Spinosad

Spinosad Topical Suspension is a pediculicide indicated for the topical treatment of head lice infestations in adult and pediatric patients 6 months of age and older. ( 1.1 ) Spinosad Topical Suspension is a scabicide indicated for the topical treatment of scabies infestations in adult and pediatric patients 4 years of age and older. ( 1.2 )

1.1 Head Lice Infestations Spinosad Topical Suspension is indicated for the topical treatment of head lice infestations in adult and pediatric patients 6 months of age and older. Adjunctive Measures for Head Lice Infestations Spinosad Topical Suspension should be used in the context of an overall lice management program: Wash in hot water or dry-clean all recently worn clothing, hats, used bedding and towels. Wash personal care items such as combs, brushes and hair clips in hot water. A fine-tooth comb or special nit comb may be used to remove dead lice and nits.

1.2 Scabies Infestations Spinosad Topical Suspension is indicated for the topical treatment of scabies infestations in adult and pediatric patients 4 years of age and older. Adjunctive Measures for Scabies Infestations Wash in hot water or dry-clean any bedding, clothing and towels used by anyone having scabies.

For topical use only. Not for oral, ophthalmic, or intravaginal use. ( 2 ) Treatment of head lice infestations ( 2.2 ): Shake bottle well Apply a sufficient amount to cover dry scalp, then apply to dry hair Rinse off with warm water after 10 minutes Repeat treatment only if live lice are seen 7 days after first treatment Treatment of scabies infestations ( 2.3 ): Shake bottle well Apply product to skin by rubbing it in to completely cover the body from the neck down to the soles of the feet Patients with balding scalp should also apply product to the scalp, hairline, temples, and forehead Allow to absorb in the skin and dry for 10 minutes before getting dressed Leave on the skin for at least 6 hours before showering or bathing 2.1 Important Administration Instructions For topical use only. Spinosad Topical Suspension is not for oral, ophthalmic, or intravaginal use. Avoid contact with eyes. If Spinosad Topical Suspension gets in or near the eyes, rinse thoroughly with water.

2.2 Treatment of Head Lice Infestations Shake bottle well. Apply a sufficient amount of Spinosad Topical Suspension to cover dry scalp, then apply to dry hair. Depending on hair length, apply up to 120 mL (one bottle) to adequately cover scalp and hair. Leave on for 10 minutes, then thoroughly rinse off with warm water. Wash hands after use. If live lice are seen 7 days after the first treatment, a second treatment should be applied. Apply Spinosad Topical Suspension on pediatric patient only under direct supervision of an adult [see Warnings and Precautions (5.1) ].

2.3 Treatment of Scabies Infestations Shake bottle well. Apply a sufficient amount of Spinosad Topical Suspension to skin to completely cover the body from the neck to the toes (including the soles of the feet). For patients with balding scalp, also apply product to the scalp, hairline, temples, and forehead. Allow to absorb into the skin and dry for 10 minutes before getting dressed. Leave on the skin for at least 6 hours before showering or bathing. Apply Spinosad Topical Suspension on pediatric patient only under direct supervision of an adult .

Topical suspension: 0.9% w/w; each gram contains 9 mg of spinosad in a viscous, slightly opaque (white soft particles may be visible), light orange-colored suspension in 120 mL bottles. Topical suspension: 0.9% w/w ( 3 )

None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Benzyl Alcohol Toxicity: Not recommended in infants below the age of 6 months; potential for increased systemic absorption. ( 5.1 )

5.1 Benzyl Alcohol Toxicity Spinosad Topical Suspension contains benzyl alcohol and is not approved for use in neonates and infants below the age of 6 months. Systemic exposure to benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants when administered intravenously [See Use in Specific Populations (8.4) ] .

