The following Structured Product Label (SPL) was submitted to the FDA by Dr. Reddy's Laboratories Inc. for the product Xeglyze (NDC 43598-921). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2 dosage and administration, 3 dosage forms and strengths, 4 contraindications, 5.1 risk of neonatal benzyl alcohol toxicity, 5.2 risk of benzyl alcohol toxicity from accidental ingestion, 6.1 clinical trials experience, 7 drug interactions, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
XEGLYZE is indicated for the topical treatment of head lice infestation in patients 6 months of age and older.
XEGLYZE should be used in the context of an overall lice management program:
Use a fine-tooth comb or special nit comb to remove dead lice and nits
For topical use only. XEGLYZE is not for oral, ophthalmic, or intravaginal use. Treatment with XEGLYZE involves a 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.
Lotion, 0.74% [weight by weight], a viscous white to off-white oil in water emulsion, containing abametapir.
None.
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 6 months. Use is not recommended in pediatric patients under 6 months of age because of the potential for increased systemic absorption.
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.
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 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 a 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 1 and 2). Of these subjects, 21 were 6 months to 4 years of age, 166 subjects were 4 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 1 provides adverse reactions that occurred in at least 1% of subjects in the XEGLYZE group and at a greater frequency than in the vehicle group.
XEGLYZE | Vehicle | |
Erythema | 14 (4.0) | 6 (2) |
Rash | 11 (3.2) | 8 (2.3) |
| Skin burning sensation | 9 (2.6) | 0 (0.0) |
| Contact dermatitis | 6 (1.7) | 4 (1.1) |
| Vomiting | 6 (1.7) | 2 (0.6) |
| Eye irritation | 4 (1.2) | 2 (0.6) |
| Hair color changes | 3 (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.
Adverse Reactions | XEGLYZE | Vehicle |
Scalp Erythema/Edema | 11 (3.2) | 5 (1.4) |
Scalp Pruritus | 2 (1.4) | 1 (0.7) |
| Eye Irritation | 6 (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.
In vitro studies suggest there is a potential for inhibition of cytochrome P450 (CYP) 3A4, 2B6 and 1A2 enzymes following a single application of XEGLYZE. Use of XEGLYZE with drugs that are substrates of these enzymes may lead to increased systemic concentrations of the interacting drugs. Avoid administration of drugs that are substrates of CYP3A4, CYP2B6, or CYP1A2 within 2 weeks after application of XEGLYZE. If this is not feasible, avoid use of XEGLYZE [see Clinical Pharmacology (12.3)].
Risk Summary
There are no available data on XEGLYZE use in pregnant women to evaluate for a 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 2 to 4% and 15 to 20%, respectively.
Data
Animal 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 6 – 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 6 – 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 a 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).
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 mother’s clinical need for XEGLYZE and any potential adverse effects on the breastfed child from XEGLYZE or from the underlying maternal condition.
The safety and effectiveness of XEGLYZE have been established in pediatric patients 6 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 6 months. XEGLYZE is not recommended in pediatric patients under 6 months of age because of the potential for increased systemic absorption due to a 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)].
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.
If accidentally swallowed, advise patients to seek medical advice immediately and to call their local Poison Control Center at 1-800-222-1222.
The active pharmacological ingredient in XEGLYZE (abametapir) Lotion is the pediculicide, abametapir, which is a dipyridyl compound. The chemical name of abametapir is 5,5'-dimethyl-2,2'-bipyridinyl.
The structural formula is:
The empirical formula is C12H12N2 and the molecular weight is 184.24.
XEGLYZE is a white to off-white oil in water emulsion, containing 0.74% [weight by weight] of abametapir, intended for topical administration. XEGLYZE contains the following inactive ingredients: benzyl alcohol, butylated hydroxytoluene, carbomer 980, light mineral oil, polysorbate 20, trolamine and water.
Abametapir (5,5’-dimethyl 2,2’-bipyridinyl) is a metalloproteinase inhibitor. Metalloproteinases have a role in physiological processes critical to egg development and survival of lice.
Absorption
The pharmacokinetics of XEGLYZE were evaluated in 3 trials, Trials A, B, and C. Each trial enrolled lice infested subjects who received a single 10-minute application of XEGLYZE. Pharmacokinetic samplings were carried out to 72 hours post-dose in adults and 8 hours post-dose in pediatric subjects in all trials.
