ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence of >= 1%) were erythema, rash, skin burning sensation, contact dermatitis, vomiting, eye irritation, pruritus, and hair color changes. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddys Laboratories. Inc., at 1-888-966-8766 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to the rates in the clinical trials of another drug, and may not reflect the rates observed in practice. The data described below reflect exposure to single 10-minute treatment of XEGLYZE in 349 subjects (6 months of age and older) with head lice infestation in randomized, double-blind, vehicle-controlled trials (Trials and 2). Of these subjects, 21 were months to years of age, 166 subjects were to 12 years of age, 57 subjects were 12 to 18 years of age, and 105 subjects were 18 years of age or older. Table provides adverse reactions that occurred in at least 1% of subjects in the XEGLYZE group and at greater frequency than in the vehicle group. Table 1: Adverse Reactions Occurring in >= 1% of the XEGLYZE Group and at Greater Frequency than in the Vehicle Group (Trials and 2) Adverse ReactionsXEGLYZE N=349 Subjects (%)Vehicle N=350 Subjects (%) Erythema14 (4.0) (2) Rash11 (3.2) (2.3) Skin burning sensation9 (2.6) (0.0) Contact dermatitis (1.7) (1.1) Vomiting6 (1.7) (0.6) Eye irritation4 (1.2)2 (0.6) Hair color changes3 (1)0 (0.0)During the trials, subjects were monitored for new onset of scalp erythema/edema, scalp pruritus, and eye irritation. The number and percentage of subjects who developed these local adverse reactions after treatment are presented in Table 2.Table 2: Monitored Local Adverse Reactions with New Onset on Day Post-Treatment (Trials and 2) Adverse ReactionsXEGLYZE Subjects (%)Vehicle Subjects (%) Scalp Erythema/Edema11 (3.2)5 (1.4) Scalp Pruritus2 (1.4)1 (0.7) Eye Irritation6 (1.7)5 (1.4) For the calculation of the percentages, the denominators are the number of subjects who did not have the monitored local adverse reaction at baseline.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Abametapir (5,5-dimethyl 2,2-bipyridinyl) is metalloproteinase inhibitor. Metalloproteinases have role in physiological processes critical to egg development and survival of lice.. 12.3 Pharmacokinetics. AbsorptionThe pharmacokinetics of XEGLYZE were evaluated in trials, Trials A, B, and C. Each trial enrolled lice infested subjects who received single 10-minute application of XEGLYZE. Pharmacokinetic samplings were carried out to 72 hours post-dose in adults and hours post-dose in pediatric subjects in all trials. Trial evaluated pharmacokinetics in adult and 12 pediatric subjects to 12 years of age. The mean (%CV) abametapir plasma maximum concentration (Cmax) and area under the concentration time curve from to hours post-dose (AUC0-8h) in the adult group were 41 (66%) ng/mL and 121 (50%) ngh/mL, respectively. The mean (%CV) Cmax and AUC0-8h in the pediatric group were 73 (57%) ng/mL and 264 (62%) ngh/mL, respectively. The mean (%CV) terminal half-life in adults was 21 (11%) hours.Trials and evaluated pharmacokinetics in 50 pediatric subjects months to 17 years old. The pharmacokinetic results for plasma abametapir are shown in Table 3. Even though the values varied between the trials, abametapir exposure increased as the age of the subject decreased. Abametapir absorption was rapid with median Tmax of 0.57 to 1.54 hours.Table Abametapir Pharmacokinetic Parameters in Subjects with Head Lice InfestationStudyAge GroupnCmax (ng/mL)Mean (%CV) AUC0-8h (ngh/mL) Mean (%CV)B6 months to <1 year14181057C5228 (50%)688 (43%)B1 year to <2 years3209 (62%)446 (65%)C8147 (49%)406 (37%)B2 years to <3 years6206 (66%)633 (57%)C8160 (48%)602 (51%)B3 years to 17 years12121 (60%)330 (49%)C752 (45%)194 (39%)Serum concentration of benzyl alcohol, an excipient in the formulation of XEGLYZE, was assessed in Trials and C. Benzyl alcohol in serum was measurable (limit of quantitation 0.5 ug/mL) in subjects out of 39 evaluable subjects. The Cmax of benzyl alcohol in these subjects ranged from 0.52 to 3.57 ug/mL [see Warnings and Precautions (5) and Use in Specific Populations (8.4)].DistributionAbametapir and its primary human metabolite, abametapir carboxyl, are highly bound to proteins in plasma. Abametapir is 91.3 92.3% bound to plasma proteins, and abametapir carboxyl is 96.0% 97.5% bound to plasma proteins.EliminationMetabolismAbametapir is extensively metabolized, primarily by the cytochrome P450 enzyme CYP1A2 to mono-hydroxylated metabolite (abametapir hydroxyl) and further to mono-carboxylated metabolite (abametapir carboxyl). Abametapir carboxyl is cleared slowly from