ZILXI

• The propellant in ZILXI is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. ( 5.1 ) • The use of tetracycline-class of drugs orally during the second and third trimesters of pregnancy, infancy and childhood up to the age of 8 years may cause permanent discoloration of the teeth (yellow-gray-brown) and reversible inhibition of bone growth. ( 5.2 , 5.3 , 5.4 , 8.4 ) • If Clostridioides difficile associated diarrhea occurs, discontinue ZILXI. ( 5.5 ) • If liver injury is suspected, discontinue ZILXI. ( 5.6 ) • If renal impairment exists, oral minocycline doses may need to be adjusted to avoid excessive systemic accumulations of the drug and possible liver toxicity. ( 5.7 ) • Oral minocycline may cause central nervous system side effects including lightheadedness, dizziness, or vertigo. ( 5.8 ) • Oral minocycline may cause intracranial hypertension in adults and adolescents. Discontinue ZILXI if symptoms occur. ( 5.9 ) • Oral minocycline has been associated with autoimmune syndromes; discontinue ZILXI immediately if symptoms occur. ( 5.10 ) • Photosensitivity can occur with oral tetracycline. Patients should minimize or avoid exposure to natural or artificial sunlight. ( 5.11 ) • Oral minocycline has been associated with anaphylaxis, serious skin reactions, erythema multiforme, and DRESS syndrome. Discontinue ZILXI immediately if symptoms occur. ( 5.12 ) 5.1 Flammability The propellant in ZILXI is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C). 5.2 Teratogenic Effects Minocycline, like other tetracycline-class drugs, may inhibit bone growth when administered orally during pregnancy. Based on animal data, when administered orally, tetracyclines cross the placenta, are found in fetal tissues, and can cause skeletal malformation and retardation of skeletal development on the developing fetus [see Use in Specific Populations ( 8.1 ) and Nonclinical Toxicology ( 13.1 )] . 5.3 Tooth Discoloration The use of tetracycline class drugs orally during tooth development (second and third trimesters 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 oral use of the tetracycline but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with oral tetracycline drugs. Use of tetracycline drugs is not recommended during tooth development. 5.4 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 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 oral 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 orally early in pregnancy [see Use in Specific Populations ( 8.1 )]. 5.5 Clostridioides difficile Associated Diarrhea Clostridioides difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including oral minocycline, 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 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, 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. 5.6 Hepatotoxicity Post-marketing cases of serious liver injury, including irreversible drug-induced hepatitis and fulminant hepatic failure (sometimes fatal) have been reported with oral minocycline use. 5.7 Metabolic Effects The anti-anabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). In patients with significantly impaired function, higher serum levels of tetracycline-class drugs may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, recommended oral or parenteral doses may lead to excessive systemic accumulations of the drug and possible liver toxicity. Under such conditions, adjust the dose downward, and if therapy is prolonged, serum level determinations of the drug may be advisable. 5.8 Central Nervous System Effects Central nervous system side effects including light-headedness, dizziness or vertigo have been reported with oral minocycline therapy. Patients who experience these symptoms should be cautioned about driving vehicles or using hazardous machinery while on minocycline therapy. These symptoms may disappear during therapy and may disappear when the drug is discontinued. 5.9 Intracranial Hypertension Intracranial hypertension has been associated with the use of oral tetracycline-class drugs. Clinical manifestations of intracranial hypertension 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 a greater risk for developing intracranial hypertension. Patients should be questioned for visual disturbances prior to initiation of treatment with tetracyclines. Concomitant use of isotretinoin and tetracycline should be avoided because isotretinoin, a systemic retinoid, is also known to cause intracranial hypertension. Although intracranial hypertension typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Because intracranial pressure can remain elevated for weeks after drug cessation, patients should be monitored until they stabilize. 5.10 Autoimmune Syndromes Tetracyclines have been associated with the development of autoimmune syndromes. The long-term use of oral minocycline has been associated with drug-induced lupus-like syndrome, autoimmune hepatitis and vasculitis. Sporadic cases of serum sickness have presented shortly after oral minocycline use. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, immediately discontinue the use of all tetracycline-class drugs, including ZILXI. 5.11 Photosensitivity Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking oral tetracyclines; this reaction has been reported less frequently with minocycline. Although ZILXI did not induce phototoxicity or photoallergic responses in human dermal safety studies, patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using minocycline. If patients need to be outdoors while using ZILXI, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Advise patients to discontinue treatment with ZILXI at the first evidence of sunburn. 5.12 Serious Skin/Hypersensitivity Reaction Cases of anaphylaxis, serious skin reactions (e.g. Stevens Johnson syndrome), erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported postmarketing with oral minocycline use. DRESS syndrome consists of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following visceral complications such as: hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis. Fever and lymphadenopathy may be present. In some cases, death has been reported with oral minocycline use. If this syndrome is recognized, discontinue ZILXI immediately. 5.13 Tissue Hyperpigmentation Oral tetracyclines 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 tissue pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as pigmentation over sites of scars or injury. 5.14 Development of Drug-Resistant Bacteria ZILXI has not been evaluated in the treatment of infections. Bacterial resistance to the tetracyclines may develop in patients using ZILXI, therefore, the susceptibility of bacteria associated with infection should be considered in selecting antimicrobial therapy. Because of the potential for drug-resistant bacteria to develop during the use of ZILXI, it should be used only as indicated. 5.15 Superinfection/Potential for Microbial Overgrowth Use of ZILXI may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, discontinue ZILXI and institute appropriate therapy.