Doxycycline Hyclate 20 mg Tablet, Film Coated, 100-count — NDC 62332-352-31 (Billing 62332-0352-31)

WARNINGS THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY AND CHILDHOOD TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY-BROWN). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported.

TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP AND IN PREGNANT OR NURSING MOTHERS UNLESS THE POTENTIAL BENEFITS MAY BE ACCEPTABLE DESPITE THE POTENTIAL RISKS. All tetracyclines form a stable calcium complex in any bone forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracyclines in doses of 25 mg/kg every 6 hours.

This reaction was shown to be reversible when the drug was discontinued. Doxycycline can cause fetal harm when administered to a pregnant woman. Results of animal studies indicate that tetracyclines cross the placenta, are 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.

Fixed drug eruptions have occurred with doxycycline and have been associated with worsening severity upon subsequent administrations, including generalized bullous fixed drug eruption (see ADVERSE REACTIONS for Tetracyclines). If severe skin reactions occur, discontinue doxycycline hyclate tablets immediately and institute appropriate therapy. Adverse Reactions for Tetracyclines: Skin: Maculopapular and erythematous rashes, and fixed drug eruption have been reported.

Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above (see WARNINGS section).

ADVERSE REACTIONS Adverse Reactions in Clinical Trials of a bioequivalent form of doxycycline hyclate capsules In clinical trials of adult patients with periodontal disease 213 patients received 20 mg BID over a 9 to 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: Incidence (%) of Adverse Reactions in Clinical Trials of Doxycycline Hyclate Capsules, 20 mg (Bioequivalent to Doxycycline Hyclate Tablets, 20 mg) vs.

Placebo Adverse Reaction Doxycycline Hyclate Capsules 20 mg BID (n=213) Placebo (n=215) Headache 55 (26%) 56 (26%) Common Cold 47 (22%) 46 (21%) Flu Symptoms 24 (11%) 40 (19%) Tooth Ache 14 (7%) 28 (13%) Periodontal Abscess 8 (4%) 21 (10%) Tooth Disorder 13 (6%) 19 (9%) Nausea 17 (8%) 12 (6%) Sinusitis 7 (3%) 18 (8%) Injury 11 (5%) 18 (8%) Dyspepsia 13 (6%) 5 (2%) Sore Throat 11 (5%) 13 (6%) Joint Pain 12 (6%) 8 (4%) Diarrhea 12 (6%) 8 (4%) Sinus 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. Psychiatric: Depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination. To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions 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.

Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

PRECAUTIONS While no overgrowth by opportunistic microorganisms such as yeast were noted during clinical studies, as with other antimicrobials, doxycycline hyclate tablets therapy may result in overgrowth of non-susceptible microorganisms including fungi. The use of tetracyclines may increase the incidence of vaginal candidiasis. Doxycycline hyclate tablets should be used with caution in patients with a history or predisposition to oral candidiasis.

The safety and effectiveness of doxycycline hyclate tablets has not been established for the treatment of periodontitis in patients with coexistant oral candidiasis. If superinfection is suspected, appropriate measures should be taken. Laboratory Tests In long term therapy, periodic laboratory evaluations of organ systems, including hematopoietic, renal, and hepatic studies should be performed.

Drug Interactions 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.

Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test. Carcinogenesis, Mutagenesis, Impairment of Fertility 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 tablets (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 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 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 hycl… [Excerpted — this section continues on DailyMed.]