BILTRICIDE- praziquantel tablet, film coated
For Healthcare Providers >

1. Patient Information
2. Manufactured For:

Patient Information ⮝

Advise patients to take Biltricide during meals as directed[see Dosage and Administration (2.2)].

Advise patients not to chew tablets and to take them with water[see Dosage and Administration (2.2)]

Advise patients that tablets may be crushed or disintegrated and mixed with semi-solid food or liquid or disintegrated to prevent choking in children under 6 years of age. Crushed or disintegrated tablets should be used within 1 hour of mixing[see Dosage and Administration (2.2)].

Advise patients not to take Biltricide if they are allergic to Biltricide or any of its components[see Contraindications (4)].

Advise patients not to take Biltricide if they are taking rifampin[see Contraindications (4) and Warnings and Precautions (5.6,7.1,7.2)].

Advise patients that the use of praziquantel can be associated with clinical deterioration during the acute phase of schistosomiasis[see Warnings and Precautions (5.1)].

Advise patients that Biltricide should not be used if they have epilepsy of or other CNS effects[see Warnings and Precautions (5.2)].

Advise patients to report any cardiac irregularities to their healthcare provider[see Warnings and Precautions (5.4)].

Advise patients not to drive a car and not to operate machinery on the day of Biltricide treatment and the following day.

Manufactured For: ⮝

Bayer HealthCare Pharmaceuticals Inc.

Whippany, NJ 07981 USA

2018 Bayer HealthCare Pharmaceuticals Inc.

1. Description
2. Clinical Pharmacology
3. Indications And Usage
4. Contraindications
5. Warnings
6. Precautions
7. Adverse Events
8. Overdosage
9. Dosage And Administration
10. How Supplied
11. Principal Display Panel - 600 Mg Tablet Bottle Label
12. Highlights Of Prescribing Information
13. Dosage Forms And Strengths
14. Warnings And Precautions
15. Adverse Reactions
16. Drug Interactions
17. Use In Specific Populations
18. 1 Indications And Usage
19. 2 Dosage And Administration
20. 3 Dosage Forms And Strengths
21. 4 Contraindications
22. 5 Warnings And Precautions
23. 6 Adverse Reactions
24. 7 Drug Interactions
25. 8.1 Pregnancy
26. 11 Description
27. 12 Clinical Pharmacology
28. 13 Nonclinical Toxicology
29. 16 How Supplied/storage And Handling
30. Package/label Principal Display Panel

Description ⮝

BILTRICIDE (praziquantel) is a trematodicide provided in tablet form for the oral treatment of schistosome infections and infections due to liver fluke.

BILTRICIDE (praziquantel) is 2-(cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinolin-4-one with the molecular formula; C19H24N2O2. The structural formula is as follows:

Praziquantel is a white to nearly white crystalline powder of bitter taste. The compound is stable under normal conditions and melts at 136-140 C with decomposition. The active substance is hygroscopic. Praziquantel is easily soluble in chloroform and dimethylsulfoxide, soluble in ethanol and very slightly soluble in water.

BILTRICIDE tablets contain 600 mg of praziquantel. Inactive ingredients: corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide and hypromellose.

Clinical Pharmacology ⮝

Praziquantel induces a rapid contraction of schistosomes by a specific effect on the permeability of the cell membrane. The drug further causes vacuolization and disintegration of the schistosome tegument.

After oral administration BILTRICIDE is rapidly absorbed (80%), subjected to a first pass effect, metabolized and eliminated by the kidneys. Maximal serum concentration is achieved 1-3 hours after dosing. The half-life of praziquantel in serum is 0.8-1.5 hours.

Special Populations

The pharmacokinetics of praziquantel were studied in 40 patients with Schistosoma mansoni infections with varying degrees of hepatic dysfunction (See table1). In patients with schistosomiasis, the pharmacokinetic parameters did not differ significantly between those with normal hepatic function (Group 1) and those with mild (Child-Pugh class A) hepatic impairment. However, in patients with moderate-to-severe hepatic dysfunction (Child-Pugh class B and C), praziquantel half-life, Cmax, and AUC increased progressively with the degree of hepatic impairment. In Child-Pugh class B, the increases in mean half-life, Cmax, and AUC relative to Group 1 were 1.58-fold, 1.76-fold, and 3.55-fold, respectively. The corresponding increases in Child-Pugh class C patients were 2.82-fold, 4.29-fold, and 15-fold for half-life, Cmax, and AUC.