Trial A evaluated pharmacokinetics in 6 adult and 12 pediatric subjects 3 to 12 years of age. The mean (%CV) abametapir plasma maximum concentration (Cmax) and area under the concentration time curve from 0 to 8 hours post-dose (AUC0-8h) in the adult group were 41 (66%) ng/mL and 121 (50%) ng*h/mL, respectively. The mean (%CV) Cmax and AUC0-8h in the pediatric group were 73 (57%) ng/mL and 264 (62%) ng*h/mL, respectively. The mean (%CV) terminal half-life in adults was 21 (11%) hours.
Trials B and C evaluated pharmacokinetics in 50 pediatric subjects 6 months to 17 years old. The pharmacokinetic results for plasma abametapir are shown in Table 3. Even though the values varied between the 2 trials, abametapir exposure increased as the age of the subject decreased. Abametapir absorption was rapid with a median Tmax of 0.57 to 1.54 hours.
| Study | Age Group | n | Cmax (ng/mL) Mean (%CV) | AUC0-8h (ng*h/mL) Mean (%CV) |
| B | 6 months to <1 year | 1 | 418 | 1057 |
| C | 5 | 228 (50%) | 688 (43%) | |
| B | 1 year to <2 years | 3 | 209 (62%) | 446 (65%) |
| C | 8 | 147 (49%) | 406 (37%) | |
| B | 2 years to <3 years | 6 | 206 (66%) | 633 (57%) |
| C | 8 | 160 (48%) | 602 (51%) | |
| B | 12 | 121 (60%) | 330 (49%) | |
| C | 3 years to 17 years | 7 | 52 (45%) | 194 (39%) |
Serum concentration of benzyl alcohol, an excipient in the formulation of XEGLYZE, was assessed in Trials B and C. Benzyl alcohol in serum was measurable (limit of quantitation = 0.5 µg/mL) in 7 subjects out of 39 evaluable subjects. The Cmax of benzyl alcohol in these 7 subjects ranged from 0.52 to 3.57 µg/mL [see Warnings and Precautions (5) and Use in Specific Populations (8.4)].
Distribution
Abametapir 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.
Elimination
Metabolism
Abametapir is extensively metabolized, primarily by the cytochrome P450 enzyme CYP1A2 to a mono-hydroxylated metabolite (abametapir hydroxyl) and further to a 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 A 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 a 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)].
Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of XEGLYZE or abametapir.
Abametapir was not mutagenic or clastogenic based on the results of two in vitro genotoxicity tests (Ames test and human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (rat micronucleus assay).
No effects on fertility have been observed in rats following repeated oral doses of up to 75 mg/kg/day abametapir (50 times the MRHD based on Cmax comparisons).
Two identical multi-center, randomized, double-blind, vehicle-controlled trials (Trials 1 and 2) were conducted in 704 subjects 6 months of age and older with head lice infestation. All subjects received a 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 6 months to 49 years of age (mean 7 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 a 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 4 presents the proportion of subjects who were free of live lice at all visits Day 1 through Day 14 in Trials 1 and 2.
| Trial 1 | Trial 2 | |||
|---|---|---|---|---|
| XEGLYZE (N=53) | Vehicle (N=55) | XEGLYZE (N=55) | Vehicle (N=53) | |
| Treatment Success | 43 (81.1%) | 28 (50.9%) | 45 (81.8%) | 25 (47.2%) |
XEGLYZE is a white to off-white oil in water emulsion containing 0.74% [weight by weight] abametapir and supplied in a polyvinyl chloride (PVC) safety-coated single-use round amber glass bottle affixed with a polypropylene child resistant cap (NDC # 43598-921-11) featuring a tri-foil inner liner. The container is filled to a nominal 200 g (approximately 7 oz. or 210 mL) of the lotion.
Store upright at room temperature, 20°C to 25°C (68°F to 77°F), with allowable excursions between 15°C and 30°C (59°F and 86°F).
Do not refrigerate or freeze.
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:
CONTAINER LABEL
NDC 43598-921-11
Xeglyze (abametapir) Lotion, 0.74%
For topical use on the scalp hair and scalp only.
Rx only
200 g
Draft-container-label (Draft Container Label)
CARTON LABEL
NDC 43598-921-11
Xeglyze (abametapir) Lotion, 0.74%
For topical use on the scalp hair and scalp only.
Rx only
200 g
Draft-carton-label (Draft Carton Label)
* Please review the disclaimer below.
