WORMAZOL

VERMOX™ CHEWABLE (mebendazole chewable tablets) is an orally administered anthelmintic.

Chemically, it is methyl 5-benzoylbenzimidazole-2-carbamate.

Its molecular formula is

C 16 H 13 N 3 O 3.

Its molecular weight is 295.30.

It has the following chemical structure

Mebendazole exhibits polymorphism.

The polymorph used in

VERMOX™ CHEWABLE is polymorph form C. Mebendazole is a white to almost white powder.

It is practically insoluble in water, in ethanol (96%) and in methylene chloride.

Each round, flat radius-edged white to yellowish chewable tablet contains 500 mg of mebendazole and is debossed with "M/500" on one side and "J" on the other side.

Inactive ingredients consist of: crospovidone, magnesium stearate, microcrystalline cellulose, povidone, purified water, strawberry flavor and sucralose.

Used to treat pinworms, ring, string and slice.

Before using this medicine, tell your doctor if you suffer from any of the following: pregnancy and breastfeeding.

You take prescription, no herbal or nutritional supplements.

If you are allergic to any of the medicines, food or other substances, if your family also has worms.

Mebendazole, a benzimidazole, is an anthelmintic. 12.3 Pharmacokinetics Absorption Following oral administration of VERMOX™ CHEWABLE 500 mg tablet, the majority of the dose remains in the gastrointestinal tract where it exerts an anthelmintic effect locally.

Dosing the

VERMOX™ CHEWABLE 500 mg tablet with a high fat meal increases the bioavailability of mebendazole.

In the clinical studies conducted in pediatric patients with soil transmitted helminth infections, the majority of these patients were administered VERMOX™ CHEWABLE 500 mg tablets with food.

Mean plasma pharmacokinetic parameters of mebendazole in healthy adult subjects under fasted and fed conditions are summarized in Table 3.

Table 3: Mean (SD) Plasma Pharmacokinetic Parameters After a Single VERMOX™ CHEWABLE 500 mg Dose in Healthy Adult Subjects (n=16) Under Fasted and Fed (High-fat Meal) Conditions Parameter Fasted Fed C max (ng/mL) 14.0 56.2 T max (h) median (range) 1.5 (0.5–3.0) 4.0 (2.0–6.0) AUC last (ng.h/mL) 175 456 Distribution The plasma protein binding of mebendazole is to 95%.

The volume of distribution is to 2 L/kg, indicating that absorbed mebendazole penetrates areas outside the vascular space.

Orally administered mebendazole is extensively metabolized primarily by the liver.

Plasma concentrations of its major metabolites (hydrolyzed and reduced forms of mebendazole) are higher than those of mebendazole.

Impaired hepatic function, impaired metabolism, or impaired biliary elimination may lead to higher plasma levels of mebendazole.

Mebendazole, the conjugated forms of mebendazole, and its metabolites likely undergo some degree of enterohepatic recirculation.

The apparent elimination half-life after an oral dose ranges from to 6 hours in most patients.

Less than 2% of orally administered mebendazole is excreted in urine and the remainder in the feces as unchanged drug or its metabolites.

Based on a limited number of blood samples, the pharmacokinetic results following single-dose administration of a 500 mg mebendazole chewable tablet to pediatric patients (age to 16 years) with single or mixed infections of T. trichiura and/or A. lumbricoides indicated that children aged to 3 years have higher systemic exposure than adults. 12.4 Microbiology Mechanism of Action Mebendazole interferes with cellular tubulin formation in the helminth and causes ultrastructural degenerative changes in its intestine.

As a result, its glucose uptake and the digestive and reproductive functions are disrupted, leading to immobilization, inhibition of egg production and death of the helminth.

Antimicrobial Activity Mebendazole is active against

Ascaris lumbricoides Trichuris trichiura Resistance There is a potential for development of resistance to mebendazole.

The mechanism of resistance to mebendazole is likely due to changes of beta-tubulin protein, which reduces binding of mebendazole to beta-tubulin; however, the clinical significance of this is not known.

