Minocycline Hydrochloride

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 Sandoz Inc., at 1-800-525-8747 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 ) ].

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 )

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: Minocycline hydrochloride extended-release tablets for oral administration contain minocycline hydrochloride, USP equivalent to 45 mg, 90 mg, or 135 mg of minocycline. In addition, 45 mg, 90 mg, and 135 mg tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, and magnesium stearate. The 45 mg extended-release tablets also contain opadry grey, which contains: titanium dioxide, triacetin, iron oxide black, and iron oxide yellow. The 90 mg extended-release tablets also contain opadry orange, which contains: titanium dioxide, triacetin, iron oxide yellow, FD&C yellow # 6, and iron oxide red. The 135 mg extended-release tablets also contain opadry yellow, which contains: titanium dioxide, triacetin and iron oxide yellow. structure formula

2 DOSAGE AND 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 99-109 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 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 )

1 INDICATIONS AND USAGE Minocycline hydrochloride extended-release tablets is 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 ) 1.1 Indication Minocycline hydrochloride extended-release tablets are 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 ) ].

10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Minocycline is not removed in significant quantities by hemodialysis or peritoneal dialysis.

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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of minocycline hydrochloride extended-release tablets for the treatment of acne is unknown. 12.2 Pharmacodynamics The pharmacodynamics of minocycline hydrochloride extended-release tablets for the treatment of acne are unknown. 12.3 Pharmacokinetics Minocycline hydrochloride extended-release tablets are not bioequivalent to non-modified release minocycline products. Based on pharmacokinetic studies in healthy adults, minocycline hydrochloride extended-release tablets produce a delayed T max at 3.5 to 4 hours as compared to a non-modified release reference minocycline product (T max at 2.25 to 3 hours). At steady-state (Day 6), the mean AUC (0 to 24) and C max were 33.32 mcg×hr/mL and 2.63 mcg/mL for minocycline hydrochloride extended-release tablets and 46.35 mcg×hr/mL and 2.92 mcg/mL for Minocin ® capsules, respectively. These parameters are based on dose adjusted to 135 mg per day for both products. A single-dose, four-way crossover study demonstrated that minocycline hydrochloride extended-release tablets used in the study (45 mg, 90 mg, 135 mg) exhibited dose-proportional pharmacokinetics. In another single-dose, five-way crossover pharmacokinetic study, minocycline hydrochloride extended-release tablets 55 mg, 80 mg, and 105 mg were shown to be dose-proportional to minocycline hydrochloride tablets 90 mg and 135 mg. When minocycline hydrochloride extended-release tablets were administered concomitantly with a meal that included dairy products, the extent and timing of absorption of minocycline did not differ from that of administration under fasting conditions. Minocycline is lipid soluble and distributes into the skin and sebum.

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

12.2 Pharmacodynamics The pharmacodynamics of minocycline hydrochloride extended-release tablets for the treatment of acne are unknown.

12.3 Pharmacokinetics Minocycline hydrochloride extended-release tablets are not bioequivalent to non-modified release minocycline products. Based on pharmacokinetic studies in healthy adults, minocycline hydrochloride extended-release tablets produce a delayed T max at 3.5 to 4 hours as compared to a non-modified release reference minocycline product (T max at 2.25 to 3 hours). At steady-state (Day 6), the mean AUC (0 to 24) and C max were 33.32 mcg×hr/mL and 2.63 mcg/mL for minocycline hydrochloride extended-release tablets and 46.35 mcg×hr/mL and 2.92 mcg/mL for Minocin ® capsules, respectively. These parameters are based on dose adjusted to 135 mg per day for both products. A single-dose, four-way crossover study demonstrated that minocycline hydrochloride extended-release tablets used in the study (45 mg, 90 mg, 135 mg) exhibited dose-proportional pharmacokinetics. In another single-dose, five-way crossover pharmacokinetic study, minocycline hydrochloride extended-release tablets 55 mg, 80 mg, and 105 mg were shown to be dose-proportional to minocycline hydrochloride tablets 90 mg and 135 mg. When minocycline hydrochloride extended-release tablets were administered concomitantly with a meal that included dairy products, the extent and timing of absorption of minocycline did not differ from that of administration under fasting conditions. Minocycline is lipid soluble and distributes into the skin and sebum.

