warnings and cautions
5 WARNINGS AND PRECAUTIONS The use of LYMEPAK 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) and enamel hypoplasia. ( 5.1 , 8.1 , 8.4 ) The use of LYMEPAK during the second and third-trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth ( 5.2 , 8.1 , 8.4 ). Clostridium difficile -associated diarrhea: Evaluate patients if diarrhea occurs. ( 5.3 ) Photosensitivity manifested by an exaggerated sunburn reaction has been observed. Limit sun exposure. ( 5.4 ) Severe skin reactions have been reported. Discontinue use and institute appropriate therapy ( 5.5 ). Jarisch-Herxheimer reaction may occur in patients with Lyme disease after the initiation of treatment. Inform patients and monitor if a severe reaction occurs. Antipyretics may reduce the severity and the duration of the reaction ( 5.6 ). Intracranial hypertension has been reported. Avoid concomitant use with isotretinoin Evaluate and monitor visual function if symptoms occur ( 5.7 ) 5.1 Tooth Discoloration and Enamel Hypoplasia The use of LYMEPAK 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 drugs of the tetracycline class, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with drugs of the tetracycline class. Advise the patient of the potential risk to the fetus if LYMEPAK is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1 , 8.4) ]. 5.2 Inhibition of Bone Growth The use of LYMEPAK during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. 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 tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if LYMEPAK is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1 , 8.4) ] . 5.3 Clostridium Difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including LYMEPAK, 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 the use of antibacterial drugs. 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 use of antibacterial drugs 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. 5.4 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 LYMEPAK, and treatment should be discontinued at the first evidence of skin erythema. 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 [see Adverse Reactions (6) ] . If severe skin reactions occur, discontinue LYMEPAK immediately and initiate appropriate therapy. 5.6 Jarisch-Herxheimer Reaction The Jarisch-Herxheimer reaction is a self-limiting systemic reaction that has been reported after the initiation of doxycycline therapy in up to 30% of patients with early Lyme disease. The reaction begins one to two hours after initiation of therapy and disappears within 12 to 24 hours. It is characterized by fever, chills, myalgias, headache, exacerbation of cutaneous lesions, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension. The pathogenesis of the Jarisch-Herxheimer reaction is unknown, but thought to be due to the release of spirochetal heat-stable pyrogen. Advise the patient of this reaction before starting LYMEPAK. Administer fluids and antipyretics to alleviate symptoms and duration of the reaction if severe. 5.7 Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline. 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. Concomitant use of isotretinoin and LYMEPAK should be avoided because isotretinoin is also known to cause pseudotumor cerebri. Although IH may improve 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. 5.8 Antianabolic Action The antianabolic action of the tetracyclines, including LYMEPAK may cause an increase in blood urea nitrogen (BUN). Studies to date indicate that this does not occur with the use of doxycycline in patients with renal impairment. 5.9 Development of Drug Resistant Bacteria Prescribing LYMEPAK 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 5.10 Potential for Microbial Overgrowth As with other antibacterial drugs, use of LYMEPAK may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue doxycycline and institute appropriate therapy.