Comfortis

Indication

Comfortis (spinosad) Topical Suspension is indicated for the topical treatment of head lice infestation in patients six (6) months of age and older.

Adjunctive Measures

Comfortis 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.

For topical use only. Comfortis Topical Suspension is not for oral, ophthalmic, or intravaginal use.

Shake bottle well. Apply sufficient Comfortis 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 Comfortis Topical Suspension with warm water. If live lice are seen 7 days after the first treatment, a second treatment should be applied. Avoid contact with eyes.

None.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Benzyl Alcohol Toxicity

Comfortis Topical Suspension contains benzyl alcohol and is not recommended 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.

Patient Counseling Information

The patient should be instructed as follows:

• Shake bottle well immediately prior to use
• Do not swallow
• Use Comfortis Topical Suspension only on dry scalp and dry scalp hair.
• Repeat treatment only if live lice are seen seven days after first treatment.
• Avoid contact with eyes. If Comfortis Topical Suspension gets in or near the eyes, rinse thoroughly with water.
• Wash hands after applying Comfortis Topical Suspension
• Use Comfortis Topical Suspension on children only under direct supervision of an adult.

Nonclinical Toxicology

Carcinogenesis, 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.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies with Comfortis Topical Suspension in pregnant women. Reproduction studies conducted in rats and rabbits were negative for teratogenic effects. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

No comparisons of animal exposure with human exposure are provided in this labeling due to the low systemic exposure noted in the clinical pharmacokinetic study which did not allow for the determination of human AUC values that could be used for this calculation.

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 teratogenic 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 teratogenic 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.

Nursing Mothers

Spinosad, the active ingredient in Comfortis Topical Suspension is not systemically absorbed; and therefore, will not be present in human milk. However, Comfortis Topical Suspension contains benzyl alcohol, which may be systemically absorbed through the skin, and the amount of benzyl alcohol excreted in human milk with use of Comfortis Topical Suspension is unknown. Caution should be exercised when Comfortis Topical Suspension is administered to a lactating woman. A lactating woman may choose to pump and discard breast milk for 8 hours (5 half-lives of benzyl alcohol) after use to avoid infant ingestion of benzyl alcohol.

Pediatric Use

The safety and effectiveness of Comfortis Topical Suspension have been established in pediatric patients 6 months of age and older with active head lice infestation.

Safety in pediatric patients below the age of 6 months has not been established. Comfortis 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.

Comfortis Topical Suspension contains benzyl alcohol which 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 low­birthweight 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, may be more likely to develop toxicity.

Geriatric Use

Clinical studies of Comfortis 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.

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.

Comfortis Topical Suspension was studied in two randomized, active-controlled trials (N=552) in subjects with head lice; the results are presented in Table 1.

Table 1: Selected Adverse Events Occurring in at least 1% of Subjects

Other less common reactions (less than 1% but more than 0.1%) were application site dryness, application site exfoliation, alopecia, and dry skin.

Systemic safety was not assessed in pediatric subjects under 6 months of age as laboratory parameters were not monitored in these controlled studies.

If oral ingestion occurs, seek medical advice immediately.

The pharmacodynamics of Comfortis Topical Suspension has not been studied.

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 (3ng/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.