PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of EMVERM(R) 100 mg chewable tablets has not been established in pediatric patients less than two years of age. Convulsions have been reported with mebendazole use in children less than one year of age [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Adverse reactions reported in clinical trials were anorexia, abdominal pain, diarrhea, flatulence, nausea, vomiting and rash (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Studies. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 subjects 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 below.Table 2: Adverse Reactions Reported in Mebendazole-treated Subjects from 39 Clinical TrialsAdverse Reaction(s)Gastrointestinal DisordersAnorexiaAbdominal PainDiarrheaFlatulenceNauseaVomitingSkin and Subcutaneous Tissue DisordersRashIncludes mebendazole formulations, dosages and treatment duration other than EMVERM(R) 100 mg tablet. 6.2Postmarketing Experience. The following adverse reactions have been identified in adult and pediatric patients postmarketing with mebendazole formulations and dosages other than the EMVERM(R) 100 mg chewable tablet. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Table 3: Adverse Reactions Identified During Postmarketing Experience with Mebendazole Adverse Reaction(s) Blood and Lymphatic System Disorders Agranulocytosis, NeutropeniaImmune System Disorders Hypersensitivity including anaphylactic reactionsNervous System Disorders Convulsions, DizzinessHepatobiliary Disorders Hepatitis, Abnormal liver testsRenal and Urinary Disorders GlomerulonephritisSkin and Subcutaneous Tissue Disorders Toxic epidermal necrolysis, Stevens-Johnson syndrome, Exanthema, Angioedema, Urticaria, Alopecia Includes mebendazole formulations, dosages and treatment duration other than EMVERM(R) 100 mg chewable tablets.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In carcinogenicity tests of mebendazole in mice and rats, no carcinogenic effects were seen at doses as high as 40 mg/kg (one to two times the human dose, based on mg/m2) given daily over two years. No mutagenic activity was observed with mebendazole in bacterial reverse gene mutation test. Mebendazole was mutagenic in the absence of S-9 when tested using continuous (24 hour) treatment incubation period in the mouse lymphoma thymidine kinase assay. Mebendazole was aneugenic in vitro in mammalian somatic cells. In the in vivo mouse micronucleus assay, orally administered mebendazole induced an increased frequency of micronucleated polychromatic erythrocytes with evidence suggestive of aneugenicity. Doses up to 40 mg/kg in rats (2 times the total daily human dose, based on mg/m2), given to males for 60 days and to females for 14 days prior to gestation, had no effect upon fetuses and offspring.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Mebendazole, benzimidazole, is an anthelmintic drug [see Microbiology (12.4)].. 12.3 Pharmacokinetics. AbsorptionFollowing oral administration of mebendazole, the majority of the dose remains in the gastrointestinal tract where it exerts an anthelmintic effect locally. Following administration of 100 mg twice daily for three consecutive days, plasma concentrations of EMVERM(R) (mebendazole) and its primary metabolite, the 2-amine hydrolyzed metabolite, do not exceed 0.03 mcg/mL and 0.09 mcg/mL, respectively. Dosing with high fat meal increases the bioavailability of mebendazole, although the overall effect of food on the amount of drug remaining in the gastrointestinal tract is not expected to be substantial. . DistributionThe plasma protein binding of mebendazole is 90 to 95%. The volume of distribution is to L/kg, indicating that absorbed mebendazole penetrates areas outside the vascular space. . MetabolismOrally 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. All metabolites are devoid of anthelmintic activity. Impaired hepatic function, impaired metabolism, or impaired biliary elimination may lead to higher plasma concentrations of mebendazole. . Excretion 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 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. 12.4Microbiology. Mechanism of ActionMebendazole interferes with cellular tubulin formation in the helminth and causes ultrastructural degenerative changes in its intestine. As 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: Ancylostoma duodenale Ascaris lumbricoides Enterobius vermicularis Necator americanus Trichuris trichiura Resistance There is 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Efficacy rates derived from various studies are shown in Table below: Table 4: Mean Cure Rates and Egg Reductions from Clinical Studies Pinworm (enterobiasis) Whipworm (trichuriasis) Roundworm (ascariasis)Hookworm Cure rates mean 95% 68% 98% 96%Egg reduction mean 93% 99% 99%.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. EMVERM(R) is contraindicated in persons with known hypersensitivity to the drug or its excipients. Patients with known hypersensitivity to the drug or its excipients (4). Patients with known hypersensitivity to the drug or its excipients (4).

