ADVERSE REACTIONS SECTION.

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 Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The following table summarizes selected adverse reactions reported in clinical trials at rate of >= 1% for minocycline hydrochloride.Table 2: Selected Treatment-Emergent Adverse Reactions in at least 1% of Clinical Trial SubjectsAdverse ReactionsMinocycline hydrochloride (1 mg/kg) = 674 (%)PLACEBO = 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) (3) Mood alteration 17 (3) (3) Somnolence 13 (2) (1) Urticaria 10 (2) (0) Tinnitus 10 (2) (1) Arthralgia (1) (0) Vertigo (1) (1) Dry mouth (1) (1) Myalgia (1) (1). 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of minocycline hydrochloride. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Adverse reactions that have been reported with minocycline hydrochloride use in 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)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis-In 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 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 significantly increased incidence of neoplasms in either males or females.Mutagenesis-Minocycline was not mutagenic in vitro in 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 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 result of use of Ximino). 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 result of use of Ximino) adversely affected spermatogenesis. Effects observed at 300 mg/kg/day included 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 deleterious effect on spermatogenesis.Ximino should not be used by individuals of either gender who are attempting to conceive child.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action of Ximino for the treatment of acne is unknown.. 12.2 Pharmacodynamics. The pharmacodynamics of Ximino for the treatment of acne are unknown.. 12.3 Pharmacokinetics. Ximino is not bioequivalent to immediate release minocycline products.Following administration of single dose of Ximino (135 mg) to 32 healthy male and female adult subjects, the mean (SD) AUC(0-) and Cmax were 17.90 (5.56) mcg hr/mL and 0.96 (0.32) mcg/mL, respectively, under fasting conditions. In separate trial, when single dose of Ximino (135 mg) was administered with high fat meal to 30 healthy male and female adult subjects, the mean (SD) AUC(0-) and Cmax were 17.16 (3.19) mcg hr/mL and 0.97 (0.25) mcg/mL, respectively.Minocycline is lipid soluble and distributes into the skin and sebum.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of minocycline hydrochloride 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, trials 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, total of 924 subjects with non-nodular moderate to severe acne vulgaris received minocycline hydrochloride or placebo for total of 12 weeks, according to the following dose assignments.Table 3: Clinical Studies Dosing TableSubjects Weight (lbs.)Subjects Weight (kg)Available Capsule Strength (mg)Actual mg/kg Dose 99 to 131 45 to 59 45 to 0.76 132 to 199 60 to 90 90 1.5 to 200 to 300 91 to 136 135 1.48 to 0.99The two primary efficacy endpoints were:1) Mean percent change in inflammatory lesion counts from Baseline to 12 weeks.2) Percentage of subjects with an Evaluators 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 1Trial 2Minocycline hydrochloride (1 mg/kg) = 300Placebo = 151Minocycline hydrochloride (1 mg/kg) = 315Placebo = 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%)Evaluators Global Severity AssessmentMinocycline hydrochloride did not demonstrate any effect on non-inflammatory lesions (benefit or worsening).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Ximino is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines [see Adverse Reactions (6.2)].. Ximino is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. The active ingredient in Ximino Extended-Release Capsules is minocycline hydrochloride, semi synthetic derivative of tetracycline. Ximino is tetracycline-class drug. Ximino is known chemically as [4 S-(4,4a,5a,12a)]-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, USP is yellow crystalline powder, sparingly soluble in water, soluble in solutions of alkali hydroxides and carbonates, slightly soluble in alcohol, practically insoluble in chloroform and in ether.Ximino (minocycline hydrochloride) Extended-Release Capsules for oral administration contain minocycline hydrochloride, USP equivalent to 45 mg, 90 mg, or 135 mg of minocycline. The Extended-Release Capsules contain the following inactive ingredients: colloidal silicon dioxide, D&C Yellow 10 (in 45 mg strength), FD&C Blue 1, FD&C Yellow (in 45 mg and 135 mg strength), gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, and titanium dioxide.The 45 mg, 90 mg, and 135 mg capsules also contain Opadry Clear which contains hypromellose, polyethylene glycol 400, polyethylene glycol 6000, and talc.Ximino Extended-Release Capsules also contain black ink which contains black iron oxide, potassium hydroxide, propylene glycol, and shellac.. structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of Ximino is approximately 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 capsule strength and body weight to achieve approximately mg/kg.Table 1: Dosing Table for XiminoPatients Weight (lbs.)Patients Weight (kg)Capsule Strength (mg)Actual mg/kg Dose 99 to 131 45 to 59 45 to 0.76 132 to 199 60 to 90 90 1.5 to 200 to 300 91 to 136 135 1.48 to 0.99Ximino may be taken with or without food [see Clinical Pharmacology (12.3)]. The capsules should be swallowed whole without chewing, crushing or splitting. Ingestion of food along with Ximino 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 Ximino is approximately mg/kg once daily for 12 weeks. (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. o45 mg Extended-Release Capsules: Opaque bluish green cap