Table 1: Pharmacokinetic parameters of praziquantel in four groups of patients with varying degrees of liver function following administration of 40 mg/kg under fasting conditions.

Patient Group	Half-life (hr)	Tmax (hr)	Cmax ( g/mL)	AUC ( g/mL* hr)
a) p<0.05 compared to Group 1
b) p<0.05 compared to Group 2
c) p<0.05 compared to Group 3
Normal hepatic function (Group 1)	2.99 1.28	1.48 0.74	0.83 0.52	3.02 0.59
Child-Pugh A (Group 2)	4.66 2.77	1.37 0.61	0.93 0.58	3.87 2.44
Child-Pugh B (Group 3)	4.74 2.16a	2.21 0.78a,b	1.47 0.74a,b	10.72 5.53a,b
Child-Pugh C (Group 4)	8.45 2.62a,b,c	3.2 1.05a,b,c	3.57 1.30a,b,c	45.35 17.50a,b,c

Indications And Usage ⮝

Biltricide is an anthelmintic indicated in patients aged one year and older for the treatment of the following infections: (1)

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

Contraindications ⮝

Known hypersensitivity to Biltricide or any of its ingredients. (4.1)

Concomitant administration with strong Cytochrome P450 (CYP450) inducers such as rifampin. (4., 5.4, 7.1)

Warnings ⮝

Therapeutically effective levels of BILTRICIDE may not be achieved when administered concomitantly with strong P450 inducers, such as rifampin (see CONTRAINDICATIONS).

Precautions ⮝

General

Approximately 80% of a dose of praziquantel is excreted in the kidneys, almost exclusively (>99%) in the form of metabolites. Excretion might be delayed in patients with impaired renal function, but accumulation of unchanged drug would not be expected. Therefore, dose adjustment for renal impairment is not considered necessary. Nephrotoxic effects of praziquantel or its metabolites are not known.

Caution should be exercised in the administration of the usual recommended dose of praziquantel to hepatosplenic schistosomiasis patients with moderate to severe liver impairment (Child-Pugh class B and C). Reduced metabolism of praziquantel by the liver in these patients may lead to considerably higher and longer lasting plasma concentrations of unmetabolized praziquantel (See CLINICAL PHARMACOLOGY/Special Populations).

Minimal increases in liver enzymes have been reported in some patients.

Patients suffering from cardiac irregularities should be monitored during treatment.

As BILTRICIDE can exacerbate central nervous system pathology due to schistosomiasis, as a general rule this drug should not be administered to individuals reporting a history of epilepsy and/or other signs of potential central nervous systems involvement such as subcutaneous nodules suggestive of cysticercosis.

When schistosomiasis or fluke infection is found to be associated with cerebral cysticercosis it is advised to hospitalize the patient for the duration of treatment.

Published in vitro data have shown a potential lack of efficacy of praziquantel against migrating schistosomulae. 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.

In addition, the use of praziquantel in patients with schistosomiasis may be associated with clinical deterioration (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, and/or cerebral vasculitis.

Information for Patients

Patients should be warned not to drive a car and not to operate machinery on the day of BILTRICIDE treatment and the following day.

Drug Interactions

Concomitant administration of rifampin, a strong P450 inducer, with praziquantel is contraindicated and must be avoided (see CONTRAINDICATIONS). In a crossover study with a 2-week washout period, 10 healthy subjects ingested a single 40 mg/kg dose of praziquantel following pre-treatment with oral rifampin (600 mg daily for 5 days). Plasma praziquantel concentrations were undetectable in 7 out of 10 subjects. When a single 40 mg/kg dose of praziquantel was administered to these healthy subjects two weeks after discontinuation of rifampin, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel was given alone. In patients receiving rifampin, for example, as part of a combination regimen for the treatment of tuberculosis, alternative agents for schistosomiasis should be considered. However, if treatment with praziquantel is necessary, treatment with rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment.