20170224

11

3 DOSAGE FORMS AND STRENGTHS The 45 mg extended-release tablets are grey colored, capsule shaped, biconvex, film-coated, debossed with ‘I113’ on one side and plain on the other side. The 90 mg extended-release tablets are light orange colored, capsule shaped, biconvex, film coated, debossed with ‘I112’ on one side and plain on the other side. The 135 mg extended-release tablets are light yellow colored, capsule shaped, biconvex film coated, debossed with ‘I111’ on one side and plain on the other side. Extended release tablets: 45 mg, 90 mg, and 135 mg ( 3 )

Minocycline Hydrochloride Minocycline Hydrochloride MINOCYCLINE HYDROCHLORIDE MINOCYCLINE FERROSOFERRIC OXIDE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE TITANIUM DIOXIDE TRIACETIN FERRIC OXIDE YELLOW HYPROMELLOSE 2208 (15000 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) capsule shaped I113 Minocycline Hydrochloride Minocycline Hydrochloride MINOCYCLINE HYDROCHLORIDE MINOCYCLINE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE TITANIUM DIOXIDE TRIACETIN FERRIC OXIDE YELLOW FD&C YELLOW NO. 6 FERRIC OXIDE RED HYPROMELLOSE 2208 (15000 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) light capsule shaped I112 Minocycline Hydrochloride Minocycline Hydrochloride MINOCYCLINE HYDROCHLORIDE MINOCYCLINE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE TITANIUM DIOXIDE TRIACETIN FERRIC OXIDE YELLOW HYPROMELLOSE 2208 (15000 MPA.S) HYPROMELLOSE 2910 (15 MPA.S) light capsule shaped I111

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a carcinogenicity study in which minocycline HCl was orally administered to male and female rats once daily for up to 104 weeks at dosages up to 200 mg/kg/day, minocycline HCl was associated in both genders 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 HCl 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 HCl did not result in a significantly increased incidence of neoplasms in either males or females. Mutagenesis 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. Impairment of Fertility Male and female reproductive performance in rats was unaffected by oral doses of minocycline of up to 300 mg/kg/day (which resulted in up to approximately 40 times the level of systemic exposure to minocycline observed in patients as a result of use of minocycline hydrochloride extended-release tablets). However, oral administration of 100 or 300 mg/kg/day of minocycline to male rats (resulting in approximately 15 to 40 times the level of systemic exposure to minocycline observed in patients as a result of use of minocycline hydrochloride extended-release tablets) adversely affected spermatogenesis. Effects observed at 300 mg/kg/day 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. Limited human studies suggest that minocycline may have a deleterious effect on spermatogenesis. Minocycline hydrochloride extended-release tablets should not be used by individuals of either gender who are attempting to conceive a child.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a carcinogenicity study in which minocycline HCl was orally administered to male and female rats once daily for up to 104 weeks at dosages up to 200 mg/kg/day, minocycline HCl was associated in both genders 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 HCl 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 HCl did not result in a significantly increased incidence of neoplasms in either males or females. Mutagenesis 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. Impairment of Fertility Male and female reproductive performance in rats was unaffected by oral doses of minocycline of up to 300 mg/kg/day (which resulted in up to approximately 40 times the level of systemic exposure to minocycline observed in patients as a result of use of minocycline hydrochloride extended-release tablets). However, oral administration of 100 or 300 mg/kg/day of minocycline to male rats (resulting in approximately 15 to 40 times the level of systemic exposure to minocycline observed in patients as a result of use of minocycline hydrochloride extended-release tablets) adversely affected spermatogenesis. Effects observed at 300 mg/kg/day 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. Limited human studies suggest that minocycline may have a deleterious effect on spermatogenesis. Minocycline hydrochloride extended-release tablets should not be used by individuals of either gender who are attempting to conceive a child.

ANDA090422

Minocycline Hydrochloride

Minocycline Hydrochloride

0781-5385

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL Minocycline Hydrochloride ER Tablets 45 mg 30 Tablets 45 mg

17 PATIENT COUNSELING INFORMATION [See FDA-approved patient labeling (Patient Information)] Patients taking minocycline hydrochloride extended-release tablets should receive the following information and instructions: • Minocycline hydrochloride extended-release tablets should not be used by pregnant women or women attempting to conceive a child [see USE IN SPECIFIC POPULATIONS ( 8.1 ), NONCLINICAL TOXICOLOGY ( 13.1 .) ]. • It is recommended that minocycline hydrochloride extended-release tablets not be used by men who are attempting to father a child [see NONCLINICAL TOXICOLOGY ( 13.1 ) ]. • Patients should be advised that pseudomembranous colitis can occur with minocycline therapy. If patients develop watery or bloody stools, they should seek medical attention. • Patients should be counseled about the possibility of hepatotoxicity. Patients should seek medical advice if they experience symptoms which can include loss of appetite, tiredness, diarrhea, skin turning yellow, bleeding easily, confusion, and sleepiness. • Patients who experience central nervous system symptoms [see WARNINGS AND PRECAUTIONS ( 5.5 ) ] should be cautioned about driving vehicles or using hazardous machinery while on minocycline therapy. Patients should seek medical help for persistent headaches or blurred vision. • Concurrent use of tetracycline may render oral contraceptives less effective [see DRUG INTERACTIONS ( 7.5 ) ]. • Autoimmune syndromes, including drug-induced lupus-like syndrome, autoimmune hepatitis, vasculitis and serum sickness have been observed with tetracycline-class drugs, including minocycline. Symptoms may be manifested by arthralgia, fever, rash and malaise. Patients who experience such symptoms should be cautioned to stop the drug immediately and seek medical help. • Patients should be counseled about discoloration of skin, scars, teeth or gums that can arise from minocycline therapy. • Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including minocycline. 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 minocycline, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Treatment should be discontinued at the first evidence of skin erythema. • Minocycline hydrochloride extended-release tablets should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of the current treatment course and increase the likelihood that bacteria will develop resistance and will not be treatable by other antibacterial drugs in the future. • Patients should be advised to swallow minocycline hydrochloride extended-release tablets whole and not to chew, crush, or split the tablets.

