PRAZIQUANTEL

1 INDICATIONS AND USAGE Praziquantel tablets are 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) Praziquantel tablets are 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 body weight 3 times a day separated by 4 to 6 hours for 1 day only. ( 2.1 ) Clonorchiasis and Opisthorchiasis : 25 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. Praziquantel 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 Praziquantel is contraindicated in: Patients who previously have shown hypersensitivity to praziquantel or any of the excipients in praziquantel tablets. 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 praziquantel. Patients taking strong Cytochrome P450 3A enzyme (CYP 3A) inducers, such as rifampin [see Warnings and Precautions ( 5.6) and Drug Interactions ( 7.1 , 7.2 )] . Known hypersensitivity to praziquantel 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 : Praziquantel 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 praziquantel administration. Monitor patients with cardiac arrhythmias during treatment ( 5.4 ). 5.1 Clinical Deterioration The use of praziquantel 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 Praziquantel can exacerbate central nervous system pathology due to schistosomiasis, paragonimiasis, or Taenia solium cysticercosis. As a general rule, consider whether to administer praziquantel 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 praziquantel 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 praziquantel 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 praziquantel 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 praziquantel 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 praziquantel 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 praziquantel. [ 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 praziquantel is necessary immediately, increase monitoring for reduced anthelmintic efficacy associated with praziquantel [ 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 praziquantel 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 praziquantel 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 praziquantel with Strong and Moderate CYP 3A inducers decrease praziquantel AUC and C max [see Clinical Pharmacology (12.3) ] which may reduce the efficacy of praziquantel. Concomitant administration of a Strong CYP 3A inducer, such as rifampin, with praziquantel 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 praziquantel 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 praziquantel 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 praziquantel 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 praziquantel tablets 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 Endo at 1-800-828-9393 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 praziquantel 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 2,507 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.