Oracea

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of ORACEA in the treatment of inflammatory lesions of rosacea is unknown.

Pharmacokinetics

ORACEA capsules are not bioequivalent to other doxycycline products. The pharmacokinetics of doxycycline following oral administration of ORACEA was investigated in 2 volunteer studies involving 61 adults. Pharmacokinetic parameters for ORACEA following single oral doses and at steady-state in healthy subjects are presented in Table 2.

Table 2: Pharmacokinetic Parameters [Mean (±SD)] for ORACEA

  N Cmax* (ng/mL) Tmax+ (hr) AUC0-∞ * (ng•hr/mL) t½* (hr)
Single Dose 40 mg capsules 30 510 ± 220.7 3.00 (1.0-4.1) 9227± 3212.8 21.2 ± 7.6
Steady-State# 40 mg capsules 31 600 ± 194.2 2.00 (1.0-4.0) 7543 ± 2443.9 23.2 ± 6.2
*Mean +Median #Day 7

Absorption

In a single-dose food-effect study involving administration of ORACEA to healthy volunteers, concomitant administration with a 1000 calorie, high-fat, high-protein meal that included dairy products, resulted in a decrease in the rate and extent of absorption (Cmax and AUC) by about 45% and 22%, respectively, compared to dosing under fasted conditions. This decrease in systemic exposure can be clinically significant, and therefore if ORACEA is taken close to meal times, it is recommended that it be taken at least one hour prior to or two hours after meals.

Distribution

Doxycycline is greater than 90% bound to plasma proteins.

Metabolism

Major metabolites of doxycycline have not been identified. However, enzyme inducers such as barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

Excretion

Doxycycline is excreted in the urine and feces as unchanged drug. It is reported that between 29% and 55.4% of an administered dose can be accounted for in the urine by 72 hours. Terminal half-life averaged 21.2 hours in subjects receiving a single dose of ORACEA.

Special Populations

Geriatric: Doxycycline pharmacokinetics have not been evaluated in geriatric patients.

Pediatric: Doxycycline pharmacokinetics have not been evaluated in pediatric patients [see WARNINGS AND PRECAUTIONS].

Gender: The pharmacokinetics of ORACEA were compared in 16 male and 14 female subjects under fed and fasted conditions. While female subjects had a higher Cmax and AUC than male subjects, these differences were thought to be due to differences in body weight/lean body mass.

Race: Differences in doxycycline pharmacokinetics among racial groups have not been evaluated.

Renal Insufficiency: Studies have shown no significant difference in serum half-life of doxycycline in patients with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life of doxycycline.

Hepatic Insufficiency: Doxycycline pharmacokinetics have not been evaluated in patients with hepatic insufficiency.

Gastric Insufficiency: In a study in healthy volunteers (N=24) the bioavailability of doxycycline is reported to be reduced at high pH. This reduced bioavailability may be clinically significant in patients with gastrectomy, gastric bypass surgery or who are otherwise deemed achlorhydric.

Drug Interactions

[see DRUG INTERACTIONS].

Microbiology

Doxycycline is a member of the tetracycline-class of drugs. The plasma concentrations of doxycycline achieved with ORACEA during administration [see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION] are less than the concentration required to treat bacterial diseases. ORACEA should not be used for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease [see INDICATIONS AND USAGE]. In vivo microbiological studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long term effects on bacterial flora of the oral cavity, skin, intestinal tract and vagina.

Clinical Studies

The safety and efficacy of ORACEA in the treatment of only inflammatory lesions (papules and pustules) of rosacea was evaluated in two randomized, placebo-controlled, multi-centered, double-blind, 16-week Phase 3 trials involving 537 subjects (total of 269 subjects on ORACEA from the two trials) with rosacea (10 to 40 papules and pustules and two or fewer nodules). Pregnant and nursing women, subjects < 18 years of age, and subjects with ocular rosacea and/or blepharitis/meibomianitis who require ophthalmologic treatment were excluded from trial. Mean baseline lesion counts were 20 and 21 for ORACEA and placebo subject groups respectively.

At Week 16, subjects in the ORACEA group were evaluated using co-primary endpoints of mean reduction in lesion counts and a dichotomized static Investigator's Global Assessment of Clear or Almost Clear (defined as 1 to 2 small papules or pustules) when compared to the placebo group in both Phase 3 trials.

Table 3: Clinical Results of ORACEA versus Placebo

  Study 1 Study 2
ORACEA Placebo ORACEA Placebo
40 mg
N=127
N=124 40 mg
N=142
N=144
Mean Change in Lesion Count from Baseline -11.8 -5.9 -9.5 -4.3
No. (%) of Subjects Clear or Almost Clear in the IGA* 39 (30.7%) 24 (19.4%) 21 (14.8%) 9 (6.3%)
*Investigator's Global Assessment

Subjects treated with ORACEA did not demonstrate significant improvement in erythema when compared to those treated with placebo.

Last reviewed on RxList: 8/12/2013
This monograph has been modified to include the generic and brand name in many instances.

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