Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Galderma (UK) Ltd, Meridien House, 69-71 Clarendon Road, Watford, Herts, WD17 1DS, UK
Pharmacotherapeutic group: Antibacterials for systemic use, Tetracyclines
ATC code: J01AA02
The pathophysiology of the inflammatory lesions of rosacea is, in part, a manifestation of a neutrophil-mediated process. Doxycycline has been shown to inhibit neutrophil activity and several pro-inflammatory reactions including those associated with phospholipase A2, endogenous nitric oxide and interleukin-6. The clinical significance of these findings is not known.
The plasma concentration of doxycycline following administration of Efracea is well below the level required to inhibit mircoorganisms commonly associated with bacterial diseases.
In vivo microbiological studies using similar exposure to the active substance for 6 to 18 months could not demonstrate any effect on the dominating bacterial flora sampled from the oral cavity, skin, intestinal tract and vagina. However, it cannot be excluded that long-term use of Efracea can lead to emergence of resistant intestinal bacteria such as Enterobacteriaceae and enterococci, as well as to enrichment of resistance genes.
Efracea has been evaluated in two pivotal randomised, double-blind, placebo-controlled, 16-week studies in 537 patients with rosacea (10 to 40 papules and pustules, and two or fewer nodules). In both studies, the mean reduction in the total inflammatory lesion count was significantly greater in the Efracea group than in the placebo group:
Table 2. Mean change from baseline to Week 16 in total inflammatory lesion count:
| Study 1 | Study 2 | |||
|---|---|---|---|---|
| EFRACEA 40 mg (N=127) | Placebo (N=124) | EFRACEA 40 mg (N=142) | Placebo (N=144) | |
| Mean (SD) change from baseline | -11.8 (9.8) | -5.9 (13.9) | -9.5 (9.6) | -4.3 (11.6) |
| Mean between-group difference (95% confidence limits) | -5.9 (-8.9, -2.9) | -5.2 (-7.7, -2.7) | ||
| p-Valuea | 0.0001 | <0.0001 | ||
a p-Value for treatment difference in change from baseline (ANOVA)
Treatment with doxycycline 40 mg modified release capsules plus ivermectin
The ANSWER study evaluated the relative efficacy of doxycycline 40 mg modified release capsules (DMR) in combination with Soolantra (IVM) vs IVM plus DMR placebo (PBO) in the treatment of severe rosacea. It was a 12-week, randomized, investigator-blind, controlled, parallel-group study of 273 male and female subjects aged ≥18 years with 20-70 inflammatory lesions (papules and pustules) on the face and a baseline Investigator’s Global Assessment (IGA) score of 4.
The primary efficacy endpoint was the percentage change from baseline in inflammatory lesion counts at Week 12. A significantly greater mean percentage reduction in inflammatory lesion count was seen for IVM + DMR compared to IVM + PBO (mean ± standard deviation: -80.29 ± 21.65 % vs -73.56 ± 30.52 %; p=0.032).
Doxycycline is almost completely absorbed after oral administration. Following oral administration of Efracea, mean peak plasma concentrations were 510 ng/mL after a single dose and 600 ng/mL at steady state (Day 7). Peak plasma levels were generally achieved at 2 to 3 hours after administration. Coadministration with a high-fat, high-protein meal that included dairy products reduced the bioavailability (AUC) of doxycycline from Efracea by about 20% and reduced the peak plasma level by 43%.
Doxycycline is greater than 90% bound to plasma proteins and has an apparent volume of distribution of 50 L.
Major metabolic pathways of doxycycline have not been identified but enzyme inducers decrease the half-life of doxycycline.
Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40% and 60% of an administered dose can be accounted for in the urine by 92 hours, and approximately 30% in the faeces. The terminal elimination half-life of doxycycline after administration of Efracea was approximately 21 h after a single dose and approximately 23 h at steady state.
The half-life of doxycycline is not significantly altered in patients with severely impaired renal function. Doxycycline is not eliminated to any great extent during haemodialysis.
There is no information on the pharmacokinetics of doxycycline in patients with hepatic impairment.
Adverse reactions seen in repeat dose studies in animals include hyperpigmentation of the thyroid and tubular degeneration in the kidney. These effects were seen at exposure levels of 1.5 to 2 times those seen in humans administered Efracea at the proposed dose. The clinical relevance of these findings remains unknown.
Doxycycline showed no mutagenic activity and no convincing evidence of clastogenic activity. In a rat carcinogenicity study increases in benign tumours of the mammary gland (fibroadenoma), uterus (polyp) and thyroid (C-cell adenoma) were noted in females.
In rats, doses of 50 mg/kg/day doxycycline caused a decrease in the straight-line velocity of sperm but did not affect male or female fertility or sperm morphology. At this dose systemic exposure experienced by rats is likely to have been approximately 4 times that seen in humans taking the recommended dose of Efracea. At doses greater than 50 mg/kg/day fertility and reproductive performance were adversely affected in rats. A peri/postnatal toxicity study in rats revealed no significant effects at therapeutically relevant doses. Doxycycline is known to cross the placenta and literature data indicate that tetracyclines can have toxic effects on the developing foetus.
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