DESCRIPTION SECTION.

11 DESCRIPTION. EMVERM(R) (mebendazole) is an orally administered, synthetic anthelmintic available as chewable tablets, each containing 100 mg of mebendazole. Inactive ingredients are: microcrystalline cellulose, corn starch, anhydrous lactose NF, sodium starch glycolate, magnesium stearate, stearic acid, sodium lauryl sulfate, sodium saccharin, and FD&C Yellow 6. Chemically, mebendazole is methyl 5-benzoylbenzimidazole-2-carbamate with molecular formula of C16H13N3O3 and the following structural formula: Mebendazole is white to slightly yellow powder with molecular weight of 295.29. It is less than 0.05% soluble in water, dilute mineral acid solutions, alcohol, ether and chloroform, but is soluble in formic acid. 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage for EMVERM(R) is described in Table below. The same dosage schedule applies to adults and pediatric patients two years of age and older. The tablet may be chewed, swallowed, or crushed and mixed with food. Table 1: Dosage of EMVERM in Adult and Pediatric Patients (two years of age and older) Pinworm (enterobiasis) Whipworm (trichuriasis) Roundworm (ascariasis) Hookworm Dose1 tablet once tablet morning and evening for consecutive days tablet morning and evening for consecutive days tablet morning and evening for consecutive days If the patient is not cured three weeks after treatment, asecond course of treatment is advised. No special procedures, such as fastingor purging, are required. Adults and Pediatrics: The tablet may be chewed, swallowed, or crushed and mixed with food (2). Pinworm (enterobiasis) Whipworm (trichuriasis) Roundworm (ascariasis) Hookworm Dose1 tablet once tablet morning and evening for consecutive days tablet morning and evening for consecutive days tablet morning and evening for consecutive days.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Chewable Tablet: 100 mg, round, light peach-colored, unscored, debossed ap above 107 on one side and plain on the other side. Chewable Tablet: 100 mg (3) Chewable Tablet: 100 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Concomitant use of mebendazole, including EMVERM(R), and metronidazole should be avoided [see Warnings and Precautions (5.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of mebendazole did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. EMVERM(R) (mebendazole) is available as 100 mg, round, light peach-colored chewable tablet, unscored, debossed ap above 107 on one side and plain on the other side. They are supplied as follows: Blister package of tablet NDC 64896-669-30Store at 68 to 77F (20 to 25C) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. EMVERM(R) is indicated for the treatment of patients two years of age and older with gastrointestinal infections caused by Ancylostoma duodenale (hookworm), Ascaris lumbricoides (roundworm), Enterobius vermicularis (pinworm), Necator americanus (hookworm), and Trichuris trichiura (whipworm). EMVERM(R) is an anthelmintic indicated for the treatment of patients two years of age and older with gastrointestinal infections caused by: Ancylostoma duodenale (hookworm), Ascaris lumbricoides (roundworm), Enterobius vermicularis (pinworm), Necator americanus (hookworm), and Trichuris trichiura (whipworm), (1).. Ancylostoma duodenale (hookworm), Ascaris lumbricoides (roundworm), Enterobius vermicularis (pinworm), Necator americanus (hookworm), and Trichuris trichiura (whipworm), (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). Advise patients that: Taking EMVERM(R) and metronidazole together may cause serious skin reactions and should be avoided [see Warning and Precautions (5.3)]. EMVERM(R) can be taken with or without food [see Dosage and Administration (2)]. Taking EMVERM(R) and metronidazole together may cause serious skin reactions and should be avoided [see Warning and Precautions (5.3)]. EMVERM(R) can be taken with or without food [see Dosage and Administration (2)].

LACTATION SECTION.