Most common adverse events for lice treatment (>1%) were application site erythema and ocular erythema. ( 6.1 ) Most common adverse reactions for scabies treatment (>1%) were application site irritation (pain and burning) and dry skin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipher Pharmaceuticals US LLC at 1-855-628-7622 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Head Lice Infestations Spinosad Topical Suspension was studied in two randomized, active-controlled trials (N=552) in subjects with head lice; Table 1 presents selected adverse events, regardless of relationship to Spinosad Topical Suspension, that occurred in at least 1% of subjects. Table 1: Selected Adverse Events Occurring in at least 1% of Subjects with Head Lice Infestation Signs Spinosad (N=552) Permethrin 1% (N=457) Application site erythema 17 (3%) 31(7%) Ocular erythema 12 (2%) 15 (3%) Application site irritation 5 (1%) 7 (2%) Other less common reactions (less than 1% but more than 0.1%) were application site dryness, application site exfoliation, alopecia, and dry skin. Scabies Infestations Spinosad Topical Suspension was studied in three randomized, double-blind, vehicle-controlled trials (Trial 1, Trial 2, and Trial 3) in 592 subjects with scabies infestation, of which 165 were ages 4-17 and 427 were adults. Subjects received a single application of Spinosad Topical Suspension to the skin from the neck to the soles of the feet, which was washed off after a minimum of 6 hours. Table 2 presents adverse reactions related to Spinosad Topical Suspension treatment that occurred in at least 1% of subjects. Table 2: Adverse Reactions Occurring in at least 1% of Subjects with Scabies Infestation (Trials 1, 2 and 3) Signs Spinosad (N=322) Vehicle (N=270) Application site irritation Application site irritation also includes application site pain and burning sensation. 8 (3%) 0 (0%) Dry skin 6 (2%) 0 (0%)

No specific antidotes for spinosad overdosage are known. If oral ingestion occurs, contact Poison Control (1-800- 222-1222) for latest recommendations and seek medical attention immediately.

Risk Summary Spinosad, the active ingredient in Spinosad Topical Suspension, is not absorbed systemically following topical application, and maternal use is not expected to result in fetal exposure to the drug. Spinosad Topical Suspension contains benzyl alcohol. Topical benzyl alcohol is unlikely to be absorbed through the skin in clinically relevant amounts; therefore, maternal use is not expected to result in fetal exposure to the drug [ see Clinical Pharmacology (12.3) ]. In animal reproduction studies, no adverse embryofetal effects were seen at oral doses of spinosad up to 200 mg/kg/day in pregnant rats or 50 mg/kg/day in pregnant rabbits administered during the period of organogenesis ( see Data ). The available data do not allow the calculation of relevant comparisons between the systemic exposure of spinosad in animal studies to the systemic exposure that would be expected in humans after topical use of Spinosad Topical Suspension. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk for 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 to 4% and 15 to 20%, respectively. Data Animal Data Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 10, 50 and 200 mg/kg/day spinosad were administered during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. No adverse embryofetal effects were noted at any dose. Maternal toxicity occurred at 200 mg/kg/day. Oral doses of 2.5, 10, and 50 mg/kg/day spinosad were administered during the period of organogenesis (gestational days 7 – 19) to pregnant female rabbits. No adverse embryofetal effects were noted at any dose. Maternal toxicity occurred at 50 mg/kg/day. A two-generation dietary reproduction study was conducted in rats. Oral doses of 3, 10, and 100 mg/kg/day spinosad were administered to male and female rats from 10-12 weeks prior to mating and throughout mating, parturition, and lactation. No reproductive/developmental toxicity was noted at doses up to 10 mg/kg/day. In the presence of maternal toxicity, increased dystocia in parturition, decreased gestation survival, decreased litter size, decreased pup body weight, and decreased neonatal survival occurred at a dose of 100 mg/kg/day.

