Natroba

Indications and Usage ( 1 ) 04/2021 Dosage and Administration ( 2 ) 04/2021 Warnings and Precautions ( 5 ) 04/2021

1 INDICATIONS AND USAGE NATROBA 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 ) NATROBA 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 NATROBA TM 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 NATROBA 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 NATROBA 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.

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

3 DOSAGE FORMS AND STRENGTHS 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 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS 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 NATROBA 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 NATROBA, 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 Natroba (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 NATROBA 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 NATROBA 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 NATROBA 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 Natroba (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%)

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Spinosad, the active ingredient in NATROBA, is not absorbed systemically following topical application, and maternal use is not expected to result in fetal exposure to the drug. NATROBA 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 NATROBA. 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. 8.2 Lactation Risk Summary Spinosad, the active ingredient in NATROBA, is not systemically absorbed by the mother following topical application. Therefore, breastfeeding is not expected to result in the exposure of the child to spinosad [see Clinical Pharmacology ( 12.3 )] . Advise breastfeeding women to remove NATROBA from the breast with soap and water before breastfeeding to avoid direct infant exposure to NATROBA. NATROBA contains benzyl alcohol. Topical benzyl alcohol is unlikely to be absorbed through the skin of breastfeeding women in clinically relevant amounts; therefore, breastfeeding is not expected to result in exposure of the infant to NATROBA [see Clinical Pharmacology ( 12.3 )] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NATROBA and any potential adverse effects on the breastfed child from NATROBA, or from the underlying maternal condition. 8.4 Pediatric Use Head Lice Infestation The safety and effectiveness of NATROBA 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 )] . NATROBA 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. NATROBA contains benzyl alcohol. Intravenous administration of benzyl alcohol has been associated with …

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

11 DESCRIPTION NATROBA (spinosad) is a slightly opaque, light orange-colored, viscous topical suspension. NATROBA 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 NATROBA 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

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied NATROBA (spinosad) topical suspension, 0.9% w/w; each gram contains 9 mg of spinosad in a slightly opaque (white soft particles may be visible), light orange-colored, viscous liquid, supplied in 4 oz (120 mL) high density polyethylene (HDPE) bottles. NDC 52246-929-04 Storage and Handling Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F).