the systemic circulation resulting in plasma concentration higher than that of abametapir. Based on data in adults in Trial above, where sampling was carried out to 72 hours, the ratios of Cmax and AUC0-72h between abametapir carboxyl and abametapir were about 30 and 250, respectively. The elimination half-life of abametapir carboxyl has not been well characterized but is estimated to be approximately (mean +- SD) 71 +- 40 hours or longer in adults.Excretion Excretion of abametapir and its human metabolites was not examined in patients. Drug Interaction Studies In vitro studies suggest that there is potential for inhibition of cytochrome P450 3A4, 2B6, and 1A2 enzymes following application of XEGLYZE due to high and prolonged systemic exposure of the metabolite abametapir carboxyl [see Drug Interactions (7) ].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Two identical multi-center, randomized, double-blind, vehicle-controlled trials (Trials and 2) were conducted in 704 subjects months of age and older with head lice infestation. All subjects received single application of either XEGLYZE or vehicle control. For the evaluation of efficacy, the youngest subject from each household was considered to be the index subject of the household (N=216). Other enrolled infested household members received the same treatment as the youngest subject and were evaluated for all efficacy and safety parameters. Index subjects ranged from months to 49 years of age (mean years), and approximately 85% of the index subjects were female, and 95% of the index subjects were Caucasian.Efficacy was assessed as the proportion of index subjects who were treated with single 10-minute application and were free of live lice at all follow-up visits on Days 1, 7, and 14. Subjects with live lice at any time up to the final evaluation were considered treatment failures. Table presents the proportion of subjects who were free of live lice at all visits Day through Day 14 in Trials and 2. Table 4: Proportion of Index Subjects Free of Live Lice at All Visits Days Through 14 After TreatmentTrial 1Trial 2XEGLYZE (N=53)Vehicle (N=55)XEGLYZE (N=55)Vehicle (N=53)Treatment Success43 (81.1%)28 (50.9%)45 (81.8%)25 (47.2%).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For topical use only. XEGLYZE is not for oral, ophthalmic, or intravaginal use. Treatment with XEGLYZE involves single application.Shake well before use. Apply XEGLYZE to dry hair in an amount (up to the full content of one bottle) sufficient to thoroughly coat the hair and scalp. Massage XEGLYZE into the scalp and throughout the hair. Avoid contact with eyes. Leave on the hair and scalp for 10 minutes and then rinse off with warm water. Wash hands after application. Hair may be shampooed any time after the treatment. Discard any unused product. Do not flush contents down sink or toilet. For topical use only. Not for oral, ophthalmic, or intravaginal use. (2) Shake well before use. (2) Apply XEGLYZE to dry hair in an amount sufficient (up to the full content of one bottle) to thoroughly coat the hair and scalp. Avoid contact with eyes. (2) Massage XEGLYZE into the scalp and throughout the hair; leave on the hair and scalp for 10 minutes and then rinse off with warm water. (2) Massage XEGLYZE into the scalp and throughout the hair; leave on the hair and scalp for 10 minutes and then rinse off with warm water. (2) For topical use only. Not for oral, ophthalmic, or intravaginal use. (2) Shake well before use. (2) Apply XEGLYZE to dry hair in an amount sufficient (up to the full content of one bottle) to thoroughly coat the hair and scalp. Avoid contact with eyes. (2) Massage XEGLYZE into the scalp and throughout the hair; leave on the hair and scalp for 10 minutes and then rinse off with warm water. (2) Massage XEGLYZE into the scalp and throughout the hair; leave on the hair and scalp for 10 minutes and then rinse off with warm water. (2).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. XEGLYZE is indicated for the topical treatment of head lice infestation in patients months of age and older. XEGLYZE should be used in the context of an overall lice management program:Wash (with hot water) or dry-clean all recently worn clothing, hats, used bedding and towels Wash personal care texts such as combs, brushes, and hair clips in hot waterUse fine-tooth comb or special nit comb to remove dead lice and nits. Wash (with hot water) or dry-clean all recently worn clothing, hats, used bedding and towels Wash personal care texts such as combs, brushes, and hair clips in hot water. XEGLYZE is pediculicide indicated for the topical treatment of head lice infestation