Concomitant administration of other drugs that increase the activity of drug metabolizing liver enzymes (P450 inducers), for example, antiepileptic drugs (phenytoin, phenobarbital and carbamazepine), and dexamethasone, may also reduce plasma levels of praziquantel. Concomitant administration of drugs that decrease the activity of drug metabolizing liver enzymes (P 450 inhibitors), for example, cimetidine, ketoconazole, itraconazole, erythromycin may increase plasma levels of praziquantel.

Grapefruit juice was reported to produce a 1.6-fold increase in the Cmax and a 1.9-fold increase in the AUC of praziquantel. However, the effect of this exposure increase on the therapeutic effect and safety of praziquantel has not been systematically evaluated.

Mutagenesis, Carcinogenesis, Impairment of Fertility

Mutagenicity studies of praziquantel published in the scientific literature are inconclusive. Long term oral carcinogenicity studies in rats and golden hamsters did not reveal any carcinogenic effect at doses up to 250 mg/kg/day (about half of the human daily dose based on body surface area). Praziquantel had no effect on fertility and general reproductive performance of male and female rats when given at oral doses ranging from 30 to 300 mg/kg body weight (up to 0.65 times the human daily dose based on body surface area).

Pregnancy Category B

Developmental toxicity studies have been performed in rats and rabbits at dose levels of 30 to 300 mg/kg body weight given repeatedly during the period of organogenesis. No harm to the fetus due to praziquantel was observed. 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. There are, however, no adequate and well-controlled studies in pregnant women. While animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing mothers

Praziquantel appeared in the milk of nursing women at a concentration of about 1/4 that of maternal serum although it is not known, whether a pharmacological effect is likely to occur in children. Women should not nurse on the day of BILTRICIDE treatment and during the subsequent 72 hours.

Pediatric use

Safety in children under 4 years of age has not been established.

Geriatric use

Clinical studies of praziquantel 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.

Adverse Events ⮝

The following side effects were observed generally in order of severity: malaise, headache, dizziness, abdominal discomfort with or without nausea, rise in temperature and urticaria. Such side effects may be more frequent and/or serious in patients with a heavy worm burden.

Post Marketing Adverse Event Reports

Additional adverse events reported from worldwide post marketing experience and from publications with praziquantel include: abdominal pain, allergic reaction (generalized hypersensitivity, including polyserositis), anorexia, arrhythmia (including bradycardia, ectopic rhythms, ventricular fibrillation, AV blocks), asthenia, bloody diarrhea, convulsion, eosinophilia, fatigue, myalgia, pruritus, rash, somnolence, vertigo and vomiting.

Overdosage ⮝

No data are available in humans.

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.

How Supplied ⮝

BILTRICIDE is supplied as a 600 mg white to orange tinged, film-coated, oblong tablet with three scores. The tablet is coded with "BAYER" on one side and "LG" on the reverse side. When broken, each of the four segments contains 150 mg of active ingredient so that the dosage can be easily adjusted to the patient's bodyweight.

Segments are broken off by pressing the score (notch) with thumbnails. If 1/4 of a tablet is required, this is best achieved by breaking the segment from the outer end.

BILTRICIDE is available in bottles of 6 tablets.

Bottles of 6	Strength 600 mg	NDC 50419-747-01
Store below 86 F (30 C).

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany

BILTRICIDE is a registered trademark of Bayer Aktiengesellschaft.

Rx Only

2/14

2014 Bayer HealthCare Pharmaceuticals Inc. Printed in USA

Principal Display Panel - 600 Mg Tablet Bottle Label ⮝

Austin/Travis Co. Health & Human Services Dept.

Biltricide
600MG
Tab #4

Date:

Name:
Dr.

