Minocycline Hydrochloride

1 INDICATIONS & USAGE Minocycline hydrochloride extended-release tablets is a tetracycline-class drug indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older. 1.1 Indication Minocycline hydrochloride extended-release tablets is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older. 1.2 Limitations of Use Minocycline hydrochloride extended-release tablets did not demonstrate any effect on non-inflammatory acne lesions. Safety of Minocycline hydrochloride extended-release tablets has not been established beyond 12 weeks of use. 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, Minocycline hydrochloride extended-release tablets should be used only as indicated [see Warnings and Precautions (5.11) ] .

2 DOSAGE & ADMINISTRATION The recommended dosage of Minocycline hydrochloride extended-release tablets is approximately 1 mg/kg once daily for 12 weeks. Higher doses have not shown to be of additional benefit in the treatment of inflammatory lesions of acne, and may be associated with more acute vestibular side effects. The following table shows tablet strength and body weight to achieve approximately 1 mg/kg. Table 1: Dosing Table for Minocycline hydrochloride extended-release tablets Patient's Weight (lbs.) Patient's Weight (kg) Tablet Strength (mg) Actual mg/kg Dose 99 to 109 45 to 49 45 1 to 0.92 110 to 131 50 to 59 55 1.10 to 0.93 132 to 157 60 to 71 65 1.08 to 0.92 158 to 186 72 to 84 80 1.11 to 0.95 187 to 212 85 to 96 90 1.06 to 0.94 213 to 243 97 to 110 105 1.08 to 0.95 244 to 276 111 to 125 115 1.04 to 0.92 277 to 300 126 to 136 135 1.07 to 0.99 Minocycline hydrochloride extended-release tablets may be taken 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, the total dosage should be decreased by either reducing the recommended individual doses and/or by extending the time intervals between doses [see Warnings and Precautions (5.4 )] . The recommended dosage of Minocycline hydrochloride extended-release tablets is approximately 1 mg/kg once daily for 12 weeks. ( 2 )

5 WARNINGS AND PRECAUTIONS The use of Minocycline hydrochloride extended-release tablets during tooth development (last half of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). (5.1) If pseudomembranous colitis occurs, discontinue Minocycline hydrochloride extended-release tablets. (5.2) If liver injury is suspected, discontinue Minocycline hydrochloride extended-release tablets. (5.3) If renal impairment exists, Minocycline hydrochloride extended-release tablets doses may need to be adjusted to avoid excessive systemic accumulations of the drug and possible liver toxicity. (5.4) Minocycline may cause central nervous system side effects including light- headedness, dizziness, or vertigo. Advise patients. (5.5) Minocycline may cause pseudotumor cerebri (benign intracranial hypertension) in adults and adolescents. Discontinue Minocycline hydrochloride extended-release tablets if symptoms occur. (5.6) Minocycline has been associated with autoimmune syndromes; discontinue Minocycline hydrochloride extended-release tablets immediately if symptoms occur. (5.7) Minocycline has been associated with anaphylaxis, serious skin reactions, erythema multiforme, and DRESS syndrome. Discontinue Minocycline hydrochloride extended-release tablets immediately if symptoms occur. (5.9) 5.1 Teratogenic Effects A. MINOCYCLINE, LIKE OTHER TETRACYCLINE-CLASS DRUGS, CAN CAUSE FETAL HARM WHEN ADMINISTERED TO A PREGNANT WOMAN. IF ANY TETRACYCLINE IS USED DURING PREGNANCY OR IF THE PATIENT BECOMES PREGNANT WHILE TAKING THESE DRUGS, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. Minocycline hydrochloride extended-release tablets should not be used during pregnancy or by individuals of either gender who are attempting to conceive a child [see Nonclinical Toxicology (13.1) & Use in Specific Populations (8.1) ] . B. THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF 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 use of the drug but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED DURING TOOTH DEVELOPMENT. C. 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 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 early in pregnancy [see Use in Specific Populations (8.1) ] . 5.2 Pseudomembranous Colitis Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including 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, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment…

