Minocycline

ZILXI is indicated for the treatment of inflammatory lesions of rosacea in adults [see Clinical Studies ( 14 )] . Limitations of Use This formulation of minocycline has not been evaluated in the treatment of infections. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, ZILXI should be used only as indicated [see Warnings and Precautions ( 5.14 )] . ZILXI is a tetracycline-class drug indicated for the treatment of inflammatory lesions of rosacea in adults. ( 1 ) Limitations of Use This formulation of minocycline has not been evaluated in the treatment of infections. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, ZILXI should be used only as indicated ( 1 ).

Topical foam, 1.5%. Each gram of ZILXI contains 15 mg of minocycline equivalent to 16 mg of minocycline hydrochloride and is supplied as a yellow suspension in a pressurized aluminum aerosol container (can). Foam, 1.5%. ( 3 )

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines or any other ingredients in ZILXI. This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines or any of the ingredients in ZILXI. ( 4 )

• 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. […]

The most commonly observed adverse reaction (incidence ≥1%) is diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Journey Medical Corporation at 1-855-531-1859 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. In three (two Phase 3 and one Phase 2) multicenter, randomized, double-blind, vehicle-controlled trials, adult subjects applied ZILXI or vehicle once daily for 12 weeks. A total of 1,087 subjects were treated with ZILXI and 591 with vehicle. The majority of subjects were White (97%) and female (70%). Approximately 67% were non-Hispanic/Latino. The mean age was 50.0 years and ages ranged from 18 to 86 years. The most common adverse reaction reported by ≥1% of subjects treated with ZILXI and more frequently than in subjects treated with vehicle was diarrhea (1% vs. 0%), respectively. During the two Phase 3 trials, local tolerability evaluations were conducted at each study visit by assessment of erythema, telangiectasia, burning/stinging, flushing/blushing, dryness, itching, peeling and hyperpigmentation. Table 1 presents local tolerance assessments by incidence rate (%) and severity grade. Subjects treated with ZILXI had improved local tolerability signs and symptoms at Week 12 when compared with corresponding baseline values. These occurred at a similar frequency and severity as subjects treated with the vehicle component of ZILXI. Table 1: Facial Cutaneous Tolerability Assessment *Hyperpigmentation was most frequently assessed as characteristic of inflammatory and post-inflammatory changes associated with inflammatory lesions of rosacea. ** Of 1,008 subjects, 897 had local tolerability assessments at Week 12. ZILXI, (%) (N=1,008**) Symptom/Severity Mild Moderate Severe Erythema 36.2 18.3

0.7 Telangiectasia 61.0 18.8 0 Burning/Stinging 13.3 2.8 0 Flushing/Blushing 39.0 9.6

0.9 Dryness 23.9 4.0

0.1 Itching 20.0 3.3 0 Skin Peeling 16.1 1.9

0.1 Hyperpigmentation* 22.5 2.8 0 In a 40-week open-label extension safety study of ZILXI (for a total of up to 52 weeks of treatment) [ NCT03276936 ], frequency and severity of local tolerability signs and symptoms at Week 52 were comparable to those reported at Week 12.

• Patients on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. ( 7.1 )
• Penicillin: avoid coadministration. ( 7.2 )

7.1 Anticoagulants Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

7.2 Penicillin Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin.

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

• Minocycline like other tetracycline-class drugs can cause fetal harm when administered orally to a pregnant woman. ( 5.2 , 5.3 , 5.4 , 8.1 )
• The use of drugs of the tetracycline-class orally during tooth development may cause permanent discoloration of teeth. ( 5.3 , 8.1 , 8.2 , 8.4 )
• Lactation: Breastfeeding not recommended. ( 8.2 )

8.1 Pregnancy Risk Summary Available data with ZILXI use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Systemic absorption of ZILXI in humans is low following once daily topical administration of ZILXI under maximal clinical use conditions [see Clinical Pharmacology ( 12.3 )] . Because of low systemic exposure, it is not expected that maternal use of ZILXI will result in significant fetal exposure to the drug. Tetracycline-class drugs may cause permanent discoloration of teeth and reversible inhibition of bone growth when administered orally during pregnancy [see Warnings and Precautions 5.2 , 5.3 , 5.4 ) . Animal reproduction studies were not conducted with ZILXI. In animal reproduction studies, oral administration of minocycline to pregnant rats and rabbits during organogenesis induced skeletal malformations in fetuses at systemic exposures of 2,000 and 1,300 times, respectively, the maximum recommended human dose (MRHD based on AUC comparison) of ZILXI ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Results of animal studies with oral administration indicate that tetracyclines cross the placenta, are found in fetal tissues, and can cause retardation of skeletal development of the developing fetus. Minocycline induced skeletal malformations (bent limb bones) in fetuses when orally administered to pregnant rats and rabbits during the period of organogenesis at doses of 30 mg/kg/day and 100 mg/kg/day, respectively, (2,000 times and 1,300 times, respectively, the systemic exposure at the MRHD based on AUC comparison). Reduced mean fetal body weight was observed when minocycline was orally administered to pregnant rats during the period of organogenesis at a dose of 10 mg/kg/day (680 times the systemic exposure at the MRHD based on AUC comparison). Minocycline was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation, at doses of 5, 10, or 50 mg/kg/day. In this study, body weight gain was significantly reduced in pregnant females that received 50 mg/kg/day (1,700 times the systemic exposure at the MRHD based on AUC comparison). No effects of treatment on the duration of the gestation period or the number of live pups born per litter were observed. Gross external anomalies observed in F1 pups (offspring of animals that received minocycline) included reduced body size, improperly rotated forelimbs, and reduced size of extremities. No effects were observed on the physical development, behavior, learning ability, or reproduction of F1 pups, and there was no effect on gross appearance of F2 pups (offspring of F1 animals).

8.2 Lactation Risk Summary Tetracycline-class drugs, including minocycline, are present in breast milk following oral administration. It is not known whether minocycline is present in human milk after topical administration to the nursing mother. There are no data on the effects of minocycline on milk production. Because of the potential for serious adverse reactions, advise patients that breastfeeding is not recommended during treatment with ZILXI [see Warnings and Precautions ( 5.2 )].

8.4 Pediatric Use The safety and effectiveness of ZILXI for the treatment of inflammatory lesions of rosacea have not been evaluated in pediatric patients.

8.5 Geriatric Use There were 278 subjects aged 65 or older in the clinical trials of ZILXI (16.6% of 1,678 subjects). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

The mechanism of action of ZILXI for the treatment of inflammatory lesions of rosacea is unknown.