Take 2 tablets by mouth 2 times a day for 1 day

123456

01/01/01

Biltricide 600MG Tab #4 NDC 76413-146-04

Batch: 123456
Lot: 123456
Exp: 01/01/01
BAYER

Federal law prohibits the transfer of this drug to any other person than the patient for whom prescribed.

BILTRICIDE praziquantel tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:76413-146(NDC:50419-747) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAZIQUANTEL (UNII: 6490C9U457) (PRAZIQUANTEL - UNII:6490C9U457) PRAZIQUANTEL 600 mg

Inactive Ingredients Ingredient Name Strength STARCH, CORN (UNII: O8232NY3SJ) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) SODIUM LAURYL SULFATE (UNII: 368GB5141J) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)

Product Characteristics Color white (white to orange tinged) Score 4 pieces Shape OVAL (capsule shaped) Size 22mm Flavor Imprint Code BAYER;LG Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:76413-146-05 5 in 1 BOTTLE; Type 0: Not a Combination Product 04/21/2011 2 NDC:76413-146-01 1 in 1 BOTTLE; Type 0: Not a Combination Product 04/21/2011 3 NDC:76413-146-02 2 in 1 BOTTLE; Type 0: Not a Combination Product 04/21/2011 4 NDC:76413-146-03 3 in 1 BOTTLE; Type 0: Not a Combination Product 04/21/2011 5 NDC:76413-146-04 4 in 1 BOTTLE; Type 0: Not a Combination Product 04/21/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA018714 04/21/2011

Labeler - Central Texas Community Health Centers (079674019)

Establishment
Name	Address	ID/FEI	Business Operations
Central Texas Community Health Centers		079674019	REPACK(76413-146) , RELABEL(76413-146)

Revised: 8/2017 Document Id: f4b54a8c-fefe-4290-bd07-3d13b4699730 34391-3 Set id: d6791c7c-749a-4595-937b-32229dd59902 Version: 1 Effective Time: 20170823 Central Texas Community Health Centers

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use BILTRICIDE safely and effectively. See full prescribing information for BILTRICIDE.
BILTRICIDE (praziquantel) tablets, for oral use

Initial U.S. Approval: 1982

Dosage Forms And Strengths ⮝

Tablets: 600 mg (with three scores (notches) on the tablet) (3)

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).

Adverse Reactions ⮝

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.

Drug Interactions ⮝

Other CYP 450 Inducers: Concomitant administration of other CYP450 inducers, for example, antiepileptic drugs and dexamethasone, may also reduce plasma levels concentrations of praziquantel. (7.1)

CYP450 Inhibitors: Concomitant administration of CYP450 inhibitors, for example, cimetidine, ketoconazole, itraconazole, erythromycin. (7.2)

Use In Specific Populations ⮝

Pediatrics: Safety has not been established in pediatric patients younger than 1 year of age. (8.4)

Hepatic Impairment: Monitor patients for adverse reactions when administering the recommended dose of Biltricide to hepatosplenic schistosomiasis patients with moderate to severe liver impairment (Child-Pugh Class B or C). (8.6)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 1/2019

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)

2 Dosage And Administration  ⮝

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.

3 Dosage Forms And Strengths  ⮝

Biltricide tablets contain 600 mg of praziquantel. The tablets are white to orange tinged, film-coated, oblong with three scores (notches), imprinted with BAYER on one side and LG on the other side.

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 (CYP450) inducers, such as rifampin, [see Warnings and Precautions (5.6) and Drug Interactions (7.1, 7.2)].

5 Warnings And Precautions  ⮝

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 Strong Cytochrome P450 Inducers

Concomitant administration of strong CYP450 inducers, such as rifampin with Biltricide is contraindicated since therapeutically effective levels of praziquantel may not be achieved. [see Contraindications (4) and Drug Interactions (7.1)].

In patients receiving rifampin who need immediate treatment for schistosomiasis, alternative agents for schistosomiasis should be considered. However, if treatment with Biltricide is necessary, discontinue rifampin 4 weeks before administration of Biltricide. Treatment with rifampin can then be restarted one day after completion of Biltricide treatment [see Drug Interactions (7.1, 7.2)].

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.

