DOXYCYCLINE HYCLATE TABLETS USP

Doxycycline has been shown to inhibit collagenase activity in vitro. ¹Additional studies have shown that doxycycline reduces the elevated collagenase activity in the gingival crevicular fluid of patients with adult periodontitis. ^2,3The clinical significance of these findings is not known.

Doxycycline is a member of the tetracycline class of antibiotics. The dosage of doxycycline achieved with this product during administration is well below the concentration required to inhibit microorganisms commonly associated with adult periodontitis. Clinical studies with this product demonstrated no effect on total anaerobic and facultative bacteria in plaque samples from patients administered this dose regimen for 9 to 18 months. This product should notbe used for reducing the numbers of or eliminating those microorganisms associated with periodontitis.

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: www.fda.gov/STIC.

The pharmacokinetics of doxycycline following oral administration of doxycycline hyclate were investigated in 4 volunteer studies involving 107 adults. Additionally, doxycycline pharmacokinetics have been characterized in numerous scientific publications. ⁴Pharmacokinetic parameters for doxycycline hyclate following single oral doses and at steady-state in healthy subjects are presented as follows:

In a randomized, multi-centered, double-blind, 9-month Phase 3 study involving 190 adult patients with periodontal disease [at least two probing sites per quadrant of between 5 and 9 mm pocket depth (PD) and attachment level (ALv)], the effects of oral administration of 20 mg twice a day of doxycycline hyclate (using a bioequivalent capsule formulation) plus scaling and root planing (SRP) were compared to placebo control plus SRP. Both treatment groups were administered a course of scaling and root planing in 2 quadrants at Baseline. Measurements of ALv, PD and bleeding-on-probing (BOP) were obtained at Baseline, 3, 6, and 9 months from each site about each tooth in the two quadrants that received SRP using the UNC-15 manual probe. Each tooth site was categorized into one of three strata based on Baseline PD: 0–3 mm (no disease), 4–6 mm (mild/moderate disease), ≥ 7 mm (severe disease). For each stratum and treatment group, the following were calculated at month 3, 6, and 9: mean change in ALv from baseline, mean change in PD from baseline, mean percentage of tooth sites per patient exhibiting attachment loss of ≥ 2 mm from baseline, and percentage of tooth sites with bleeding on probing. The results are summarized in the following table.

In long term therapy, periodic laboratory evaluations of organ systems, including hematopoietic, renal, and hepatic studies should be performed.

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

Since bacterial antibiotics, such as the tetracycline class of antibiotics, may interfere with the bactericidal action of members of the β-lactam (e.g., penicillin) class of antibiotics, it is not advisable to administer these antibiotics concomitantly.

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations, and by bismuth subsalicylate.

Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.

Concurrent use of tetracyclines may render oral contraceptives less effective.

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

Doxycycline hyclate 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 nine times that observed in female humans that used doxycycline hyclate (exposure comparison based upon AUC values). No impact upon tumor incidence was observed in male rats at 200 mg/kg/day, or in either gender at the other dosages studied. Evidence of oncogenic activity was obtained in studies with related compounds, i.e., oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors).

Doxycycline hyclate demonstrated no potential to cause genetic toxicity in an in vitropoint mutation study with mammalian cells (CHO/HGPRT forward mutation assay) or in an in vivomicronucleus assay conducted in CD-1 mice. However, data from an in vitroassay with CHO cells for potential to cause chromosomal aberrations suggest that doxycycline hyclate is a weak clastogen.

Oral administration of doxycycline hyclate 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 hyclate 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 10 times the amount of doxycycline hyclate contained in the recommended daily dose of doxycycline hyclate for a 60 kg human when compared on the basis of body surface area estimates (mg/m ²). Although doxycycline impairs the fertility of rats when administered at sufficient dosage, the effect of doxycycline hyclate on human fertility is unknown.

Teratogenic Effects:(See WARNINGSSection).

Results from animal studies indicate that doxycycline crosses the placenta and is found in fetal tissues.

Nonteratogenic Effects: (See WARNINGSSection).

The effect of tetracyclines on labor and delivery is unknown.

Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from doxycycline, the use of doxycycline hyclate in nursing mothers is contraindicated. (See WARNINGSSection).

The use of doxycycline hyclate tablets in infancy and childhood is contraindicated. (See WARNINGSsection).

In clinical trials of adult patients with periodontal disease 213 patients received 20 mg BID over a 9 – 12 month period. The most frequent adverse reactions occurring in studies involving treatment with a bioequivalent form of doxycycline hyclate capsules or placebo are listed below:

The following adverse reactions have been observed in patients receiving tetracyclines:

Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity has been reported rarely. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATIONSection).

Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and fixed drug eruption have been reported. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See WARNINGSSection).

Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNINGSSection).

Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus.

Psychiatric: Depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination

Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature]

DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.