Head Lice Infestation The safety and effectiveness of Spinosad Topical Suspension for the topical treatment of head lice infestation have been established in pediatric patients 6 months of age and older [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] . Spinosad Topical Suspension is not recommended in pediatric patients below the age of 6 months because of the potential for increased systemic absorption due to a high ratio of skin surface area to body mass and the potential for an immature skin barrier. Spinosad Topical Suspension contains benzyl alcohol. Intravenous administration of 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 benzyl alcohol dosages >99 mg/kg/day in neonates and low-birthweight infants when administered intravenously. 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 of benzyl alcohol, may be more likely to develop toxicity [see Warning and Precautions (5.1) ] . Scabies Infestation The safety and effectiveness of Spinosad Topical Suspension for the topical treatment of scabies infestation have been established in pediatric patients 4 years of age and older. Use of Spinosad Topical Suspension in this age group is supported by Trial 1 and Trial 2 which included 165 pediatric subjects ages 4 to 17 years old with scabies infestation. The safety and efficacy were generally consistent between pediatric and adult patients. [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] . The safety and effectiveness of Spinosad Topical Suspension have not been established in pediatric patients less than 4 years of age with scabies infestation.

Clinical studies of Spinosad Topical Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Spinosad Topical Suspension is a slightly opaque, light orange-colored, viscous topical suspension. Spinosad Topical Suspension is a pediculicide and scabicide. Spinosad, the active ingredient, is derived from the fermentation of a soil actinomycete bacterium, Saccharopolyspora spinosa . Spinosad is a mixture of spinosyn A and spinosyn D in a ratio of approximately 5 to 1 (spinosyn A to spinosyn D). Spinosyn A: The chemical name is: 1 H -as-Indaceno[3,2-d]oxacyclododecin-7,a5-dione, 2-[(6-deoxy-2,3,4-tri-O- methyl-alpha-L-mannopyranosyl)oxy]-13-[[2R,5S,6R)-5-(dimethylamino) tetrahydro-6-methyl-2 H -pyran-2- yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-14-methyl-, (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)- Spinosyn D: The chemical name is: 1 H -as-Indaceno[3,2-d]oxacyclododecin-7,15-dione, 2-[(6-deoxy-2,3,4-tri-O- methyl-alpha-L-mannopyranosyl)oxy]-13-[[2R,5S,6R)-5-(dimethylamino) tetrahydro-6-methyl-2 H -pyran-2- yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-4,14-dimethyl-, (2S,3aSR,5aS,5bS,9S,13S,14R,16aS,16bS)- Spinosyn A (C 41 H 65 NO 10 ) MW 731.461 Spinosyn D (C 42 H 67 NO 10 ) MW 745.477 Spinosad Topical Suspension contains 9 mg spinosad per gram in a vehicle consisting of Benzyl Alcohol, Butylated Hydroxytoluene, Ceteareth-20, Cetearyl Alcohol, FD&C Yellow #6, Hexylene Glycol, Hydroxyethyl Cellulose, Isopropyl Alcohol, Propylene Glycol, Stearalkonium Chloride, Water, Hydrochloric acid (HCl) as pH adjuster. Chemical Structure Chemical Structure

12.1 Mechanism of Action Spinosad causes neuronal excitation in insects. After periods of hyperexcitation, lice and mites become paralyzed and die.

