Zilxi

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 ]. 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).

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 ].

Pediatric Use

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

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.

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).

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 and Nonclinical Toxicology ].

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.

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 ].

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Drug/Laboratory Test Interactions

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

Mechanism of Action

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

Pharmacodynamics

The pharmacodynamics of ZILXI for the treatment of inflammatory lesions of rosacea are unknown.

Pharmacokinetics

In a pharmacokinetic study, male and female subjects 18 years of age or older with inflammatory lesions of rosacea (N=20) applied approximately 2 grams of ZILXI topically to the face once daily for 14 days.

The mean ± SD maximum plasma concentration (Cmax) and area under the concentration time curve from 0 to 24 hours post dose (AUC0-24h) for minocycline on Day 1 were 1.3 ± 0.9 ng/mL and 22.5 ± 16.2 h·ng/mL, respectively. After daily application of ZILXI in subjects with inflammatory lesions of rosacea for 14 days, steady-state was reached by Day 1 and systemic accumulation of minocycline was not evident.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a carcinogenicity study in which minocycline hydrochloride was orally administered to male and female rats once daily for up to 104 weeks at dosages up to 200 mg/kg/day, minocycline hydrochloride was associated in both sexes with follicular cell tumors of the thyroid gland, including increased incidences of adenomas, carcinomas and the combined incidence of adenomas and carcinomas in males, and adenomas and the combined incidence of adenomas and carcinomas in females. In a carcinogenicity study in which minocycline hydrochloride was orally administered to male and female mice once daily for up to 104 weeks at dosages up to 150 mg/kg/day, exposure to minocycline hydrochloride did not result in a significantly increased incidence of neoplasms in either males or females.

Minocycline was not mutagenic in vitro in a bacterial reverse mutation assay (Ames test) or CHO/HGPRT mammalian cell assay in the presence or absence of metabolic activation. Minocycline was not clastogenic in vitro using human peripheral blood lymphocytes or in vivo in a mouse micronucleus test.

Male and female reproductive performance in rats was unaffected by oral doses of minocycline of up to 300 mg/kg/day (27,500 times the systemic exposure at the MRHD based on AUC comparison). However, oral administration of 100 or 300 mg/kg/day of minocycline to male rats (10,000 or 27,500 times, respectively, the systemic exposure at the MRHD based on AUC comparison), adversely affected spermatogenesis.

Effects observed at 300 mg/kg/day of oral minocycline included a reduced number of sperm cells per gram of epididymis, an apparent reduction in the percentage of sperm that were motile, and (at 100 and 300 mg/kg/day) increased numbers of morphologically abnormal sperm cells. Morphological abnormalities observed in sperm samples included absent heads, misshapen heads, and abnormal flagella.