found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). evidence of embryotoxicity has also been noted in animals treated early in pregnancy. if any tetracyclines are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. the catabolic action of the tetracyclines may cause an increase in bun. previous studies have not observed an increase in bun with the use of doxycycline in patients with impaired renal function. photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.

congestion 11 (5%) 11 (5%) coughing 9 (4%) 11 (5%) sinus headache 8 (4%) 8 (4%) rash 8 (4%) 6 (3%) back pain 7 (3%) 8 (4%) back ache 4 (2%) 9 (4%) menstrual cramp 9 (4%) 5 (2%) acid indigestion 8 (4%) 7 (3%) pain 8 (4%) 5 (2%) infection 4 (2%) 6 (3%) gum pain 1(<1%) 6 (3%) bronchitis 7 (3%) 5 (2%) muscle pain 2 (1%) 6 (3%) note: percentages are based on total number of study participants in each treatment group. adverse reactions for tetracyclines 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 administration section). skin: maculopapular and erythematous rashes. exfoliative dermatitis has been reported but is uncommon. photosensitivity is discussed above. (see warnings section). renal toxicity: rise in bun has been reported and is apparently dose related. (see warnings section). hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. blood: hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.

gimen for 9 to 18 months. this product should not be used for reducing the numbers of or eliminating those microorganisms associated with periodontitis. pharmacokinetics the pharmacokinetics of doxycycline following oral administration of doxycycline hyclate tablets were investigated in 4 volunteer studies involving 107 adults. additionally, doxycycline pharmacokinetics have been characterized in numerous scientific publications. 4 pharmacokinetic parameters for doxycycline hyclate tablets following single oral doses and at steady-state in healthy subjects are presented as follows: pharmacokinetic parameters for doxycycline hyclate tablets n c max * (ng/ml) t max † (hr) cl/f * (l/hr) t 1/2 * (hr) single dose 20 mg (tablet) 20 362 ± 101 1.4 (1 to 2.5) 3.85 ± 1.3 18.1 ± 4.85 steady-state 20 mg bid ‡ 30 790 ± 285 2 (0.98 to 12) 3.76 ± 1.06 not determined * mean ± sd † mean and range ‡ steady-state data were obtained from normal volunteers administered a bioequivalent formulation. absorption doxycycline is well absorbed after oral administration. in a single-dose study, concomitant administration of doxycycline hyclate tablets with a 1000 calorie, high-fat, high-protein meal which included dairy products, in healthy volunteers, resulted in a decrease in the rate and extent of absorption and delay in the time to maximum concentrations. distribution doxycycline is greater than 90% bound to plasma proteins. its apparent volume of distribution is variously reported as between 52.6 and 134 l. 4,6 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 variously reported that between 29% and 55.4% of an administered dose can be accounted for in the urine by 72 hours. 5,6 half-life averaged 18 hours in subjects receiving a single 20 mg doxycycline dose. special populations geriatric doxycycline pharmacokinetics have not been evaluated in geriatric patients. pediatric doxycycline pharmacokinetics have not been evaluated in pediatric patients (see warnings section). gender doxycycline pharmacokinetics were compared in 9 men and 11 women under fed and fasted conditions. while female subjects had a higher rate (cmax) and extent of absorption (auc), these differences are thought to be due to differences in body weight/lean body mass. differences in other pharmacokinetic parameters were not significant. 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 half-life of doxycycline. hepatic insufficiency doxycycline pharmacokinetics have not been evaluated in patients with hepatic insufficiency. drug interactions (see precautions section) clinical study 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 to 3 mm (no disease), 4 to 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. clinical results at nine months of doxycycline hyclate capsules, 20 mg, as an adjunct to srp (bioequivalent to doxycycline hyclate tablets, 20 mg) parameter baseline pocket depth ≥ 7 mm 0 to 3 mm 4 to 6 mm number of patients (doxycycline hyclate tablets 20mg bid) 90 90 79 number of patients (placebo) 93 93 78 mean gain (sd * ) in alv † doxycycline hyclate tablets 20 mg bid 0.25 (0.29) mm 1.03 (0.47) mm ‡ 1.55 (1.16) mm ‡ placebo 0.2 (0.29) mm 0.86 (0.48) mm 1.17 (1.15) mm mean decrease (sd * ) in pd § doxycycline hyclate tablets 20 mg bid 0.16 (0.19) mm ¶ 0.95 (0.47) mm ¶ 1.68 (1.07) mm ¶ placebo 0.05 (0.19) mm 0.69 (0.48) mm 1.2 (1.06) mm % of sites (sd * ) with loss of alv † ≥ 2 mm doxycycline hyclate tablets 20 mg bid 1.9 (4.2)% 1.3 (4.5)% 0.3 (9.4)% ‡ placebo 2.2 (4.1)% 2.4 (4.4)% 3.6 (9.4)% % of sites (sd * ) with bop # doxycycline hyclate tablets 20 mg bid 39 (19)% ¶ 64 (18)% ‡ 75 (29)% placebo 46 (19)% 70 (18)% 80 (29)% * sd=standard deviation † alv=clinical attachment level ‡ p<0.05 vs. the placebo control group. § pd=pocket depth ¶ p<0.01 vs. the placebo control group. # bop=bleeding on probing

mutation assay) or in an in vivo micronucleus assay conducted in cd-1 mice. however, data from an in vitro assay 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 tablets 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 tablets on human fertility is unknown.