7 Drug Interactions  ⮝

7.1 CYP450 Inducers

Rifampin

Concomitant administration of rifampin, a strong CYP450 inducer, with Biltricide is contraindicated. In patients receiving rifampin, for example, as part of a combination regimen for the treatment of tuberculosis, alternative drugs for schistosomiasis should be considered. If treatment with Biltricide is necessary, treatment with rifampin should be discontinued 4 weeks before administration of praziquantel. Treatment with rifampin can then be restarted one day after completion of praziquantel treatment. [See Contraindications (4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3).]

Other CYP 450 Inducers

Concomitant administration of other drugs that are CYP450 inducers, for example, antiepileptic drugs (phenytoin, phenobarbital and carbamazepine), and dexamethasone, may also reduce plasma concentrations of praziquantel. [See Warnings and Precautions (5.6).]

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 may increase plasma concentrations of praziquantel. In addition, grapefruit juice was also reported to produce a 1.6-fold increase in the Cmax and a 1.9-fold increase in the AUC of praziquantel. The effect of this exposure increase on the therapeutic effect and safety of Biltricide has not been systematically evaluated [see Dosage and Administration (2.2)].

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)].

11 Description  ⮝

Biltricide (praziquantel) is an anthelmintic, trematodicide provided in tablet form for oral administration.

Praziquantel is 2-(cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinolin-4-one with the molecular formula; C19H24N2O2. The structural formula is as follows:

Praziquantel is a white to nearly white crystalline powder of bitter taste. The compound is stable under normal conditions and melts at 136 to 140 C with decomposition. The active substance is hygroscopic. Praziquantel is easily soluble in chloroform and dimethylsulfoxide, soluble in ethanol and very slightly soluble in water.

Biltricide tablets contain 600 mg of praziquantel. Inactive ingredients: corn starch, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium lauryl sulfate, and titanium dioxide .

12 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

Praziquantel is an anthelmintic drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption

After oral administration, 80% of an administered Biltricide dose is absorbed, with maximal serum concentrations of praziquantel achieved 1 to 3 hours after dosing.

Elimination

Following oral administration of Biltricide, the elimination half-life of praziquantel in serum ranges between 0.8 to 1.5 hours.

Metabolism

Praziquantel is rapidly metabolized by the cytochrome P450 enzyme system and undergoes a first pass effect after oral administration of Biltricide.

Excretion

Approximately 80% of an oral dose of Biltricide is excreted in the kidneys, almost exclusively (greater than 99%) in the form of praziquantel metabolites.

Specific Populations

Patients with Hepatic Impairment

The pharmacokinetics of praziquantel were studied in 40 patients with Schistosoma mansoni infections with varying degrees of hepatic impairment (See Table 1). In patients with schistosomiasis, the pharmacokinetic parameters did not differ significantly between those with normal hepatic function (Group 1) and those with mild (Child-Pugh class A) hepatic impairment. However, in patients with moderate-to-severe hepatic impairment (Child-Pugh class B and C), praziquantel half-life, Cmax, and AUC increased progressively with the degree of hepatic impairment. In Child-Pugh class B, the increases in mean half-life, Cmax, and AUC relative to Group 1 were 1.58-fold, 1.76-fold, and 3.55-fold, respectively. The corresponding increases in Child-Pugh class C patients were 2.82-fold, 4.29-fold, and 15-fold for half-life, Cmax, and AUC.

Table 1: Pharmacokinetic parameters of praziquantel in four groups of patients with varying degrees of liver function following administration of 40 mg/kg of Biltricide under fasting conditions.

Patient Group	Half-life (hr)	Tmax (hr)	Cmax ( g/mL)	AUC ( g/mL* hr)
Normal hepatic function (Group 1)	2.99 1.28	1.48 0.74	0.83 0.52	3.02 0.59
Child-Pugh A (Group 2)	4.66 2.77	1.37 0.61	0.93 0.58	3.87 2.44
Child-Pugh B (Group 3)	4.74 2.16a	2.21 0.78a,b	1.47 0.74a,b	10.72 5.53a,b
Child-Pugh C (Group 4)	8.45 2.62a,b,c	3.2 1.05a,b,c	3.57 1.30a,b,c	45.35 17.50a,b,c

a) p<0.05 compared to Group 1

b) p<0.05 compared to Group 2

c) p<0.05 compared to Group 3

Patients with Renal Impairment

Excretion of praziquantel following oral administration of Biltricide might be delayed in patients with impaired renal function, but accumulation of unchanged drug would not be expected.