8.2Lactation. Risk Summary Limited data from case reports demonstrate that small amount of mebendazole is present in human milk following oral administration. There are no reports of effects on the breastfed infant, and the limited reports on the effects on milk production are inconsistent. The limited clinical data during lactation precludes clear determination of the risk of EMVERM(R) to breastfed infant; therefore, developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for EMVERM(R) and any potential adverse effects on the breastfed infant from EMVERM(R) or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Mebendazole, benzimidazole, is an anthelmintic drug [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4Microbiology. Mechanism of ActionMebendazole interferes with cellular tubulin formation in the helminth and causes ultrastructural degenerative changes in its intestine. As 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: Ancylostoma duodenale Ascaris lumbricoides Enterobius vermicularis Necator americanus Trichuris trichiura Resistance There is 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In carcinogenicity tests of mebendazole in mice and rats, no carcinogenic effects were seen at doses as high as 40 mg/kg (one to two times the human dose, based on mg/m2) given daily over two years. No mutagenic activity was observed with mebendazole in bacterial reverse gene mutation test. Mebendazole was mutagenic in the absence of S-9 when tested using continuous (24 hour) treatment incubation period in the mouse lymphoma thymidine kinase assay. Mebendazole was aneugenic in vitro in mammalian somatic cells. In the in vivo mouse micronucleus assay, orally administered mebendazole induced an increased frequency of micronucleated polychromatic erythrocytes with evidence suggestive of aneugenicity. Doses up to 40 mg/kg in rats (2 times the total daily human dose, based on mg/m2), given to males for 60 days and to females for 14 days prior to gestation, had no effect upon fetuses and offspring.

OVERDOSAGE SECTION.

10 OVERDOSAGE. 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 signsIn the event of accidental overdose, gastrointestinal signs/symptoms may occur.. TreatmentThere is no specific antidote.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. 1.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing oral administration of mebendazole, the majority of the dose remains in the gastrointestinal tract where it exerts an anthelmintic effect locally. Following administration of 100 mg twice daily for three consecutive days, plasma concentrations of EMVERM(R) (mebendazole) and its primary metabolite, the 2-amine hydrolyzed metabolite, do not exceed 0.03 mcg/mL and 0.09 mcg/mL, respectively. Dosing with high fat meal increases the bioavailability of mebendazole, although the overall effect of food on the amount of drug remaining in the gastrointestinal tract is not expected to be substantial. . DistributionThe plasma protein binding of mebendazole is 90 to 95%. The volume of distribution is to L/kg, indicating that absorbed mebendazole penetrates areas outside the vascular space. . MetabolismOrally 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. All metabolites are devoid of anthelmintic activity. Impaired hepatic function, impaired metabolism, or impaired biliary elimination may lead to higher plasma concentrations of mebendazole. . Excretion 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 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe available published literature on mebendazole use in pregnant women has not reported clear association between mebendazole and potential risk of major birth defects or miscarriages [see Data]. There are risks to the mother and fetus associated with untreated helminthic infection during pregnancy [see Clinical Considerations].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 0.5-fold the total daily maximum recommended human dose [MRHD]). Maternal toxicity was present at the highest of these doses [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have 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.. Clinical ConsiderationsDisease-Associated 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.. DataHuman DataSeveral published studies, including prospective pregnancy registries, case-control, retrospective cohort, and randomized controlled studies, have reported no association between mebendazole use and potential risk of major birth defects or miscarriage. Overall, these studies did not identify 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.Animal DataEmbryo-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 lowered body weight gain and decreased pregnancy rate. Maternal toxicity, including body weight loss in one animal and maternal death in 11 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 0.5-fold the total daily MRHD, based on mg/m2).