevent progression from asymptomatic infection to acute schistosomiasis, or from asymptomatic infection/acute schistosomiasis into chronic phase. 5.4 Cardiac Arrhythmias Bradycardia, ectopic rhythms, ventricular fibrillation, and AV blocks has been observed with Biltricide administration. Monitor patients with cardiac arrhythmias during treatment. 5.5 Hepatic Impairment in Hepatosplenic Schistosomiasis Patients Reduced hepatic metabolism of praziquantel results in higher and sustained plasma concentrations of unmetabolized praziquantel in patients with liver impairment [see Clinical Pharmacology ( 12.3 )]. Monitor patients for adverse reactions when administering the recommended dose of Biltricide to hepatosplenic schistosomiasis patients with moderate or severe liver impairment (Child-Pugh Class B or C). 5.6 Concomitant Administration with Cytochrome P450 Enzyme Inducers Strong Cytochrome P450 3A Enzyme (CYP 3A) Inducers Concomitant administration of strong CYP 3A inducers, such as rifampin, with Biltricide is contraindicated since therapeutically effective levels of praziquantel are unlikely to be achieved. [see Contraindications ( 4 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.3 )]. Moderate CYP 3A Inducers Avoid concomitant administration of Biltricide with moderate CYP 3A inducers, such as efavirenz, due to risk of a clinically significant decrease in praziquantel plasma concentrations which may lead to reduced therapeutic effect of Biltricide [see Drug Interactions ( 7.1 )] . In patients receiving a clinically significant CYP 3A inducer drug who need immediate treatment for schistosomiasis, alternative agents for schistosomiasis should be considered, where possible. If Biltricide is necessary immediately, increase monitoring for reduced anthelmintic efficacy associated with Biltricide [see Drug Interactions ( 7.1 )]. In patients receiving a clinically significant CYP 3A inducer drug whose treatment could be delayed, discontinue the CYP 3A inducer drug at least 2 weeks to 4 weeks before administration of Biltricide and, where possible, consider starting alternative medications that are not CYP 3A inducers. The CYP 3A inducer drug can be restarted one day after completion of Biltricide treatment, if needed [see Drug Interactions ( 7.1 )].

7 DRUG INTERACTIONS Moderate CYP 3A Inducers : Avoid concomitant administration of moderate CYP 3A inducers, for example, efavirenz ( 5.6 , 7.1 ) 7.1 CYP 3A Inducers Strong and Moderate CYP 3A Inducers Concomitant administration of Biltricide with Strong and Moderate CYP 3A inducers decrease praziquantel AUC and Cmax [see Clinical Pharmacology ( 12.3 )] which may reduce the efficacy of Biltricide. Concomitant administration of a Strong CYP 3A inducer, such as rifampin, with Biltricide is contraindicated [see Contraindications ( 4)] . Concomitant administration of a Moderate CYP 3A inducer, such as efavirenz, should be avoided unless the benefit outweighs the risks [see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 ).] 7.2 CYP450 inhibitors Concomitant administration of drugs that decrease the activity of drug metabolizing liver enzymes (CYP450 inhibitors), for example, cimetidine, ketoconazole, itraconazole, erythromycin, and ritonavir may increase plasma concentrations of praziquantel. In addition, grapefruit juice was also reported to produce a 1.6-fold increase in the C max and a 1.9-fold increase in the AUC of praziquantel. The effect of this exposure increase on the safety of Biltricide has not been systematically evaluated [see Dosage and Administration ( 2.2 )].