in patients months of age and older. XEGLYZE should be used in the context of an overall lice management program:Wash (with hot water) or dry-clean all recently worn clothing, hats, used bedding and towels Wash personal care texts such as combs, brushes and hair clips in hot waterUse fine-tooth comb or special nit comb to remove dead lice and nits (1) Wash (with hot water) or dry-clean all recently worn clothing, hats, used bedding and towels Wash personal care texts such as combs, brushes and hair clips in hot water. Use fine-tooth comb or special nit comb to remove dead lice and nits (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Inform the patient and caregiver of the following instructions:Do not ingest XEGLYZE.Keep out of reach of children. Use on children should be under the direct supervision of an adult because of the risk of benzyl alcohol toxicity [see Warnings and Precautions (5) and Use in Specific Populations (8.4) ].Avoid contact with eyes.Wash hands after application.Hair may be shampooed any time after the treatment. Treatment with XEGLYZE involves single application. Do not re-treat.Discard any unused portion. Do not flush contents down sink or toilet.Manufactured by Groupe Parima Inc., for Dr. Reddys Laboratories, S.A. Elisabethenanlage 11, 4051 Basel, SwitzerlandDistributed by Dr. Reddys Laboratories Inc., 107 College Road East, Princeton, NJ 08540XeglyzeTM is registered trademark of Dr. Reddys Laboratories, S.A.Issued: 01 2022. Do not ingest XEGLYZE.. Keep out of reach of children. Use on children should be under the direct supervision of an adult because of the risk of benzyl alcohol toxicity [see Warnings and Precautions (5) and Use in Specific Populations (8.4) ].. Avoid contact with eyes.. Wash hands after application.. Hair may be shampooed any time after the treatment. Treatment with XEGLYZE involves single application. Do not re-treat.. Discard any unused portion. Do not flush contents down sink or toilet.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of XEGLYZE have been established in pediatric patients months of age and older [see Clinical Pharmacology (12) and Clinical Studies (14)]. The safety and effectiveness of XEGLYZE have not been established in pediatric patients below the age of months. XEGLYZE is not recommended in pediatric patients under months of age because of the potential for increased systemic absorption due to high ratio of skin surface to body mass and the potential for an immature skin barrier.XEGLYZE contains benzyl alcohol. Benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants. The gasping syndrome (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with intravenously administered benzyl alcohol dosages >99 mg/kg/day in neonates and low birthweight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity [see Warnings and Precautions (5.1) ]. Because of the risk of accidental ingestion, XEGLYZE should be administered to pediatric patients only under direct adult supervision [see Warnings and Precautions (5.2) ].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe pharmacokinetics of XEGLYZE were evaluated in trials, Trials A, B, and C. Each trial enrolled lice infested subjects who received single 10-minute application of XEGLYZE. Pharmacokinetic samplings were carried out to 72 hours post-dose in adults and hours post-dose in pediatric subjects in all trials. Trial evaluated pharmacokinetics in adult and 12 pediatric subjects to 12 years of age. The mean (%CV) abametapir plasma maximum concentration (Cmax) and area under the concentration time curve from to hours post-dose (AUC0-8h) in the adult group were 41 (66%) ng/mL and 121 (50%) ngh/mL, respectively. The mean (%CV) Cmax and AUC0-8h in the pediatric group were 73 (57%) ng/mL and 264 (62%) ngh/mL, respectively. The mean (%CV) terminal half-life in adults was 21 (11%) hours.Trials and evaluated pharmacokinetics in 50 pediatric subjects months to 17 years old. The pharmacokinetic results for plasma abametapir are shown in Table 3. Even though the values varied between the trials, abametapir exposure increased as the age of the subject decreased. Abametapir absorption was rapid with median Tmax of 0.57 to 1.54 hours.Table Abametapir Pharmacokinetic Parameters in Subjects with Head Lice InfestationStudyAge GroupnCmax (ng/mL)Mean (%CV) AUC0-8h (ngh/mL) Mean (%CV)B6 months to <1 year14181057C5228 (50%)688 (43%)B1 year to <2 years3209 (62%)446 (65%)C8147 (49%)406 (37%)B2 years to <3 years6206 (66%)633 (57%)C8160 (48%)602 (51%)B3 years to 17 years12121 (60%)330 (49%)C752 (45%)194 (39%)Serum concentration of benzyl alcohol, an excipient in the formulation of