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Adverse reactions reported in clinical trials were anorexia, abdominal pain, diarrhea, flatulence, nausea, vomiting and rash. .

To report SUSPECTED ADVERSE

REACTIONS, contact Janssen Pharmaceuticals, Inc.fda.gov/medwatch. 6.1 Clinical Studies 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 safety of mebendazole was evaluated in 6276 adult and pediatric subjects one year of age and older who participated in 39 clinical trials for treatment of single or mixed parasitic infections of the gastrointestinal tract.

In these trials, the formulations, dosages and duration of mebendazole treatment varied.

Adverse reactions reported in mebendazole-treated subjects from the 39 clinical trials are shown in Table 1 below.

Table 1: Adverse Reactions Reported in Mebendazole-Treated Subjects from 39 Clinical Trials Includes mebendazole formulations, dosages and treatment duration other than VERMOX™ CHEWABLE 500 mg tablet Adverse Reaction(s) Gastrointestinal.

Disorders Anorexia Abdominal Pain Diarrhea Flatulence Nausea Vomiting Skin and Subcutaneous Tissue.

Disorders Rash Clinical Studies with Mebendazole Chewable 500 mg Tablet The safety profile of mebendazole chewable 500 mg tablets administered as a single dose was evaluated in 677 pediatric subjects aged to 16 years and in 34 adults.

The safety profile was consistent with the known safety profile of mebendazole. 6.2 Postmarketing Experience The following adverse reactions have been identified in adult and pediatric patients postmarketing with mebendazole formulations and dosages other than the VERMOX™ CHEWABLE 500 mg tablet.

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.

Table 2: Adverse Reactions Identified During Postmarketing Experience with Mebendazole Includes mebendazole formulations, dosages and treatment durations other than VERMOX™ CHEWABLE 500 mg tablet Adverse Reaction(s) Blood and Lymphatic System.

Disorders Agranulocytosis, Neutropenia Immune System.

Disorders Hypersensitivity including anaphylactic reactions Nervous System.

Disorders Convulsions, Dizziness Hepatobiliary.

Disorders Hepatitis, Abnormal liver tests Renal and Urinary.

Disorders Glomerulonephritis Skin and Subcutaneous Tissue.

Disorders Toxic epidermal necrolysis, Stevens-Johnson syndrome, Exanthema, Angioedema, Urticaria, Alopecia.

In patients treated at dosages substantially higher than recommended or for prolonged periods of time, the following adverse reactions have been reported: alopecia, reversible transaminase elevations, hepatitis, agranulocytosis, neutropenia, and glomerulonephritis.

Symptoms and signs

In the event of accidental overdose, gastrointestinal signs/symptoms may occur.

There is no specific antidote.

VERMOX™ CHEWABLE is contraindicated in persons with a known hypersensitivity to the drug or its excipients.

Patients with a known hypersensitivity to the drug or its excipients.

The recommended dosage in patients one year of age and older is one VERMOX™ CHEWABLE 500 mg tablet taken as a single dose.

VERMOX™ CHEWABLE 500 mg tablet completely before swallowing.

Do not swallow the tablet whole.

For patients who have difficulty chewing the tablet, approximately 2 mL to 3 mL of drinking water can be added to a suitably sized spoon and the VERMOX™ CHEWABLE 500 mg tablet placed into the water.

Within 2 minutes, the tablet absorbs the water and turns into a soft mass with semi-solid consistency, which can then be swallowed.

VERMOX™ CHEWABLE 500 mg tablet can be taken without regard to food intake.

The recommended dosage in patients one year of age and older is one single tablet of VERMOX™ CHEWABLE 500 mg taken as a single dose, chewed completely before swallowing.

Information for administration instructions for patients who have difficulty chewing the tablets.

VERMOX™ CHEWABLE tablets are supplied as 500 mg, round, flat radius-edged white to yellowish chewable tablets that are debossed with "M/500" on one side and "J" on the other side.

They are supplied as follows

Bottles of 200 tablets NDC 50458-675-20 Store below 30°C. Keep container tightly closed.

Unused tablets should be discarded 1 month after the bottle is first opened.