12.2 Pharmacodynamics The pharmacodynamics of Spinosad Topical Suspension has not been studied.

12.3 Pharmacokinetics Head Lice Infestations An open-label, single-center trial was conducted over a period of seven days to determine the pharmacokinetic profile of spinosad 1.8% in pediatric subjects with head lice infestation. Fourteen (14) subjects, 4 – 15 years of age, with head lice were enrolled into the trial. All subjects applied a single topical (scalp) treatment of spinosad 1.8% for 10 minutes, after which the test article was washed off, and subjects underwent plasma sampling. Results demonstrated that spinosad was below the limit of quantitation (3 ng/mL) in all samples. Plasma concentration of benzyl alcohol was not determined in these subjects. An open-label, two-center trial was conducted over a period of 23 days to determine the pharmacokinetic profile of spinosad 0.9% and the ingredient benzyl alcohol in pediatric subjects with a head lice infestation. Twenty-six (26) subjects between 6 months to 4 years of age were enrolled into the study per protocol. All subjects applied a single topical (scalp) treatment of spinosad 0.9% for 10 minutes, after which the test article was washed off, and subjects underwent plasma sampling over a 12 hour period. Plasma spinosad concentrations were below the limit of quantitation (3 ng/mL) in all samples. Benzyl alcohol was quantifiable (above 1 µg/mL) in a total of 8 plasma samples in 6 out of 26 subjects (25%): four out of 12 subjects in the 6 months to <2 years age group and two out of 14 subjects in the 2 to 4 years age group. The highest observed concentration was 2.37 µg/mL. Benzyl alcohol concentrations at 12 hours post-treatment were below limit of quantification (1 µg/mL) for all subjects. Scabies Infestations An open-label multi-center trial was conducted to determine the pharmacokinetic profile of spinosad 0.9% and the ingredient benzyl alcohol in pediatric subjects with scabies infestation. The PK bioavailability study was completed in 19 pediatrics subjects 5 to 16 years of age. All subjects applied a single topical body treatment of spinosad 0.9% from the neck down to the soles of the feet and allowed treatment to remain on the body for a minimum of 6 hours after which the test article was washed off. Subjects underwent plasma sampling over a 12- hour period after treatment. Plasma spinosad concentrations were below the limit of quantification (3 ng/mL) in all samples. Benzyl alcohol was quantifiable (above 1 µg/mL) in a total of 9 plasma samples in 6 out of 19 subjects (32%): in 3 out of 10 subjects in the 5 to 9 year age group and in 3 out of 9 subjects in the 10 to 16 years age group. The highest observed concentration was 3.94 µg/mL at 0.5 hours post-treatment but was below limit of quantification at 1 hour post-treatment for one subject in the 10 to 16 years age group. There were two subjects with a benzyl alcohol concentration at 3 hours post-treatment with the highest value of 3.53 µg/mL for one subject in the 5 to 9 years age group. Plasma concentrations were below limit of quantification (1 µg/mL) at 3 hours for all other subjects; no subject had measurable concentrations at the 6 and12 hour time points. The mean (SD) C max , T max , and AUC 0-12h values for benzyl alcohol were 2.737 (1.107) µg/mL, 1.42 (1.242) hours, and 19.240 µg∙h/mL, respectively.

Spinosad causes neuronal excitation in insects. After periods of hyperexcitation, lice and mites become paralyzed and die.

The pharmacodynamics of Spinosad Topical Suspension has not been studied.

Head Lice Infestations An open-label, single-center trial was conducted over a period of seven days to determine the pharmacokinetic profile of spinosad 1.8% in pediatric subjects with head lice infestation. Fourteen (14) subjects, 4 – 15 years of age, with head lice were enrolled into the trial. All subjects applied a single topical (scalp) treatment of spinosad 1.8% for 10 minutes, after which the test article was washed off, and subjects underwent plasma sampling. Results demonstrated that spinosad was below the limit of quantitation (3 ng/mL) in all samples. Plasma concentration of benzyl alcohol was not determined in these subjects. An open-label, two-center trial was conducted over a period of 23 days to determine the pharmacokinetic profile of spinosad 0.9% and the ingredient benzyl alcohol in pediatric subjects with a head lice infestation. Twenty-six (26) subjects between 6 months to 4 years of age were enrolled into the study per protocol. All subjects applied a single topical (scalp) treatment of spinosad 0.9% for 10 minutes, after which the test article was washed off, and subjects underwent plasma sampling over a 12 hour period. Plasma spinosad concentrations were below the limit of quantitation (3 ng/mL) in all samples. Benzyl alcohol was quantifiable (above 1 µg/mL) in a total of 8 plasma samples in 6 out of 26 subjects (25%): four out of 12 subjects in the 6 months to <2 years age group and two out of 14 subjects in the 2 to 4 years age group. The highest observed concentration was 2.37 µg/mL. Benzyl alcohol concentrations at 12 hours post-treatment were below limit of quantification (1 µg/mL) for all subjects. Scabies Infestations An open-label multi-center trial was conducted to determine the pharmacokinetic profile of spinosad 0.9% and the ingredient benzyl alcohol in pediatric subjects with scabies infestation. The PK bioavailability study was completed in 19 pediatrics subjects 5 to 16 years of age. All subjects applied a single topical body treatment of spinosad 0.9% from the neck down to the soles of the feet and allowed treatment to remain on the body for a minimum of 6 hours after which the test article was washed off. Subjects underwent plasma sampling over a 12- hour period after treatment. Plasma spinosad concentrations were below the limit of quantification (3 ng/mL) in all samples. Benzyl alcohol was quantifiable (above 1 µg/mL) in a total of 9 plasma samples in 6 out of 19 subjects (32%): in 3 out of 10 subjects in the 5 to 9 year age group and in 3 out of 9 subjects in the 10 to 16 years age group. The highest observed concentration was 3.94 µg/mL at 0.5 hours post-treatment but was below limit of quantification at 1 hour post-treatment for one subject in the 10 to 16 years age group. There were two subjects with a benzyl alcohol concentration at 3 hours post-treatment with the highest value of 3.53 µg/mL for one subject in the 5 to 9 years age group. Plasma concentrations were below limit of quantification (1 µg/mL) at 3 hours for all other subjects; no subject had measurable concentrations at the 6 and12 hour time points. The mean (SD) C max , T max , and AUC 0-12h values for benzyl alcohol were 2.737 (1.107) µg/mL, 1.42 (1.242) hours, and 19.240 µg∙h/mL, respectively.

