5.1 Hypersensitivity Reaction and Serious Skin Reactions

Cases of anaphylaxis, serious skin reactions (e.g., Stevens-Johnson syndrome), erythema multiforme, and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported postmarketing with minocycline use in patients with acne. 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. If this syndrome is recognized, discontinue EMROSI immediately.

5.2 Tooth Discoloration and Enamel Hypoplasia

The use of tetracycline class drugs, including EMROSI 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). Permanent discoloration of the teeth is more common during long-term use of tetracycline-class drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use of EMROSI is not recommended during tooth development.

Advise the patient of the potential risk to the fetus if EMROSI is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)].

5.3 Inhibition of Bone Growth

The use of tetracycline-class drugs, including EMROSI, during the second and third trimesters of pregnancy, infancy, and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines, including EMROSI, 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.

Advise the patient of the potential risk to the fetus if EMROSI is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)].

5.4 Clostridioides difficile-Associated Diarrhea (Antibiotic-Associated Colitis)

Clostridium difficileassociated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including minocycline, and may range in severity from mild diarrhea to fatal colitis.

C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficilecause 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, discontinue EMROSI.

5.5 Hepatotoxicity

Postmarketing cases of serious liver injury, including irreversible drug-induced hepatitis and fulminant hepatic failure (sometimes fatal) have been reported with minocycline use in the treatment of acne. Discontinue EMROSI if liver injury is suspected.

5.6 Central Nervous System Effects

Central nervous system side effects including light-headedness, dizziness or vertigo have been reported with minocycline therapy. Caution patients who experience these symptoms about driving vehicles or using hazardous machinery while on EMROSI. These symptoms may disappear during therapy and usually rapidly disappear when the drug is discontinued.

5.7 Idiopathic Intracranial Hypertension

Idiopathic Intracranial hypertension has been associated with the use of tetracyclines. Clinical manifestations of idiopathic 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 idiopathic intracranial hypertension are at a greater risk for developing idiopathic intracranial hypertension. Avoid concomitant use of isotretinoin and EMROSI because isotretinoin, a systemic retinoid, is also known to cause idiopathic intracranial hypertension.

Permanent visual loss may exist, even after the medication is discontinued. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Because intracranial pressure can remain elevated for weeks after drug cessation, monitor patients until they stabilize.

5.8 Autoimmune Syndromes

Tetracyclines have been associated with the development of autoimmune syndromes. The long-term use of minocycline in the treatment of acne has been associated with drug-induced lupus-like syndrome, autoimmune hepatitis and vasculitis. Sporadic cases of serum sickness have presented shortly after minocycline use. Symptoms may be manifested by fever, rash, arthralgia, and malaise. Evaluate symptomatic patients. If symptoms occur, immediately discontinue EMROSI.

5.9 Metabolic Effects

The anti-anabolic action of the tetracyclines, including EMROSI, may cause an increase in blood urea nitrogen (BUN). In patients with significantly impaired renal function, higher serum levels of EMROSI may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, monitor serum levels of EMROSI during treatment, and discontinue EMROSI if necessary.

5.10 Photosensitivity

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including minocycline. Advise patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using EMROSI. Instruct patients to use sunscreen products and wear protective apparel (e.g., hat) when exposure to sun cannot be avoided.

5.11 Tissue Hyperpigmentation

Tetracycline-class antibiotics are known to cause hyperpigmentation. EMROSI 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 over sites of scars or injury.

5.12 Development of Drug-Resistant Bacteria

Bacterial resistance to the tetracyclines may develop in patients using EMROSI, Because of the potential for drug-resistant bacteria to develop during the use of EMROSI, use EMROSI only as indicated.

5.13 Superinfection

Use of EMROSI may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue EMROSI and institute appropriate therapy.

5.14 Laboratory Monitoring

Perform periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic studies.

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 two clinical trials, MVOR-1 and MVOR-2, a total of 638 adult subjects were analyzed under the safety population with 243 subjects in EMROSI group, 237 subjects in doxycycline (40 mg) group and 158 subjects in placebo group [see Clinical Studies (14)].

The most common adverse reaction reported by ≥1% of subjects treated with EMROSI and more frequently than in subjects receiving placebo was dyspepsia, which was reported in 2% of subjects treated with EMROSI and none of the subjects receiving placebo.

6.2 Postmarketing Experience

The following adverse reactions have been reported with post-approval use of minocycline hydrochloride in a variety of indications. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and hypersensitivity reactions:anaphylaxis, angioedema, DRESS syndrome, erythema multiforme, Stevens-Johnson syndrome, acute febrile neutrophilic dermatosis (Sweet’s syndrome), fixed drug eruptions, balanitis, anaphylactoid purpura photosensitivity, pigmentation of skin and mucous membranes.

Autoimmune conditions:polyarthralgia, pericarditis, exacerbation of systemic lupus, pulmonary infiltrates with eosinophilia, lupus-like syndrome.

Central nervous system:idiopathic intracranial hypertension, bulging fontanels in infants, decreased hearing.

Endocrine:brown-black microscopic thyroid discoloration, abnormal thyroid function.

Oncology:thyroid cancer.

Oral:glossitis, dysphagia, tooth discoloration.

Gastrointestinal:enterocolitis, pancreatitis, hepatitis, liver failure.

Renal:acute renal failure.

Hematology:hemolytic anemia, thrombocytopenia, eosinophilia.

7.1 Anticoagulants

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

7.2 Penicillin

Because bacteriostatic drugs may interfere with the bactericidal action of penicillin, avoid giving EMROSI in conjunction with penicillin.

7.3 Antacids and Iron Preparations

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium and iron-containing preparations.

7.4 Drug/Laboratory Test Interactions

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

8.1 Pregnancy

Risk Summary

Tetracycline-class drugs, including EMROSI, may cause permanent discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.4)]. A few postmarketing cases of limb reductions have been reported over decades of use; however, the association is unclear. The limited data from postmarketing reports are not sufficient to inform a drug-associated risk for birth defects or miscarriage.

In animal reproduction studies conducted in pregnant rats and rabbits, bent limb bones were observed following oral administration of minocycline hydrochloride during organogenesis at systemic exposure of approximately 7.1 and 4.8 times, respectively, the maximum recommended human dose (MRHD) based on AUC exposures (see Data).

If the patient becomes pregnant while taking this drug, advise the patient of the risk to the fetus and discontinue treatment.

The 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 to 4% and 15 to 20%, respectively.

Data

Human Data

The use of tetracycline class drugs, including EMROSI, during tooth development (second and third trimesters of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of deciduous teeth (yellow-gray-brown). Permanent discoloration of the teeth is more common during long-term use of the drug but has been observed following repeated short-term courses [see Warnings and Precautions (5.2)].

Animal Data

Results of animal studies indicate that minocycline hydrochloride crosses the placenta, are found in fetal tissues, and can cause delayed skeletal development in the developing fetus. Evidence of embryotoxicity has been noted in animals treated early in pregnancy [see Warnings and Precautions (5.3)].

Minocycline hydrochloride induced skeletal malformations (bent limb bones) in fetuses when administered to pregnant rats and rabbits during the period of organogenesis at doses of 30 mg/kg/day and 100 mg/kg/day, respectively, (7.1 and 4.8 times, respectively, the MRHD based on AUC comparison). Reduced mean fetal body weight was observed in studies in which minocycline hydrochloride was administered to pregnant rats at an oral dose of 10 mg/kg/day (2.4 times the MRHD based on AUC comparison).

Minocycline hydrochloride 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 (6 times 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 offspring of animals that received minocycline hydrochloride at 50 mg/kg/day 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 the offspring of animals that received minocycline hydrochloride.

8.2 Lactation

Risk Summary

Tetracycline-class antibiotics, including minocycline, are present in breast milk following oral administration. There are no data on the effects of minocycline on milk production. Because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during EMROSI therapy and for 4 days after the final dose [see Warnings and Precautions (5.2, 5.3)].

8.4 Pediatric Use

The safety and effectiveness of EMROSI have not been established in pediatric patients.

