Minolira Extended Release (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of MINOLIRA for the treatment of acne is unknown.

12.2 Pharmacodynamics

The pharmacodynamics of MINOLIRA for the treatment of acne are unknown.

12.3 Pharmacokinetics

The pharmacokinetics of minocycline following oral administration of a single dose of MINOLIRA (135 mg) was investigated in 77 healthy male and female adult subjects under fasting conditions. The pharmacokinetic parameters of minocycline under fasting conditions are presented in Table 3.

Table 3 : Pharmacokinetic Parameters of Minocycline Following Administration of a Single Dose of MINOLIRA (135 mg) under Fasting Conditions (N = 77)
Cmax (ng/mL) Tmax (hr)* AUC0-t (ng∙hr/mL) T1/2 (hr)
*
Median (Min-Max)
Mean ± SD 700 ± 261 2.0 (1.0 – 4.5) 10874 ± 3717 15.6 ± 2.46

In a separate trial, a single dose of MINOLIRA (135 mg) was administered orally with a high-fat, high-calorie meal that included dairy products to 36 healthy male and female adult subjects. The estimated calorie content of the meal was 848 Kcal, consisting of 145 Kcal from protein, 250 Kcal from carbohydrates, and 453 Kcal from fat. The pharmacokinetic parameters of minocycline under fed conditions are presented in Table 4.

Table 4 : Pharmacokinetic Parameters of Minocycline Following Administration of a Single Dose of MINOLIRA (135 mg) under Fed Conditions (N = 36)
Cmax (ng/mL) Tmax (hr)* AUC0-t (ng∙hr/mL) T1/2 (hr)
*
Median (Min-Max)
Mean ± SD 707 ± 190 3.5 (1.5 – 6.0) 12000 ± 2967 17.1 ± 3.03

Minocycline is lipid soluble and distributes into the skin and sebum.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a carcinogenicity study in which minocycline hydrochloride was orally administered to male and female rats once daily for up to 104 weeks at dosages up to 200 mg/kg/day, minocycline hydrochloride was associated in both genders with follicular cell tumors of the thyroid gland, including increased incidences of adenomas, carcinomas, and the combined incidence of adenomas and carcinomas in males, and adenomas and the combined incidence of adenomas and carcinomas in females. In a carcinogenicity study in which minocycline hydrochloride was orally administered to male and female mice once daily for up to 104 weeks at dosages up to 150 mg/kg/day, exposure to minocycline hydrochloride did not result in a significantly increased incidence of neoplasms in either males or females.

Minocycline was not mutagenic in vitro in a bacterial reverse mutation assay (Ames test) or CHO/HGPRT mammalian cell assay in the presence or absence of metabolic activation. Minocycline was not clastogenic in vitro using human peripheral blood lymphocytes or in vivo in a mouse micronucleus test.

Male and female reproductive performance in rats was unaffected by oral doses of minocycline of up to 300 mg/kg/day (which resulted in up to approximately 40 times the level of systemic exposure to minocycline observed in patients administered MINOLIRA). However, oral administration of 100 or 300 mg/kg/day of minocycline to male rats (resulting in approximately 15 to 40 times the level of systemic exposure to minocycline observed in patients administered MINOLIRA) adversely affected spermatogenesis. Effects observed at 300 mg/kg/day included a reduced number of sperm cells per gram of epididymis, an apparent reduction in the percentage of sperm that were motile, and (at 100 and 300 mg/kg/day) increased numbers of morphologically abnormal sperm cells. Morphological abnormalities observed in sperm samples included absent heads, misshapen heads, and abnormal flagella.

14 CLINICAL STUDIES

The safety and efficacy of minocycline hydrochloride extended-release tablets in the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris was assessed in two 12-week, multi-center, randomized, double-blind, placebo-controlled, trials in subjects ≥12 years. The mean age of subjects was 20 years and subjects were from the following racial groups: White (73%), Hispanic (13%), Black (11%), Asian/Pacific Islander (2%), and Other (2%).

In two efficacy and safety trials, a total of 924 subjects with non-nodular moderate to severe acne vulgaris received minocycline hydrochloride extended-release tablets (approximately 1 mg/kg) or placebo for a total of 12 weeks.

The two primary efficacy endpoints were:

1) Mean percent change in inflammatory lesion counts from Baseline to 12 weeks.

2) Percentage of subjects with an Evaluator’s Global Severity Assessment (EGSA) of clear or almost clear at 12 weeks.

Efficacy results are presented in Table 5.

Table 5: Efficacy Results at Week 12
Trial 1 Trial 2
Minocycline Hydrochloride Extended Release Tablets (1 mg/kg) N=300 Placebo N=151 Minocycline Hydrochloride Extended Release Tablets (1 mg/kg) N=315 Placebo N=158
*
Evaluator’s Global Severity Assessment
Mean Percent Improvement in Inflammatory Lesions 43.1% 31.7% 45.8%
Number of subjects clear or almost clear on EGSA * 52 (17.3%) 12 (7.9%) 50 (15.9%) 15 (9.5%)

Minocycline hydrochloride did not demonstrate any effect on non-inflammatory lesions (benefit or worsening).

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