minocycline hydrochloride

1 INDICATIONS AND USAGE Minocycline hydrochloride extended-release tablets are 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 are 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 AND ADMINISTRATION The recommended dosage of minocycline hydrochloride extended-release tablets USP are approximately 1 mg/kg once daily for 12 weeks. ( 2 ) The recommended dosage of minocycline hydrochloride extended-release tablet USP are 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 USP Patient's Weight ( lbs .) Patient's Weight ( kg ) Tablet Strength ( mg ) Actual mg / kg Dose 99 - 109 45 - 49 45 1 - 0.92 110 - 131 50 - 59 55 1.10 - 0.93 132 - 157 60 - 71 65 1.08 - 0.92 158 - 186 72 - 84 80 1.11 - 0.95 187 - 212 85 - 96 90 1.06 - 0.94 213 - 243 97 - 110 105 1.08 - 0.95 244 - 276 111 - 125 115 1.04 - 0.92 277 - 300 126 - 136 135 1.07 - 0.99 Minocycline hydrochloride extended-release tablets USP may be taken with or without food [see CLINICAL PHARMACOLOGY (12.3) ]. Ingestion of food along with minocycline hydrochloride extended-release tablets USP 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) ] .

3 DOSAGE FORMS AND STRENGTHS Extended-release tablets: 45 mg, 55 mg, 65 mg, 80 mg, 90 mg, 105 mg, 115 mg and 135 mg (3) 45 mg extended-release tablets are grey colored, modified capsule shaped, biconvex, coated tablets, debossed with "531" on one side and plain on other side. 55 mg extended-release tablets are yellow colored, modified capsule shaped, biconvex, coated tablets, debossed with "550" on one side and plain on other side. 65 mg extended-release tablets are blue colored, modified capsule shaped, biconvex, coated tablets, debossed with "532" on one side and plain on other side. 80 mg extended-release tablets are whitish blue colored, modified capsule shaped, biconvex, coated tablets, debossed with "551" on one side and plain on other side. 90 mg extended-release tablets are light yellow colored, modified capsule shaped, biconvex, coated tablets, debossed with "533" on one side and plain on other side. 105 mg extended-release tablets are light blue colored, modified capsule shaped, biconvex, coated tablets, debossed with "552" on one side and plain on other side. 115 mg extended-release tablets are green colored, modified capsule shaped, biconvex, coated tablets, debossed with "534" on one side and plain on other side. 135 mg extended-release tablets are light pink colored, modified capsule shaped, biconvex, coated tablets, debossed with "535" on one side and plain on other side.

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

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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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. 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.

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, can not 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 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended. ( 8.2 ). 8.1 Pregnancy Risk Summary Tetracycline class drugs, including minocycline 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, 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 mg/kg/day, 10 mg/kg/day, 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. 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 minocycline therapy and for 4 day …

12.1 Mechanism of Action The mechanism of action of minocycline hydrochloride extended-release tablets for the treatment of acne is unknown.

11 DESCRIPTION Minocycline hydrochloride, a semi synthetic derivative of tetracycline, is [ 4S -(4α,4aα,5aα,12aα)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10, 12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide mono hydrochloride. The structural formula is represented below: C 23 H 27 N 3 O 7 •HCl M. W. 493.95 Each minocycline hydrochloride extended-release tablet, USP intended for oral administration contains minocycline hydrochloride equivalent to 45 mg, 55 mg, 65 mg, 80 mg, 90 mg, 105 mg, 115 mg or 135 mg of minocycline. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol (55 mg, 65 mg, 80 mg, 90 mg, 105 mg, 115 mg and 135 mg only), titanium dioxide and triacetin. Additionally, the 45 mg tablets contain ferric oxide black and ferric oxide yellow; the 55 mg tablets contain ferric oxide red and ferric oxide yellow; the 65 mg tablets contain FD & C blue #2 aluminum lake; the 80 mg tablets contain FD & C blue #2 aluminum lake and FD & C red #40 aluminum lake; the 90 mg tablets contain D & C yellow #10 aluminum lake, ferric oxide red and ferric oxide yellow; the 105 mg tablets contain FD & C blue #2 aluminum lake and FD & C red #40 aluminum lake; the 115 mg tablets contain FD & C blue #2 aluminum lake and ferric oxide yellow; the 135 mg tablets contain D & C red #27 aluminum lake, D & C yellow #10 aluminum lake and FD & C blue #2 aluminum lake. USP dissolution test-8 used. USP organic impurities procedure pending. figure