XEGLYZE, was assessed in Trials and C. Benzyl alcohol in serum was measurable (limit of quantitation 0.5 ug/mL) in subjects out of 39 evaluable subjects. The Cmax of benzyl alcohol in these subjects ranged from 0.52 to 3.57 ug/mL [see Warnings and Precautions (5) and Use in Specific Populations (8.4)].DistributionAbametapir and its primary human metabolite, abametapir carboxyl, are highly bound to proteins in plasma. Abametapir is 91.3 92.3% bound to plasma proteins, and abametapir carboxyl is 96.0% 97.5% bound to plasma proteins.EliminationMetabolismAbametapir is extensively metabolized, primarily by the cytochrome P450 enzyme CYP1A2 to mono-hydroxylated metabolite (abametapir hydroxyl) and further to mono-carboxylated metabolite (abametapir carboxyl). Abametapir carboxyl is cleared slowly from the systemic circulation resulting in plasma concentration higher than that of abametapir. Based on data in adults in Trial above, where sampling was carried out to 72 hours, the ratios of Cmax and AUC0-72h between abametapir carboxyl and abametapir were about 30 and 250, respectively. The elimination half-life of abametapir carboxyl has not been well characterized but is estimated to be approximately (mean +- SD) 71 +- 40 hours or longer in adults.Excretion Excretion of abametapir and its human metabolites was not examined in patients. Drug Interaction Studies In vitro studies suggest that there is potential for inhibition of cytochrome P450 3A4, 2B6, and 1A2 enzymes following application of XEGLYZE due to high and prolonged systemic exposure of the metabolite abametapir carboxyl [see Drug Interactions (7) ].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on XEGLYZE use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In embryofetal development studies conducted with oral administration of abametapir during organogenesis, no evidence of fetal harm or malformations, independent of maternal toxicity were observed in pregnant rats and rabbits at doses that produced exposures up to 50 times and equivalent to the maximum recommended human dose (MRHD) in rats and rabbits, respectively. The highest dose evaluated in rabbits was limited due to maternal toxicity associated with the vehicle used in the study (see Data).The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.DataAnimal Data Systemic embryofetal development studies were performed in rats and rabbits. Oral doses of 10, 25 and 75 mg/kg/day abametapir were administered during the period of organogenesis (gestational days - 17) to pregnant rats. In the presence of maternal toxicity, embryofetal toxicity (lower fetal body weights and delayed ossification) was noted at 75 mg/kg/day. No treatment related effects on malformations were noted at 75 mg/kg/day (50 times the MRHD based on Cmax comparisons). Oral doses of 4, 16 and 40 mg/kg/day abametapir were administered during the period of organogenesis (gestational days - 19) to pregnant rabbits. No treatment related effects on embryofetal toxicity or malformations were noted at 40 mg/kg/day (~1 time the MRHD based on Cmax comparisons). Maternal toxicity related to the vehicle limited the maximum dose in pregnant rabbits. In perinatal and postnatal development study in rats, oral doses of 10, 25 and 75 mg/kg/day were administered from the beginning of organogenesis (gestational day 6) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal lethality, and decreased fetal body weight gain were noted at 75 mg/kg/day. No treatment related effects on postnatal development were noted at 75 mg/kg/day (47 times the MRHD based on Cmax comparisons).

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION XEGLYZE (zeg lyze) (abametapir) LotionImportant: XEGLYZE is for use on scalp hair and scalp only. Do not use XEGLYZE in your mouth, eyes, or vagina.What is XEGLYZEXEGLYZE is prescription medicine used to get rid of head lice in people months of age and older. After XEGLYZE is rinsed off, fine-tooth comb may be used to remove dead lice and nits from the hair and scalp. All personal texts exposed to the hair or lice should be washed in hot water or dry-cleaned. See How do stop the spread of lice at the end of the XEGLYZE Instructions for Use.It is not known if XEGLYZE is safe and effective in children under months of age.Before you use XEGLYZE, tell your healthcare provider if you or your child:have any skin conditions or sensitivitieshave any other medical conditionsare pregnant or plan to become pregnant. It is not known if XEGLYZE can harm your unborn babyare breastfeeding or plan to breastfeed. It is not known if XEGLYZE passes into your breast milk. How should use XEGLYZESee the Instructions for Use for detailed information about the right way to apply XEGLYZE.Use XEGLYZE exactly as your healthcare provider tells you to use it. Your healthcare provider will prescribe the treatment that is right for you. Do not change your treatment without talking to your healthcare provider.Use XEGLYZE on dry hair.Completely cover all of your hair and scalp with XEGLYZE.Children will need an adult to apply XEGLYZE for them.Do not swallow XEGLYZE. If swallowed, call your Poison Control Center at 1-800-222-1222.Do not get XEGLYZE into your eyes. If XEGLYZE gets in your eye, gently flush with water. Wash your hands after you apply XEGLYZE.You may shampoo your hair any time after the treatment.When you complete your dose of XEGLYZE, do not use XEGLYZE again. Throw away any unused XEGLYZE. Do not flush XEGLYZE down sink or toilet.What are the possible side effects of XEGLYZEThe most common side effects of XEGLYZE include:Redness of the skin or scalpRashBurning sensation of the skinSkin irritationVomitingEye irritationItchy scalpChanges in your hair colorTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of XEGLYZE. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.How should store XEGLYZEStore upright at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F and 86F) [See USP Controlled Room Temperature].Do not refrigerate or freeze XEGLYZE.Discard (throw away) any unused product.Keep XEGLYZE and all medicines out of reach of children.General information about the safe and effective use of XEGLYZEMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use XEGLYZE for condition for which it was not prescribed. Do not give XEGLYZE to other people, even if they have the same symptoms you have. It may harm them. You can also ask your pharmacist or healthcare provider for information about XEGLYZE that is written for health professionals.What are the ingredients in XEGLYZEActive ingredient: abametapir Inactive ingredients: benzyl alcohol 2.0%, butylated hydroxytoluene, carbomer homopolymer type C, light mineral oil, polysorbate 20, trolamine and water.Manufactured by Groupe Parima, Inc., for Dr. Reddys Laboratories, S.A. Elisabethenanlage 11, 4051 Basel, Switzerland XEGLYZE is registered trademark of Dr. Reddys Laboratories, S.A.Distributed by Dr. Reddys Laboratories, Inc.,107 College Road East, Princeton, NJ 08540.This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 01/2022. have any skin conditions or sensitivities. have any other medical conditions. are pregnant or plan to become pregnant. It is not known if XEGLYZE can harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if XEGLYZE passes into your breast milk. Use XEGLYZE exactly as your healthcare provider tells you to use it. Your healthcare provider will prescribe the treatment that is right for you. Do not change your treatment without talking to your healthcare provider.. Use XEGLYZE on dry hair.. Completely cover all of your hair and scalp with XEGLYZE.. Children will need an adult to apply XEGLYZE for them.. Do not swallow XEGLYZE. If swallowed, call your Poison Control Center at 1-800-222-1222.. Do not get XEGLYZE into your eyes. If XEGLYZE gets in your eye, gently flush with water. Wash your hands after you apply XEGLYZE.. You may shampoo your hair any time after the treatment.. When you complete your dose of XEGLYZE, do not use XEGLYZE again. Throw away any unused XEGLYZE. Do not flush XEGLYZE down sink or toilet.. Redness of the skin or scalp. Rash. Burning sensation of the skin. Skin irritation. Vomiting. Eye irritation. Itchy scalp. Changes in your hair color. Store upright at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F and 86F) [See USP Controlled Room Temperature].. Do not refrigerate or freeze XEGLYZE.. Discard (throw away) any unused product.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on XEGLYZE use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In embryofetal development studies conducted with oral administration of abametapir during organogenesis, no evidence of fetal harm or malformations, independent of maternal toxicity were observed in pregnant rats and rabbits at doses that produced exposures up to 50 times and equivalent to the maximum recommended human dose (MRHD) in rats and rabbits, respectively. The highest dose evaluated in rabbits was limited due to maternal toxicity associated with the vehicle used in the study (see Data).The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.DataAnimal Data Systemic embryofetal development studies were performed in rats and rabbits. Oral doses of 10, 25 and 75 mg/kg/day abametapir were administered during the period of organogenesis (gestational