14 CLINICAL STUDIES The safety and efficacy of minocycline hydrochloride extended-release tablets in the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris was assessed in two 12-week, multi-center, randomized, double-blind, placebo-controlled, studies in subjects ≥ 12 years. The mean age of subjects was 20 years and subjects were from the following racial groups: White (73%), Hispanic (13%), Black (11%), Asian/Pacific Islander (2%), and Other (2%). In two efficacy and safety trials, a total of 924 subjects with non-nodular moderate to severe acne vulgaris received minocycline hydrochloride extended-release tablets or placebo for a total of 12 weeks, according to the following dose assignments. Table 3: Clinical Studies Dosing Table Subject’s Weight (lbs) Subject’s Weight (kg) Available Caplet Strength (mg) Actual mg/kg Dose 99 – 131 45 – 59 45 1 – 0.76 132 – 199 60 – 90 90 1.5 – 1 200 – 300 91 – 136 135 1.48 – 0.99 The two primary efficacy endpoints were: 1. Mean percent change in inflammatory lesion counts from Baseline to 12 weeks. 2. Percentage of subjects with an Evaluator’s Global Severity Assessment (EGSA) of clear or almost clear at 12 weeks. Efficacy results are presented in Table 4. Table 4: Efficacy Results at Week 12 Trial 1 Trial 2 Minocycline Hydrochloride Extended-Release Tablets Placebo Minocycline Hydrochloride Extended-Release Tablets Placebo (1 mg/kg) N=300 N = 151 (1 mg/kg) N= 315 N = 158 Mean Percent Improvement in Inflammatory Lesions 43.1% 31.7% 45.8% 30.8% No. (%) of Subjects Clear or Almost Clear on the EGSA* 52 (17.3%) 12 (7.9%) 50 (15.9%) 15 (9.5%) *Evaluator’s Global Severity Assessment Minocycline hydrochloride extended-release tablets did not demonstrate any effect on non-inflammatory lesions (benefit or worsening).

8.5 Geriatric Use Clinical studies of minocycline hydrochloride extended-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

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 ) ].

8.4 Pediatric Use Minocycline hydrochloride extended-release tablet is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years and older. Safety and effectiveness in pediatric patients below the age of 12 has not been established. Use of tetracycline-class antibiotics below the age of 8 is not recommended due to the potential for tooth discoloration [see WARNINGS AND PRECAUTIONS ( 5.1 ) ].

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 USE IN SPECIFIC POPULATIONS • Minocycline like other tetracycline-class drugs can cause fetal harm when administered to a pregnant woman. ( 5.1 , 8.1 ) • The use of drugs of the tetracycline class during tooth development may cause permanent discoloration of teeth. ( 5.1 , 8.4 ) 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 ) ]. 8.4 Pediatric Use Minocycline hydrochloride extended-release tablet is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years and older. Safety and effectiveness in pediatric patients below the age of 12 has not been established. Use of tetracycline-class antibiotics below the age of 8 is not recommended due to the potential for tooth discoloration [see WARNINGS AND PRECAUTIONS ( 5.1 ) ]. 8.5 Geriatric Use Clinical studies of minocycline hydrochloride extended-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Minocycline hydrochloride extended-release tablets are available as follows: The 45 mg extended-release tablets are grey colored, capsule shaped, biconvex, film-coated, debossed with ‘I113’ on one side and plain on the other side. NDC 0781-5385-31, bottle of 30 tablets NDC 0781-5385-01, bottle of 100 tablets NDC 0781-5385-10, bottle of 1000 tablets The 90 mg extended-release tablets are light orange colored, capsule shaped, biconvex, film coated, debossed with ‘I112’ on one side and plain on the other side. NDC 0781-5386-31, bottle of 30 tablets NDC 0781-5386-01, bottle of 100 tablets NDC 0781-5386-10, bottle of 1000 tablets The 135 mg extended-release tablets are light yellow colored, capsule shaped, biconvex film coated, debossed with ‘I111’ on one side and plain on the other side. NDC 0781-5387-31, bottle of 30 tablets NDC 0781-5387-01, bottle of 100 tablets NDC 0781-5387-10, bottle of 1000 tablets 16.2 Storage Store at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature]. 16.3 Handling Keep out of reach of children. Protect from light, moisture, and excessive heat. Dispense in tight, light-resistant container with child-resistant closure.