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 10 and 40 mg/kg/day and higher mortality rate at 40 mg/kg/day. At doses of 10 mg/kg/day (approximately 0.2-fold the total daily MRHD, based on mg/m2) 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 (1.6 to 3.9-fold the total daily MRHD, based on mg/m2).In 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 (1.9-fold the total daily MRHD, based on mg/m2), 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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION EMVERM(R) (EM-verm) (mebendazole) Chewable Tablets USP, for oral useWhat is EMVERM Emverm is prescription medicine used to treat adults and children years of age and older with intestinal worm infections caused by pinworm, whipworm, roundworm, or hookworm. Who should not take EMVERM Do not take Emverm if you are allergic to mebendazole or any of the ingredients in Emverm. See the end of this leaflet for complete list of ingredients in Emverm. Before you take EMVERM, tell your healthcare provider about all of your medical conditions, including if you: are pregnant or plan to become pregnant. It is not known if EMVERM will harm your unborn baby.are breastfeeding or plan to breastfeed. EMVERM can pass into your milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take EMVERM. Do not breastfeed while taking EMVERM.Tell your healthcare provider about all the medicines you take, including prescription and over-the--counter medicines, vitamins, and herbal supplements. Using EMVERM with certain other medicines can change the way these medicines act, causing serious side effects. Know the medicines you take. Keep list of them to show to your healthcare provider or pharmacist when you get new medicine.How should take EMVERM Take EMVERM exactly as your healthcare provider tells you to take it. Take EMVERM by mouth with or without food. EMVERM tablets may be chewed, swallowed, or crushed and mixed with food. If you take too much EMVERM, you might have symptoms that include stomach cramps, nausea, vomiting or diarrhea. What should avoid while taking EMVERMDo not take Emverm with metronidazole (a medicine used to treat bacterial and protozoan infections) as serious skin reactions called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can happen. What are the possible side effects of EMVERM EMVERM may cause serious side effects, including: Low white blood cell count (neutropenia). Neutropenia can cause you to get other infections. Your healthcare provider will check your blood count regularly during your treatment with EMVERM. Tell your healthcare provider right away if you have fever or any signs of an infection while taking EMVERMSevere skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis). EMVERM may cause rare, but serious skin reactions when taken with metronidazole and other medicines that contain mebendazole. These severe allergic reactions may be life-threatening and need to be treated in hospital. Call your healthcare provider right away or get emergency medical help if you have any allergic reactions or the following symptoms: severe skin blisterssores around the mouth, nose, eyes, vagina or penis (genitals)peeling skinswollen face, lips, mouth, tongue or throatitchy rash (hives)The most common side effects of EMVERM include: loss of appetite (anorexia)stomach paindiarrheapassing gasnauseavomitingrashTell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of EMVERM. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store EMVERM Store at room temperature between 68F to 77F (20C to 25C). Safely throw away medicine that is out of date or no longer needed. Keep EMVERM and all medicines out of the reach of children. General information about the safe and effective use of EMVERM.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use EMVERM for condition for which it was not prescribed. Do not give EMVERM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about EMVERM that is written for health professionals. What are the ingredients in EMVERM Active ingredient: mebendazoleInactive ingredients: microcrystalline cellulose, corn starch, anhydrous lactose NF, sodium starch glycolate, magnesium stearate, stearic acid, sodium lauryl sulfate, sodium saccharin, and FD&C Yellow 6.Manufactured by: AlcamiWilmington, NC 28405Distributed by: Amneal Specialty, division ofAmneal Pharmaceuticals LLCBridgewater, NJ 08807For more information, call Amneal Pharmaceuticals at 1-877-835-5472.This Patient Information has been approved by the U.S. Food and Drug Administration. Rev. 01-2019-00. are pregnant or plan to become pregnant. It is not known if EMVERM will harm your unborn baby.. are breastfeeding or plan to breastfeed. EMVERM can pass into your milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take EMVERM. Do not breastfeed while taking EMVERM.. Take EMVERM exactly as your healthcare provider tells you to take it. Take EMVERM by mouth with or without food. EMVERM tablets may be chewed, swallowed, or crushed and mixed with food. If you take too much EMVERM, you might have symptoms that include stomach cramps, nausea, vomiting or diarrhea. Low white blood cell count (neutropenia). Neutropenia can cause you to get other infections. Your healthcare provider will check your blood count regularly during your treatment with EMVERM. Tell your healthcare provider right away if you have fever or any signs of an infection while taking EMVERM. Severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis). EMVERM may cause rare, but serious skin reactions when taken with metronidazole and other medicines that contain mebendazole. These severe allergic reactions may be life-threatening and need to be treated in hospital. Call your healthcare provider right away or get emergency medical help if you have any allergic reactions or the following symptoms: severe skin blisterssores around the mouth, nose, eyes, vagina or penis (genitals)peeling skinswollen face, lips, mouth, tongue or throatitchy rash (hives). severe skin blisters. sores around the mouth, nose, eyes, vagina or penis (genitals). peeling skin. swollen face, lips, mouth, tongue or throat. itchy rash (hives). loss of appetite (anorexia). stomach pain. diarrhea. passing gas. nausea. vomiting. rash. Store at room temperature between 68F to 77F (20C to 25C). Safely throw away medicine that is out of date or no longer needed.