days - 17) to pregnant rats. In the presence of maternal toxicity, embryofetal toxicity (lower fetal body weights and delayed ossification) was noted at 75 mg/kg/day. No treatment related effects on malformations were noted at 75 mg/kg/day (50 times the MRHD based on Cmax comparisons). Oral doses of 4, 16 and 40 mg/kg/day abametapir were administered during the period of organogenesis (gestational days - 19) to pregnant rabbits. No treatment related effects on embryofetal toxicity or malformations were noted at 40 mg/kg/day (~1 time the MRHD based on Cmax comparisons). Maternal toxicity related to the vehicle limited the maximum dose in pregnant rabbits. In perinatal and postnatal development study in rats, oral doses of 10, 25 and 75 mg/kg/day were administered from the beginning of organogenesis (gestational day 6) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal lethality, and decreased fetal body weight gain were noted at 75 mg/kg/day. No treatment related effects on postnatal development were noted at 75 mg/kg/day (47 times the MRHD based on Cmax comparisons).. 8.2 Labor and Delivery. Risk Summary No data are available regarding the presence of abametapir in human milk or the effects of abametapir on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for XEGLYZE and any potential adverse effects on the breastfed child from XEGLYZE or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of XEGLYZE have been established in pediatric patients months of age and older [see Clinical Pharmacology (12) and Clinical Studies (14)]. The safety and effectiveness of XEGLYZE have not been established in pediatric patients below the age of months. XEGLYZE is not recommended in pediatric patients under months of age because of the potential for increased systemic absorption due to high ratio of skin surface to body mass and the potential for an immature skin barrier.XEGLYZE contains benzyl alcohol. Benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants. The gasping syndrome (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with intravenously administered benzyl alcohol dosages >99 mg/kg/day in neonates and low birthweight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity [see Warnings and Precautions (5.1) ]. Because of the risk of accidental ingestion, XEGLYZE should be administered to pediatric patients only under direct adult supervision [see Warnings and Precautions (5.2) ].. 8.5 Geriatric Use. Clinical studies of XEGLYZE did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Risk of Neonatal Benzyl Alcohol Toxicity: Systemic exposure to benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants. Safety and effectiveness in pediatric patients below the age of months have not been established. Use is not recommended in pediatric patients under months of age because of the potential for increased systemic absorption. (5.1) Risk of Benzyl Alcohol Toxicity from Accidental Ingestion: Administer only under direct supervision of an adult. (5.2). Risk of Neonatal Benzyl Alcohol Toxicity: Systemic exposure to benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants. Safety and effectiveness in pediatric patients below the age of months have not been established. Use is not recommended in pediatric patients under months of age because of the potential for increased systemic absorption. (5.1) Risk of Benzyl Alcohol Toxicity from Accidental Ingestion: Administer only under direct supervision of an adult. (5.2). 5.1 Risk of Neonatal Benzyl Alcohol Toxicity. XEGLYZE contains benzyl alcohol. Systemic exposure to benzyl alcohol has been associated with serious and fatal adverse reactions including gasping syndrome in neonates and low birth weight infants. The gasping syndrome is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity [see Use in Specific Populations (8.4) ].The safety and effectiveness of XEGLYZE have not been established in pediatric patients below the age of months. Use is not recommended in pediatric patients under months of age because of the potential for increased systemic absorption.. 5.2 Risk of Benzyl Alcohol Toxicity from Accidental Ingestion. In order to prevent accidental ingestion in pediatric patients, XEGLYZE should only be administered under direct supervision of an adult.Ingestion of benzyl alcohol in large quantities may result in gastrointestinal (nausea, vomiting, diarrhea) and central nervous system (headache, ataxia, convulsions, coma) adverse reactions. Serious adverse reactions may include respiratory depression and death. If accidentally swallowed, advise the patient or the caregiver to call their Poison Control Center at 1-800-222-1222.