6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling: • Clinical Deterioration [see Warnings and Precautions ( 5.1 )] • Central Nervous System (CNS) Effects [see Warnings and Precautions ( 5.2 )] • Potential Lack of Efficacy During the Acute Phase of Schistosomiasis [see Warnings and Precautions ( 5.3 )] • Cardiac Arrhythmias [see Warnings and Precautions ( 5.4 )] • Hepatic Impairment in Hepatosplenic Schistosomiasis Patients [see Warnings and Precautions ( 5.5 )] • Concomitant Administration with Strong Cytochrome P450 Inducers [see Warnings and Precautions ( 5.6 )] The following adverse reactions associated with the use of Biltricide were identified in clinical studies, published literature or postmarketing reports. Because some of these reactions were 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. The following adverse reactions were observed in both adults and pediatric patients: General disorders and administration site conditions: malaise, pyrexia Nervous system disorders: headache , dizziness Gastrointestinal disorders: abdominal discomfort, nausea Skin and subcutaneous tissue disorders: urticaria Such adverse reactions may be more frequent and/or serious in patients with a heavy worm burden. Additional adverse reactions reported from worldwide post marketing experience and from publications with Biltricide and various formulations of praziquantel include: Blood and lymphatic system disorders: eosinophilia Cardiac disorders: arrhythmia (including bradycardia, ectopic rhythms, ventricular fibrillation, AV blocks) Ear and labyrinth disorders: vertigo, tinnitus Eye disorders: visual disturbance Gastrointestinal disorders: abdominal pain, bloody diarrhea, vomiting General disorders and administration site conditions: polyserositis, asthenia, fatigue, gait disturbance Hepatobiliary disorders: hepatitis Immune system disorders: allergic reaction, generalized hypersensitivity, anaphylactic reaction Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: convulsion, somnolence, intention tremor Respiratory, thoracic and mediastinal disorders: pneumonitis, dyspnea, wheezing Skin and subcutaneous tissue disorders: pruritus, rash, Stevens-Johnson syndrome Pediatric patients 1 to 17 years of age treated with Biltricide and various formulations of praziquantel experienced similar adverse reactions as those observed in adult patients. The adverse reactions reported were malaise, headache, dizziness, abdominal discomfort (with or without nausea), pyrexia and urticaria. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary Published studies have not identified an association with Biltricide use during pregnancy and major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data) . In animal reproduction studies conducted in pregnant rats and rabbits no adverse developmental outcomes were observed with oral administration of praziquantel during organogenesis at approximately 0.65 times (rats) or 1.3 times (rabbits) the highest recommended human daily dose of 75 mg/kg/day, based on body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Two randomized controlled clinical trials have been conducted using praziquantel for the treatment of schistosoma infection in pregnant women. In one randomized controlled trial in pregnant women with schistosoma ( S. japonicum) infection, 186 pregnant women were treated with praziquantel compared to 184 women who received placebo. Treatment with praziquantel during pregnancy had no effect on birthweight, and there were no differences in rates of miscarriage, fetal death and major birth defects between the praziquantel-treated and control patients. In another randomized controlled trial that included 2507 pregnant women in Uganda, 18% of women were infected with schistosoma infection. Treatment with praziquantel during pregnancy had no effect on mean birth weight, perinatal mortality or major birth defects. In other published studies, including a retrospective observational study, case series and case reports, there have been no reports of major birth defects, stillbirths or other adverse pregnancy outcomes associated with the use of praziquantel during pregnancy. Animal Data No evidence of fetal harm was observed in rats and rabbits at praziquantel dose levels of 30 to 300 mg/kg body weight given repeatedly by oral administration during the period of organogenesis. These doses were up to 0.65 times (rats) or 1.3 times (rabbits) the highest recommended human daily dose of 75 mg/kg/day, based on body surface area. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of praziquantel in human milk at low concentrations. There is no information on the effects of praziquantel in the breastfed infant or effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Biltricide and any potential adverse effects on the breastfed infant from Biltricide or from the underlying maternal condition. 8.4 Pediatric Use Safety and dosing recommendations of Biltricide in pediatric patients 1 to 17 years have been established. Safety of Biltricide in pediatric patients younger than 1 year of age has not been established. Post-marketing experience and published literature indicates that pediatric patients 1 to 17 years of age treated with praziquantel experience similar adverse reactions as adults treated with praziquantel [see Adverse Reactions ( 6 )] . 8.5 Geriatric Use Clinical studies of Biltricide did not include a sufficient number of subjects ages 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in these patients [see Clinical Pharmacology ( 12.3 )]. 8.6 Hepatic Impairment Following oral administration of Biltricide to patients with liver impairment, reduced hepatic metabolism of praziquantel results in higher and sustained plasma concentrations of unmetabolized praziquantel [see Clinical Pharmacology ( 12.3 )]. Monitor patients for adverse reactions when administering the recommended dose of Biltricide to hepatosplenic schistosomiasis patients with moderate or severe liver impairment (Child-Pugh Class B or C). 8.7 Renal Impairment No dosage adjustment of Biltricide is necessary in patients with renal impairment. Nephrotoxic effects of Biltricide or its metabolites are not known [see Clinical Pharmacology ( 12.3 )] .