10 OVERDOSAGE Minocycline is not removed in significant quantities by hemodialysis or peritoneal dialysis. In case of overdosage, discontinue minocycline, treat symptomatically, and institute supportive measures. Call Poison Control Center at 1-800 222-1222 for the latest recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Minocycline Hydrochloride Extended-release Tablets, USP 45 mg are grey colored, modified capsule shaped, biconvex, coated tablets, debossed with "531" on one side and plain on other side and are supplied as follows: NDC 68382-531-06 in bottles of 30 tablets with child resistance closure NDC 68382-531-16 in bottles of 90 tablets with child resistance closure NDC 68382-531-01 in bottles of 100 tablets with child resistance closure NDC 68382-531-05 in bottles of 500 tablets NDC 68382-531-10 in bottles of 1000 tablets NDC 68382-531-30 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Minocycline Hydrochloride Extended-release Tablets, USP 55 mg are yellow colored, modified capsule shaped, biconvex, coated tablets, debossed with "550" on one side and plain on other side and are supplied as follows: NDC 68382-550-06 in bottles of 30 tablets with child resistance closure NDC 68382-550-16 in bottles of 90 tablets with child resistance closure NDC 68382-550-01 in bottles of 100 tablets with child resistance closure NDC 68382-550-05 in bottles of 500 tablets NDC 68382-550-10 in bottles of 1000 tablets NDC 68382-550-30 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Minocycline Hydrochloride Extended-release Tablets, USP 65 mg are blue colored, modified capsule shaped, biconvex, coated tablets, debossed with "532" on one side and plain on other side and are supplied as follows: NDC 68382-532-06 in bottles of 30 tablets with child resistance closure NDC 68382-532-16 in bottles of 90 tablets with child resistance closure NDC 68382-532-01 in bottles of 100 tablets with child resistance closure NDC 68382-532-05 in bottles of 500 tablets NDC 68382-532-10 in bottles of 1000 tablets NDC 68382-532-30 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Minocycline Hydrochloride Extended-release Tablets, USP 80 mg are whitish blue colored, modified capsule shaped, biconvex, coated tablets, debossed with "551" on one side and plain on other side and are supplied as follows: NDC 68382-551-06 in bottles of 30 tablets with child resistance closure NDC 68382-551-16 in bottles of 90 tablets with child resistance closure NDC 68382-551-01 in bottles of 100 tablets with child resistance closure NDC 68382-551-05 in bottles of 500 tablets NDC 68382-551-10 in bottles of 1000 tablets NDC 68382-551-30 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Minocycline Hydrochloride Extended-release Tablets, USP 90 mg are light yellow colored, modified capsule shaped, biconvex, coated tablets, debossed with "533" on one side and plain on other side and are supplied as follows: NDC 68382-533-06 in bottles of 30 tablets with child resistance closure NDC 68382-533-16 in bottles of 90 tablets with child resistance closure NDC 68382-533-01 in bottles of 100 tablets with child resistance closure NDC 68382-533-05 in bottles of 500 tablets NDC 68382-533-10 in bottles of 1000 tablets NDC 68382-533-30 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Minocycline Hydrochloride Extended-release Tablets, USP 105 mg are light blue colored, modified capsule shaped, biconvex, coated tablets, debossed with "552" on one side and plain on other side and are supplied as follows: NDC 68382-552-06 in bottles of 30 tablets with child resistance closure NDC 68382-552-16 in bottles of 90 tablets with child resistance closure NDC 68382-552-01 in bottles of 100 tablets with child resistance closure NDC 68382-552-05 in bottles of 500 tablets NDC 68382-552-10 in bottles of 1000 tablets NDC 68382-552-30 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Minocycline Hydrochloride Extended-release Tablets, USP 115 mg are green colored, modified capsule shaped, biconvex, coated tablets, debossed with "534" on one side and plain on other side and are supplied as follows: NDC 68382-534-06 in bottles of 30 tablets with child resistance closure NDC 68382-534-16 in bottles o …