FDA label e7232ef3-07b9-4416-b235-c697d2f309fa

5 WARNINGS AND PRECAUTIONS The use of Doxycycline 40 mg during tooth development (last half of pregnancy, infancy and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). (5.1) If pseudomembranous colitis occurs, discontinue Doxycycline 40 mg. (5.2) If renal impairment exists, Doxycycline 40 mg doses may need to be adjusted to avoid excessive systemic accumulations of the drug and possible liver injury. (5.3) Photosensitivity can occur with Doxycycline 40 mg; Patients should minimize or avoid exposure to natural or artificial sunlight. (5.4) Tetracyclines have been associated with the development of autoimmune syndromes; if symptoms develop, discontinue Doxycycline 40 mg immediately. (5.5) Doxycycline 40 mg may cause pseudotumor cerebri (benign intracranial hypertension). Discontinue Doxycycline 40 mg if symptoms occur. (5.7) Bacterial resistance to tetracyclines may develop in patients using Doxycycline 40 mg. It should only be used as indicated. (5.8) 5.1 Teratogenic Effects Doxycycline 40 mg should not be used during pregnancy. Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm when administered to a pregnant woman. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be informed of the potential hazard to the fetus and treatment stopped immediately. The use of drugs of the tetracycline-class during tooth development (last half of pregnancy, infancy, and childhood up 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 drug but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline drugs, therefore, should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted in animals treated early in pregnancy. 5.2 Pseudomembranous Colitis Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including doxycycline, and may range in severity from mild to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.3 Metabolic Effects The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy is prolonged, serum level determinations of the drug may be advisable. 5.4 Photosensitivity Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Although this was not observed during the duration of the clinical studies with Doxycycline 40 mg, patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using Doxycycline 40 mg. If patients need to be outdoors while using Doxycycline 40 mg, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. 5.5 Autoimmune Syndromes Tetracyclines have been associated with the development of autoimmune syndromes. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use of all tetracycline-class drugs should be discontinued immediately. 5.6 Tissue Hyperpigmentation Tetracycline-class drugs are known to cause hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has been reported to occur independently of time or amount of drug administration, whereas other pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as over sites of scars or injury. 5.7 Pseudotumor cerebri Pseudotumor cerebri (benign intracranial hypertension) in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. While both of these conditions and related symptoms usually resolve after discontinuation of the tetracycline, the possibility for permanent sequelae exists. Patients should be questioned for visual disturbances prior to initiation of treatment with tetracyclines and should be routinely checked for papilledema while on treatment. 5.8 Development of Drug Resistant Bacteria Bacterial resistance to tetracyclines may develop in patients using Doxycycline 40 mg. Because of the potential for drug-resistant bacteria to develop during the use of Doxycycline 40 mg, it should only be used as indicated. 5.9 Superinfection As with other antibiotic preparations, use of Doxycycline 40 mg may result in overgrowth of non-susceptible microorganisms, including fungi. If superinfection occurs, Doxycycline 40 mg should be discontinued and appropriate therapy instituted. Although not observed in clinical trials with Doxycycline 40 mg, the use of tetracyclines may increase the incidence of vaginal candidiasis. Doxycycline 40 mg should be used with caution in patients with a history of or predisposition to Candida overgrowth. 5.10 Laboratory Monitoring Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic studies should be performed. Appropriate tests for auto- immune syndromes should be performed as indicated.

6 ADVERSE REACTIONS Some of the most common adverse reactions (incidence >2% and more common than with placebo) are nasopharyngitis, sinusitis, diarrhea, hypertension and aspartate aminotransferase increase. (6) To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials of Doxycycline 40 mg: In controlled clinical trials of adult subjects with mild to moderate rosacea, 537 subjects received Doxycycline 40 mg or placebo over a 16-week period. The following table summarizes selected adverse reactions that occurred in the clinical trials at a rate of ≥ 1% for the active arm: Note: Percentages 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 at higher, antimicrobial doses: 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 the patients experiencing esophagitis and/or esophageal ulceration took their medication immediately before lying down [ see Dosage and Administration (2) ] . Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above [ see Warnings and Precautions (5.4) ] . Renal toxicity: Rise in BUN has been reported and is apparently dose- related [ see Warnings and Precautions (5.3) ] . 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. table-1 table-1b 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of Doxycycline 40 mg Nervous system: Pseudotumor cerebri (benign intracranial hypertension), headache.