4 CONTRAINDICATIONS This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. This drug is contraindicated in persons who have shown 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) The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. (7.3) To avoid contraceptive failure, female patients are advised to use a second form of contraceptive during treatment with minocycline. (7.5) 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 Methoxyflurane The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. 7.4 Antacids and Iron Preparations Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium and iron-containing preparations. 7.5 Low Dose Oral Contraceptives In a multi-center study to evaluate the effect of Minocycline hydrochloride extended-release tablets on low dose oral contraceptives, hormone levels over one menstrual cycle with and without Minocycline hydrochloride extended-release tablets 1 mg/kg once-daily were measured. Based on the results of this trial, minocycline-related changes in estradiol, progestinic hormone, FSH and LH plasma levels, of breakthrough bleeding, or of contraceptive failure, cannot be ruled out. To avoid contraceptive failure, female patients are advised to use a second form of contraceptive during treatment with minocycline. 7.6 Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

8.1 Pregnancy Teratogenic Effects: Pregnancy category D [see Warnings and Precautions (5.1) ] Minocycline hydrochloride extended-release tablets should not be used during pregnancy. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and stop treatment immediately. There are no adequate and well-controlled studies on the use of minocycline in pregnant women. Minocycline, like other tetracycline-class drugs, crosses the placenta and may cause fetal harm when administered to a pregnant woman. Rare spontaneous reports of congenital anomalies including limb reduction have been reported with minocycline use in pregnancy in post-marketing experience. Only limited information is available regarding these reports; therefore, no conclusion on causal association can be established. Minocycline induced skeletal malformations (bent limb bones) in fetuses when administered to pregnant rats and rabbits in doses of 30 mg/kg/day and 100 mg/kg/day, respectively, (resulting in approximately 3 times and 2 times, respectively, the systemic exposure to minocycline observed in patients as a result of use of Minocycline hydrochloride extended-release tablets). Reduced mean fetal body weight was observed in studies in which minocycline was administered to pregnant rats at a dose of 10 mg/kg/day (which resulted in approximately the same level of systemic exposure to minocycline as that observed in patients who use Minocycline hydrochloride extended-release tablets). Minocycline was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats from day 6 of gestation through the period of lactation (postpartum day 20), 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 (resulting in approximately 2.5 times the systemic exposure to minocycline observed in patients as a result of use of Minocycline hydrochloride extended-release tablets). 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).

8.3 Nursing Mothers Tetracycline-class antibiotics are excreted in human milk. Because of the potential for serious adverse effects on bone and tooth development in nursing infants from the tetracycline-class antibiotics, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.1) ] .

6 ADVERSE REACTIONS 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-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial 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. Table 2: Selected Treatment-Emergent Adverse Reactions in at least 1% of Clinical Trial Subjects 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) Headache 152 (23) 83 (23) Fatigue 62 (9) 24 (7) Dizziness 59 (9) 17 (5) Pruritus 31 (5) 16 (4) Malaise 26 (4) 9 (3) Mood alteration 17 (3) 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) Dry mouth 7 (1) 5 (1) Myalgia 7 (1) 4 (1) 6.2 Postmarketing Experience Adverse reactions that have been reported with Minocycline hydrochloride use in a variety of indications include: Skin and hypersensitivity reactions : fixed drug eruptions, balanitis, erythema multiforme, Stevens-Johnson syndrome, anaphylactoid purpura, photosensitivity, pigmentation of skin and mucous membranes, hypersensitivity reactions, angioneurotic edema, anaphylaxis, DRESS syndrome [see Warnings and Precautions (5.9) ] . Autoimmune conditions : polyarthralgia, pericarditis, exacerbation of systemic lupus, pulmonary infiltrates with eosinophilia, transient lupus-like syndrome. Central nervous system : pseudotumor cerebri, 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 : reversible acute renal failure. Hematology : hemolytic anemia, thrombocytopenia, eosinophilia. Preliminary studies suggest that use of minocycline may have deleterious effects on human spermatogenesis [see Nonclinical Toxicology (13.1) ] .