When the bottle is first opened this Discard After date should be written on the bottle label in the place provided.

Store below 30°C. Keep container tightly closed.

Unused tablets should be discarded 1 month after the bottle is first opened.

When the bottle is first opened this Discard After date should be written on the bottle label in the place provided.

The available published literature on mebendazole use in pregnant women has not reported a clear association between mebendazole and a potential risk of major birth defects or miscarriages.

There are risks to the mother and fetus associated with untreated helminthic infection during pregnancy.

In animal reproduction studies, adverse developmental effects (i.e., skeletal malformations, soft tissue malformations, decreased pup weight, embryolethality) were observed when mebendazole was administered to pregnant rats during the period of organogenesis at single oral doses as low as 10 mg/kg (approximately 0.2-fold the maximum recommended human dose (MRHD)).

Maternal toxicity was present at the highest of these doses.

The estimated background risk of major birth defects and miscarriage for the indicated populations is 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 2–4% and 15–20%, respectively.

Maternal and/or Embryo/Fetal Risks Untreated soil-transmitted helminth infections in pregnancy are associated with adverse outcomes including maternal iron deficiency anemia, low birth weight, neonatal and maternal death.

Several published studies, including prospective pregnancy registries, case-control, retrospective cohort, and randomized controlled studies, have reported no association between mebendazole use and a potential risk of major birth defects or miscarriage.

Overall, these studies did not identify a specific pattern or frequency of major birth defects with mebendazole use.

However, these studies cannot definitely establish the absence of any mebendazole-associated risk because of methodological limitations, including recall bias, confounding factors and, in some cases, small sample size or exclusion of first trimester mebendazole exposures.

Embryo-fetal developmental toxicity studies in rats revealed no adverse effects on dams or their progeny at doses up to 2.5 mg/kg/day on gestation days 6–15 (the period of organogenesis).

Dosing at ≥10 mg/kg/day resulted in a lowered body weight gain and a decreased pregnancy rate.

Maternal toxicity, including body weight loss in one animal and maternal death in of 20 animals, was seen at 40 mg/kg/day. At 10 mg/kg/day, increased embryo-fetal resorption (100% were resorbed at 40 mg/kg/day), decreased pup weight and increased incidence of malformations (primarily skeletal) were observed.

Mebendazole was also embryotoxic and teratogenic in pregnant rats at single oral doses during organogenesis as low as 10 mg/kg (approximately 0.2-fold the MRHD, based on mg/m 2 ).

In embryo-fetal developmental toxicity studies in mice dosed on gestation days 6–15, doses of 10 mg/kg/day and higher resulted in decreased body weight gain at and 40 mg/kg/day and a higher mortality rate at 40 mg/kg/day. At doses of 10 mg/kg/day (approximately 0.1-fold the MRHD, based on mg/m 2 ) and higher, embryo-fetal resorption increased (100% at 40 mg/kg) and fetal malformations, including skeletal, cranial, and soft tissue anomalies, were present.

Dosing of hamsters and rabbits did not result in embryotoxicity or teratogenicity at doses up to 40 mg/kg/day (0.6 to 1.6-fold the MRHD, based on mg/m 2 ).

In a peri.

• and post-natal toxicity study in rats, mebendazole did not adversely affect dams or their progeny at 20 mg/kg/day. At 40 mg/kg (0.8-fold the MRHD, based on mg/m 2 ), a reduction of the number of live pups was observed and there was no survival at weaning.

No abnormalities were found on gross and radiographic examination of pups at birth.

The safety and effectiveness of

VERMOX™ CHEWABLE 500 mg tablets have been established in pediatric patients to 16 years of age.

Use of

VERMOX™ CHEWABLE 500 mg tablets in children is supported by evidence from adequate and well-controlled studies of VERMOX™ CHEWABLE 500 mg tablets.

The safety and effectiveness of mebendazole, including VERMOX™ CHEWABLE have not been established in pediatric patients less than one year of age.

Convulsions have been reported with mebendazole use in this.

Clinical studies of mebendazole did not include sufficient numbers of subjects aged and older to determine whether they respond differently from younger subjects.