Drug Interaction Studies

Rifampin (CYP450 Inducer)

In a crossover study with a 2-week washout period, 10 healthy subjects ingested a single 40 mg/kg oral dose of Biltricide following pre-treatment with oral rifampin (600 mg daily for 5 days). Plasma praziquantel concentrations were undetectable in 7 out of 10 subjects. When a single 40 mg/kg oral dose of Biltricide was administered to these same healthy subjects two weeks after discontinuation of rifampin, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when Biltricide was given alone.

12.4 Microbiology

Praziquantel induces a rapid contraction of schistosomes by a specific effect on the permeability of the cell membrane. The drug further causes vacuolization and disintegration of the schistosome tegument. However, the mechanism of action is unknown.

Praziquantel is active against schistosoma (for example, Schistosoma mekongi, Schistosoma japonicum, Schistosoma mansoni and Schistosoma hematobium), and infections due to the liver flukes, Clonorchis sinensis/Opisthorchis viverrini[see Indications and Usage (1)]. Published in vitro data have shown a potential lack of efficacy of praziquantel against migrating schistosomulae [see Warnings and Precautions (5.3)].

13 Nonclinical Toxicology  ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Mutagenicity studies of praziquantel published in the scientific literature are inconclusive. Long term oral carcinogenicity studies in rats and golden hamsters did not reveal any carcinogenic effect at doses up to 250 mg/kg/day (about half of the human daily dose based on body surface area). Praziquantel had no effect on fertility and general reproductive performance of male and female rats when given at oral doses ranging from 30 to 300 mg/kg body weight (up to 0.65 times the human daily dose based on body surface area).

16 How Supplied/storage And Handling  ⮝

Biltricide is supplied as 600 mg tablets containing praziquantel. The tablets are white to orange tinged, film-coated, oblong tablets with three scores. The tablet is coded with BAYER on one side and LG on the reverse side.

Biltricide is available in bottles of six 600 mg tablets, NDC 50419-747-01.

Store below 86 F (30 C).

Package/label Principal Display Panel  ⮝

Biltricide 600 mg Tablets Bottle Label

8339661 NDC 50419-747-01

Biltricide

Tablets

(praziquantel)

600 mg

6 Tablets

Rx Only

BILTRICIDE praziquantel tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50419-747 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PRAZIQUANTEL (UNII: 6490C9U457) (PRAZIQUANTEL - UNII:6490C9U457) PRAZIQUANTEL 600 mg

Inactive Ingredients Ingredient Name Strength STARCH, CORN (UNII: O8232NY3SJ) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561) SODIUM LAURYL SULFATE (UNII: 368GB5141J) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)

Product Characteristics Color white (white to orange tinged) Score 4 pieces Shape OVAL (capsule shaped) Size 22mm Flavor Imprint Code BAYER;LG Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50419-747-01 6 in 1 BOTTLE; Type 0: Not a Combination Product 04/21/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA018714 04/21/2011

Labeler - Bayer HealthCare Pharmaceuticals Inc. (005436809)

Establishment
Name	Address	ID/FEI	Business Operations
Bayer AG		314947622	MANUFACTURE(50419-747) , ANALYSIS(50419-747) , API MANUFACTURE(50419-747) , PACK(50419-747) , PARTICLE SIZE REDUCTION(50419-747) , STERILIZE(50419-747)

Revised: 1/2019 Document Id: 67d482dd-ab97-4f44-865f-dcb77ed1eda6 34391-3 Set id: 34ce1cdd-648e-4f1e-8512-bf3d4cc22eb9 Version: 7 Effective Time: 20190108 Bayer HealthCare Pharmaceuticals Inc.