warnings and cautions
5 WARNINGS AND PRECAUTIONS 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). ( 5.1 ) Clostridioides difficile -associated diarrhea (CDAD) has been reported: Evaluate patients if diarrhea occurs. ( 5.2 ) Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Limit sun exposure. ( 5.3 ) Overgrowth of non-susceptible organisms, including fungi, may occur. If such infections occur, discontinue use and institute appropriate therapy. ( 5.4 ) 5.1 Tooth Development 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 it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use DORYX in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. 5.2 Clostridioides difficile -Associated Diarrhea Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including DORYX Tablets, and may range in severity from mild diarrhea 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 antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C . difficile , and surgical evaluation should be instituted as clinically indicated. 5.3 Photosensitivity 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. 5.4 Potential for Microbial Overgrowth DORYX may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibacterial should be discontinued and appropriate therapy instituted. 5.5 Severe Skin Reactions Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline. 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 (6) ] . If severe skin reactions occur discontinue DORYX, immediately and institute appropriate therapy. 5.6 Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including DORYX. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Avoid concomitant use of isotretinoin and DORYX because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. 5.7 Skeletal Development All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every six 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 have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. 5.8 Antianabolic Action The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. 5.9 Malaria Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains. Doxycycline does not suppress P. falciparum's sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas. 5.10 Development of Drug-Resistant Bacteria Prescribing DORYX in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 5.11 Laboratory Monitoring for Long-Term Therapy In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed.