Abametapir ( July 2020)- Head lice treatmentDrug Name:
Abametapir ( July 2020)- Head lice treatment
List Of Brands:
Indication Type Description:
Pregnancy and lactation
U.S. FDA APPROVED DRUGS DURING 2020
___________________ CONTRAINDICATIONS____________________ None. (4) _______________ 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 6 months have not been established. Use is not recommended in pediatric patients under 6 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) ____________________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. Reddy’s Laboratories. Inc., at 1-888-966-8766 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________DRUG INTERACTIONS____________________ For 2 weeks after XEGLYZE application, avoid taking drugs that are substrates of CYP3A4, CYP2B6 or CYP1A2. Otherwise, avoid use of XEGLYZE. (7) See 17 for PATIENT CO
17 PATIENT COUNSELING INFORMATIO
Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Page 9 of 10 Reference ID: 4645747 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 a 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. Reddy’s Laboratories, S.A. Elisabethenanlage 11, 4051 Basel, Switzerland
Distributed by Dr. Reddy’s Laboratories Inc., 107 College Road East, Princeton, NJ 08540 XEGLYZETM is a registered trademark of Dr. Reddy’s Laboratories, S.A. Issued: 06 / 2020 Product Insert Item Number Here
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.3 Pharmacokinetics 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 postdose 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. Table 3 Abametapir Pharmacokinetic Parameters in Subjects with Head Lice Infestation 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 3 years to 17 years 12 121 (60%) 330 (49%) C 7 52 (45%) 194 (39%) Page 7 of 10 Reference ID: 4645747 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)].
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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). Page 8 of 10 Reference ID: 4645747 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). 14 CLINICAL STUDIES
Pregnancy and lactation:
7 DRUG INTERACTIONS 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)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on XEGLYZE use in pregnant women to evaluate for a drugassociated 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). Page 4 of 10 Reference ID: 4645747 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). 8.2 Lactation 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. 8.4 Pediatric Use 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 Page 5 of 10 Reference ID: 4645747 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)]. 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.
10 OVERDOSAGE If accidentally swallowed, advise patients to seek medical advice immediately and to call their local Poison Control Center at 1-800-222-1222.
11 DESCRIPTION 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'-dimethyl2,2'-bipyridinyl. The structural formula is: