Minocycline Hydrochloride

1 INDICATIONS & USAGE Minocycline hydrochloride extended-release tablets is indicated to treat inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older. Limitations of Use Minocycline hydrochloride extended-release tablets did not demonstrate any effect on non-inflammatory acne lesions. This formulation of minocycline has not been evaluated in the treatment of infections [see Clinical Studies ( 14 )]. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, use minocycline hydrochloride extended-release tablets only as indicated [see Warnings and Precautions ( 5.12 )]. Minocycline hydrochloride extended-release tablets is a tetracycline-class drug indicated to treat inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older. ( 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 and to maintain the effectiveness of other antibacterial drugs, use minocycline hydrochloride extended-release tablets only as indicated. ( 1 )

2 DOSAGE & ADMINISTRATION The recommended dosage of minocycline hydrochloride extended-release tablets is approximately 1 mg/kg once daily for 12 weeks. Table 1 provides the recommended minocycline hydrochloride extended-release tablets dosage based upon weight ranges. Table 1: Dosing Table for Minocycline hydrochloride extended-release tablets Patient's Weight(kg) Recommended Dosage (mg/day) 45 to 49 45 50 to 59 55 60 to 71 65 72 to 84 80 85 to 96 90 97 to 110 105 111 to 125 115 126 to 136 135 Higher dosages have not shown to be of additional benefit in the treatment of inflammatory lesions of acne and may be associated with more acute vestibular adverse reactions. Swallow tablets whole. Do not chew, crush, or split the extended-release tablets. Administer minocycline hydrochloride extended-release tablets with or without food [see Clinical Pharmacology ( 12.3 )]. Ingestion of food along with minocycline hydrochloride extended-release tablets may help reduce the risk of esophageal irritation and ulceration. In patients with renal impairment, decrease the daily dosage by either reducing the recommended individual doses and/or by extending the time intervals between doses [see Warnings and Precautions ( 5.9 )]. The recommended dosage of Minocycline hydrochloride extended-release tablets is approximately 1 mg/kg once daily for 12 weeks. ( 2 )

5 WARNINGS AND PRECAUTIONS Serious Skin/Hypersensitivity Reactions: Minocycline has been associated with anaphylaxis, serious skin reactions, erythema multiforme, and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Discontinue immediately if symptoms occur. ( 5.1 ) Tooth Discoloration and Enamel Hypoplasia: Use 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). ( 5.2 , 8.1 , 8.4 ) Inhibition of Bone Growth: Use 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. ( 5.3 , 8.1 , 8.4 ) Clostridioides difficile-Associated Diarrhea (Antibiotic-Associated Colitis): Discontinue if Clostridioides difficile-associated diarrhea (antibiotic-associated colitis) occurs. ( 5.4 ) Hepatotoxicity: Discontinue if liver injury is suspected. ( 5.5 ) Central Nervous System Effects: May cause central nervous system side effects including light-headedness, dizziness, or vertigo. ( 5.6 ) Idiopathic Intracranial Hypertension: May cause idiopathic intracranial hypertension in adults and adolescents. Discontinue if symptoms occur. ( 5.7 ) Autoimmune Syndromes: Minocycline has been associated with autoimmune syndromes; discontinue immediately if symptoms occur. ( 5.8 ) Metabolic Effects: If renal impairment exists, reduce minocycline hydrochloride extended-release tablets dosage. ( 5.9 ) 5.1 Serious Skin/Hypersensitivity 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, minocycline hydrochloride extended-release tablets should be discontinued immediately. Fixed drug eruptions have occurred with minocycline and other tetracyclines. Worsening severity upon subsequent administrations, including generalized bullous fixed drug eruption, has been observed with other tetracyclines [see ADVERSE REACTIONS ( 6.2 )] . If severe skin/hypersensitivity reactions occur, discontinue minocycline hydrochloride extended-release tablets and institute appropriate therapy. 5.2 Tooth Discoloration and Enamel Hypoplasia The use of tetracycline-class drugs, including minocycline hydrochloride extended-release tablets, 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-graybrown). 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 minocycline hydrochloride extended-release tablets is not recommended during tooth development. Advise the patient of the potential risk to the fetus if minocycline hydrochloride extended-release tablets 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 minocycline hydrochloride extended-release tablets, 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 minocycline hydrochloride extended-release tablets, form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature human infants given ora…

4 CONTRAINDICATIONS Minocycline hydrochloride extended-release tablets is contraindicated in patients with history of a hypersensitivity reaction to any of the tetracyclines [see Warnings and Precautions ( 5.1 )]. Known hypersensitivity to any of the tetracyclines. ( 4 )

7 DRUG INTERACTIONS Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. ( 7.1 ) 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 Because bacteriostatic drugs may interfere with the bactericidal action of penicillin, avoid giving minocycline hydrochloride extended-release tablets 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 minocycline hydrochloride extended-release tablets 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, fetuses with bent limb bones were observed following oral administration of minocycline during organogenesis at systemic exposures 3 and 2 times, respectively, the exposure associated with the maximum recommended human dose (MRHD) (see Data) . If a patient becomes pregnant while taking this drug, advise the patient of the risk to the fetus and to 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 minocycline hydrochloride extended-release tablets, 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 tetracyclines cross 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 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 (3 times the MRHD and 2 times the MRHD on an AUC comparison basis, respectively). Reduced mean fetal body weight was observed in studies in which minocycline was administered to pregnant rats at an oral dose of 10 mg/kg/day (approximately equal to the MRHD on an AUC comparison basis). 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 dosages 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 (2.5 times the MRHD on an AUC comparison basis). 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 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Skin/Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Clostridioides difficile -Associated Diarrhea (Antibiotic-Associated Colitis) [see Warnings and Precautions ( 5.4 )] Hepatotoxicity [see Warnings and Precautions ( 5.5 )] Central Nervous System Effects [see Warnings and Precautions ( 5.6 )] Idiopathic Intracranial Hypertension [see Warnings and Precautions ( 5.7 )] The most commonly observed adverse reactions (incidence ≥ 5%) are headache, fatigue, dizziness, and pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 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. The following table summarizes selected adverse reactions reported in clinical trials at a rate of ≥1% for minocycline hydrochloride extended-release tablets and higher than placebo. Table 2: Selected Treatment-Emergent Adverse Reactions in at Least 1% of Clinical Trial Subjects and Higher than Placebo Adverse Reactions Minocycline Hydrochloride Extended-Release Tablets (1 mg/kg) N = 674 (%) PLACEBO N = 364 (%) At least one treatment-emergent event 379 (56) 197 (54) Fatigue 62 (9) 24 (7) Dizziness 59 (9) 17 (5) Pruritus 31 (5) 16 (4) Malaise 26 (4) 9 (3) Somnolence 13 (2) 3 (1) Urticaria 10 (2) 1 (0) Tinnitus 10 (2) 5 (1) Arthralgia 9 (1) 2 (0) Vertigo 8 (1) 3 (1) 6.2 Postmarketing Experience The following adverse reactions have been reported with minocycline hydrochloride use 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.