SPL UNCLASSIFIED SECTION.

5.1Risk of Convulsions. Although EMVERM(R) is approved for use in children two years of age and older, convulsions have been reported in infants below the age of year during post-marketing experience with mebendazole, including EMVERM(R) [see Adverse Reactions (6.2) and Use in Specific Populations (8.4)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThe available published literature on mebendazole use in pregnant women has not reported clear association between mebendazole and potential risk of major birth defects or miscarriages [see Data]. There are risks to the mother and fetus associated with untreated helminthic infection during pregnancy [see Clinical Considerations].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 0.5-fold the total daily maximum recommended human dose [MRHD]). Maternal toxicity was present at the highest of these doses [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have 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.. Clinical ConsiderationsDisease-Associated 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.. DataHuman DataSeveral published studies, including prospective pregnancy registries, case-control, retrospective cohort, and randomized controlled studies, have reported no association between mebendazole use and potential risk of major birth defects or miscarriage. Overall, these studies did not identify 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.Animal DataEmbryo-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 lowered body weight gain and decreased pregnancy rate. Maternal toxicity, including body weight loss in one animal and maternal death in 11 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 0.5-fold the total daily MRHD, based on mg/m2).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 10 and 40 mg/kg/day and higher mortality rate at 40 mg/kg/day. At doses of 10 mg/kg/day (approximately 0.2-fold the total daily MRHD, based on mg/m2) 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 (1.6 to 3.9-fold the total daily MRHD, based on mg/m2).In 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 (1.9-fold the total daily MRHD, based on mg/m2), 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.. 8.2Lactation. Risk Summary Limited data from case reports demonstrate that small amount of mebendazole is present in human milk following oral administration. There are no reports of effects on the breastfed infant, and the limited reports on the effects on milk production are inconsistent. The limited clinical data during lactation precludes clear determination of the risk of EMVERM(R) to breastfed infant; therefore, developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for EMVERM(R) and any potential adverse effects on the breastfed infant from EMVERM(R) or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of EMVERM(R) 100 mg chewable tablets has not been established in pediatric patients less than two years of age. Convulsions have been reported with mebendazole use in children less than one year of age [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. 8.5 Geriatric Use. Clinical studies of mebendazole did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Risk of Convulsions: Convulsions in infants below the age of year have been reported (5.1).Hematologic Effects: Neutropenia and agranulocytosis have been reported in patients receiving mebendazole at higher doses and for prolonged duration. Monitor blood counts in these patients (5.2).Metronidazole and Serious Skin Reactions: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) have been reported with the concomitant use of mebendazole and metronidazole. Avoid concomitant use of mebendazole and metronidazole (5.3).. Risk of Convulsions: Convulsions in infants below the age of year have been reported (5.1).. Hematologic Effects: Neutropenia and agranulocytosis have been reported in patients receiving mebendazole at higher doses and for prolonged duration. Monitor blood counts in these patients (5.2).. Metronidazole and Serious Skin Reactions: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) have been reported with the concomitant use of mebendazole and metronidazole. Avoid concomitant use of mebendazole and metronidazole (5.3).. 5.1Risk of Convulsions. Although EMVERM(R) is approved for use in children two years of age and older, convulsions have been reported in infants below the age of year during post-marketing experience with mebendazole, including EMVERM(R) [see Adverse Reactions (6.2) and Use in Specific Populations (8.4)]. 5.2Hematologic Effects. Agranulocytosis and neutropenia have been reported with mebendazole use at higher doses and for more prolonged durations than is recommended for the treatment of soil-transmitted helminth infections. Monitor blood counts if EMVERM(R) is used at higher doses or for prolonged duration. 5.3Metronidazole Drug Interaction and Serious Skin Reactions. Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) have been reported with the concomitant use of mebendazole and metronidazole. Avoid concomitant use of mebendazole, including EMVERM(R) and metronidazole.