, Mutagenesis, Impairment of Fertility In an oral (diet) mouse carcinogenicity study, spinosad was administered to CD-1 mice at doses of 0.0025, 0.008, and 0.036% in the diet (approximately 3.4, 11.4, and 50.9 mg/kg/day for males and 4.2, 13.8, and 67.0 mg/kg/day for females) for 18 months. No treatment-related tumors were noted in the mouse carcinogenicity study up to the highest doses evaluated in this study of 50.9 mg/kg/day in male mice and 13.8 mg/kg/day in female mice. Female mice treated with a dose of 67.0 mg/kg/day were not evaluated in this study due to high mortality. In an oral (diet) rat carcinogenicity study, spinosad was administered to Fischer 344 rats at doses of 0.005, 0.02, 0.05, and 0.1% in the diet (approximately 2.4, 9.5, 24.1 and 49.4 mg/kg/day for males and 3.0, 12.0, 30.1 and 62.8 mg/kg/day for females) for 24 months. No treatment-related tumors were noted in the rat carcinogenicity study in male or female rats up to the highest doses evaluated in this study of 24.1 mg/kg/day in male rats and 30.1 mg/kg/day in female rats. Rats in the highest dose group in this study were not evaluated due to high mortality. Spinosad demonstrated no evidence of mutagenic or clastogenic potential based on the results of four in vitro genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster ovary cell chromosome aberration assay, and rat hepatocyte unscheduled DNA synthesis assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay). Oral administration of spinosad (in diet) to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 10 mg/kg/day [see Use In Specific Populations (8.1) ] .

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information) Important Administration Instructions Instruct the patient to: Shake bottle well immediately prior to application. Do not swallow. Avoid contact with eyes. If Spinosad Topical Suspension gets in or near the eyes, rinse thoroughly with water. Apply Spinosad Topical Suspension on pediatric patient only under direct supervision of an adult. If skin/scalp irritation occurs after use, contact your physician [see Adverse Reactions (6.1) ] . Head Lice Infestation Treatment Apply Spinosad Topical Suspension only on dry scalp and dry scalp hair. Repeat treatment only if live lice are seen seven (7) days after first treatment. Wash hands after applying Spinosad Topical Suspension. Scabies Infestation Treatment Apply Spinosad Topical Suspension to completely cover the body from the neck to the toes (including the soles of the feet). For patients with balding scalp,also apply product to the scalp, hairline, temples, and forehead. Allow it to absorb in the skin and dry for 10 minutes before getting dressed. Leave on the skin for at least 6 hours before showering or bathing. Wash your hands after applying Spinosad Topical Suspension to someone else. For breastfeeding women, remove Spinosad Topical Suspension from the breast with soap and water before breastfeeding to avoid direct infant exposure to Spinosad Topical Suspension [see Use in Specific Populations (8.2) ]

Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F).