Tooth discoloration and inhibition of bone growth have been observed in pediatric patients with the use of tetracycline class antibiotics [see Warnings and Precaution (5.2, 5.3)].

8.5 Geriatric Use

Of the 653 subjects in the phase 3 clinical trials of EMROSI, 101 (15.5%) subjects were 65 years of age and older and 25 (3.8%) were 75 years of age and older. No overall differences in safety or effectiveness of EMROSI have been observed between subjects 65 years of age and older and younger adult subjects.

12.1 Mechanism of Action

The mechanism of action of EMROSI for the treatment of rosacea is unknown.

12.2 Pharmacodynamics

The pharmacodynamics of EMROSI for the treatment of rosacea are unknown.

12.3 Pharmacokinetics

EMROSI is not bioequivalent to any other minocycline products. The pharmacokinetics of minocycline following administration of EMROSI was investigated in two studies that enrolled 32 healthy, adult subjects. In Study 1, the plasma pharmacokinetic parameters for EMROSI following single dose administration under fasting and fed states are presented in Table 1.

Table 1: Plasma Pharmacokinetic Parameters [Mean (%CV)] for EMROSI (40 mg)

Note: * Median (Range)

In Study 2, minocycline plasma PK following EMROSI single (Day 1) and after repeated (Day 21) once daily administrations in eight (8) subjects were found to be similar with overlapping ranges. The mean C maxwas 382.83 ng/mL versus 337.74 ng/mL and AUC 0-24was 3549.64 ng*hr/mL versus 3957.62 ng*hr/mL, respectively on Day 1 versus Day 21.

Absorption:In Study 1, the median plasma T maxof minocycline from EMROSI was 1.50 hours (1.00 - 4.17). In Study 2, the median plasma T maxvalues of minocycline from EMROSI on Day 1 and Day 21 were 1.75 and 1.5 hours, respectively.

Effect of Food:Following administration of EMROSI with a high-fat meal (1011 Kcal, 53% fat), T maxwas delayed by approximately 3 hours. The high fat meal did not impact the C maxhowever, the AUC infwas increased by 15.26% ( Table 1) [see Dosage and Administration (2)].

Distribution:Minocycline is lipid soluble and distributes into the skin and sebum. In Study 1, the mean apparent volume of distribution (Vz/F) values of minocycline following oral administration of EMROSI at fasting and fed condition were 229.61 (±67.83) L and 199.83 (±43.71) L, respectively.

Elimination:The mean apparent elimination half-life (t ½) of minocycline from EMROSI was approximately 15 hours independent of fasting and fed dosing condition.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In an oral carcinogenicity study in rats in which minocycline hydrochloride was administered once daily for up to 104 weeks at doses up to 200 mg/kg/day, minocycline hydrochloride increased incidences of follicular cell tumors of the thyroid gland in both sexes, including 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 an oral carcinogenicity study in mice in which minocycline hydrochloride was administered once daily for up to 104 weeks at doses up to 150 mg/kg/day, minocycline hydrochloride did not increase tumor incidence.

Minocycline hydrochloride 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 hydrochloride was not clastogenic in vitrousing human peripheral blood lymphocytes or in vivoin a mouse micronucleus test.

Male and female reproductive performance in rats was unaffected by oral doses of minocycline hydrochloride up to 300 mg/kg/day (95 times the MRHD based on AUC comparison). However, doses of 100 mg/kg/day (36 times the MRHD based on AUC comparison) and higher to male rats adversely affected spermatogenesis. At 100 mg/kg/day, minocycline increased morphological abnormalities, including absent heads, misshapen heads, and abnormal flagella. At 300 mg/kg/day, minocycline also reduced the number of sperm cells per gram of epididymis and reduced the percentage of motile sperm.

How Supplied

EMROSI is an opaque, brownish-red colored, hard gelatin capsule, imprinted “MEC” on both cap and body with white ink.

Bottles of 30 capsules with child-resistant closure, NDC 69489-131-30.

Storage and Handling

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions are permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].

Protect from light, moisture, and excessive heat.