DOXYCYCLINE (Page 4 of 5)

12.4 Microbiology

Doxycycline is a member of the tetracycline-class of drugs. The plasma concentrations of doxycycline achieved with Doxycycline during administration [see Clinical Pharmacology (12.3) and Dosage and Administration (2.2)] are less than the concentration required to treat bacterial diseases. Doxycycline 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 (1.2) ]. 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Doxycycline was assessed for potential to induce carcinogenesis in a study in which the compound was administered to Sprague-Dawley rats by gavage at dosages of 20, 75, and 200 mg/kg/day for two years. An increased incidence of uterine polyps was observed in female rats that received 200 mg/kg/day, a dosage that resulted in a systemic exposure to doxycycline approximately 12.2 times that observed in female humans who use Doxycycline [exposure comparison based upon area under the curve (AUC) values]. No impact upon tumor incidence was observed in male rats up to at 200 mg/kg/day, or in females at the lower dosages studied.

Doxycyline was assessed for potential to induce carcinogenesis in CD-1 mice by gavage at dosages 20, 75, and 150 mg/kg/day in males and at dosages of 20, 100, and 300 mg/kg/day in females. No impact upon tumor incidence was observed in male and female mice at systemic exposures approximately 4.2 and 8.3 times that observed in humans, respectively.

Doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with mammalian cells (CHO/HGPRT forward mutation assay) or in an in vivo micronucleus assay conducted in CD-1 mice. However, data from an in vitro mammalian chromosomal aberration assay conducted with CHO cells suggest that doxycycline is a weak clastogen. Oral administration of doxycycline to male and female Sprague-Dawley rats adversely affected fertility and reproductive performance, as evidenced by increased time for mating to occur, reduced sperm motility, velocity, and concentration, abnormal sperm morphology, and increased pre-and post-implantation losses. Doxycycline induced reproductive toxicity at all dosages that were examined in this study, as even the lowest dosage tested (50 mg/kg/day) induced a statistically significant reduction in sperm velocity. Note that 50 mg/kg/day is approximately 3.6 times the amount of doxycycline contained in the recommended daily dose of Doxycycline when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats when administered at sufficient dosage, the effect of Doxycycline on human fertility is unknown.

14 CLINICAL STUDIES

The safety and efficacy of Doxycycline 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 Doxycycline from the two trials) with rosacea (10 to 40 papules and pustules and two or fewer nodules). Mean baseline lesion counts were 20 and 21 for Doxycycline and placebo subject groups respectively. 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 trials.

At Week 16, subjects in the Doxycycline 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 Doxycycline versus Placebo
*
Investigator’s Global Assessment
Study 1 Study 2
Doxycycline Placebo Doxycycline Placebo
40 mgN=127 N=124 40 mgN=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%)

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Doxycycline (beige opaque capsule imprinted with “GLD 40”) containing doxycycline, USP in an amount equivalent to 40 mg of anhydrous doxycycline.

Bottle of 30 (NDC 68308-668-30).

Storage:

All products are to be stored at controlled room temperatures of 59°F — 86°F (15°C — 30°C) and dispensed in tight, light-resistant containers (USP).

Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information)

Patients taking Doxycycline Capsules 40 mg should receive the following information and instructions:

  • Advise pregnant women that doxycycline, like other tetracycline-class drugs, may cause permanent discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy [see Warnings and Precautions (5.1 and 5.2) and Use in Specific Populations (8.1) ].
  • Advise women not to breastfeed during treatment with Doxycycline and for 5 days after the last dose [see Use in Specific Populations (8.2) ].
  • Advise patients that use of tetracycline class drugs orally during tooth development (infancy and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown).
  • Advise patients that use of doxycycline, like other tetracycline-class drugs, may cause inhibition of bone growth when administered during infancy and childhood.
  • Advise patients that pseudomembranous colitis can occur with doxycycline therapy. If patients develop watery or bloody stools, they should seek medical attention.
  • Advise patients that pseudotumor cerebri can occur with doxycycline therapy. If patients experience headache or blurred vision they should seek medical attention.
  • Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including doxycycline. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using doxycycline. If patients need to be outdoors while using doxycycline, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Treatment should be discontinued at the first evidence of sunburn.
  • Autoimmune syndromes, including drug-induced lupus-like syndrome, autoimmune hepatitis, vasculitis and serum sickness have been observed with tetracycline-class drugs, including doxycycline. Symptoms may be manifested by arthralgia, fever, rash and malaise. Patients who experience such symptoms should be cautioned to stop the drug immediately and seek medical help.
  • Counsel patients about discoloration of skin, scars, teeth or gums that can arise from doxycycline therapy.
  • Advise patients to take Doxycycline exactly as directed. Increasing doses beyond 40 mg every morning may increase the likelihood that bacteria will develop resistance and will not be treatable by other antibacterial drugs in the future.

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