and opaque yellow body hard gelatin capsule with RI18 imprinted on both cap and body in black ink containing one plain to mottled, yellow to grayish yellow colored film-coated, round tablet plain on both sides.o90 mg Extended-Release Capsules: Opaque light blue cap and body hard gelatin capsule with RI19 imprinted on both cap and body in black ink containing two plain to mottled, yellow to grayish yellow colored film-coated, round tablets plain on both sides.o135 mg Extended-Release Capsules: Opaque bluish green cap and opaque light blue body hard gelatin capsule with RI20 imprinted on both cap and body in black ink containing three plain to mottled, yellow to grayish yellow colored film-coated, round tablets plain on both sides.. o45 mg Extended-Release Capsules: Opaque bluish green cap and opaque yellow body hard gelatin capsule with RI18 imprinted on both cap and body in black ink containing one plain to mottled, yellow to grayish yellow colored film-coated, round tablet plain on both sides.. o90 mg Extended-Release Capsules: Opaque light blue cap and body hard gelatin capsule with RI19 imprinted on both cap and body in black ink containing two plain to mottled, yellow to grayish yellow colored film-coated, round tablets plain on both sides.. o135 mg Extended-Release Capsules: Opaque bluish green cap and opaque light blue body hard gelatin capsule with RI20 imprinted on both cap and body in black ink containing three plain to mottled, yellow to grayish yellow colored film-coated, round tablets plain on both sides.. Extended-Release Capsules: 45 mg, 90 mg, and 135 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oPatients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. (7.1)oThe concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. (7.3)oTo avoid contraceptive failure, female patients are advised to use second form of contraceptive during treatment with minocycline. (7.5). oPatients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. (7.1). oThe concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. (7.3). oTo avoid contraceptive failure, female patients are advised to use 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 multi-center study to evaluate the effect of minocycline hydrochloride (administered as another extended-release formulation which is bioequivalent to Ximino) on low dose oral contraceptives, hormone levels over one menstrual cycle with and without minocycline hydrochloride 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 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of minocycline hydrochloride 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.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Ximino (minocycline hydrochloride) Extended-Release Capsules are hard-gelatin capsules containing minocycline hydrochloride, USP equivalent to 45 mg, 90 mg, or 135 mg minocycline. The Extended-Release Capsules are supplied as follows:Ximino (minocycline hydrochloride) Extended-Release Capsules 45 mg: Opaque bluish green cap and opaque yellow body hard gelatin capsule with RI18 imprinted on both cap and body in black ink containing one plain to mottled, yellow to grayish yellow colored film-coated, round tablet plain on both sides and are supplied as follows:NDC 10631-330-30 Bottle of 30NDC 10631-330-05 Bottle of 500NDC 10631-330-69 Blister pack of 10Ximino (minocycline hydrochloride) Extended-Release Capsules 90 mg: Opaque light blue cap and body hard gelatin capsule with RI19 imprinted on both cap and body in black ink containing two plain to mottled, yellow to grayish yellow colored film-coated, round tablets plain on both sides and are supplied as follows:NDC 10631-331-30 Bottle of 30NDC 10631-331-05 Bottle of 500NDC 10631-331-69 Blister pack of 10Ximino (minocycline hydrochloride) Extended-Release Capsules 135 mg: Opaque bluish green cap and opaque light blue body hard gelatin capsule with RI20 imprinted on both cap and body in black ink containing three plain to mottled, yellow to grayish yellow colored film-coated, round tablets plain on both sides and are supplied as follows:NDC 10631-332-30 Bottle of 30NDC 10631-332-05 Bottle of 500NDC 10631-332-69 Blister pack of 10. 16.2 Storage. Store at 20o - 25o (68o - 77o F); excursions are permitted to 15oC 30o (59o - 86o F) [See USP Controlled Room Temperature].. 16.3 Handling. Protect from light, moisture, and excessive heat.Dispense in tight, light-resistant container with child-resistant closure.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Ximino 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)Limitations of UseXimino did not demonstrate any effect on non-inflammatory acne lesions. Safety of Ximino has not been established beyond 12 weeks of use. This formulation of minocycline has not been evaluated in the treatment of infections. (14). 1.1 Indication. Ximino is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older.To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, Ximino should be used only as indicated [see Warnings and Precautions (5.11)].. 1.2 Limitations of Use. Ximino did not demonstrate any effect on non-inflammatory acne lesions. Safety of Ximino 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling (Patient Information)Patients taking Ximino should receive the following information and instructions:oXimino should not be used by pregnant women or women attempting to conceive child [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].oIt is recommended that Ximino not be used by men who are attempting to father child [see Nonclinical Toxicology (13.1)].oPatients should be advised that pseudomembranous colitis can occur with minocycline therapy. If patients develop watery or bloody stools, they should seek medical attention.oPatients 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.oPatients 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.oConcurrent use of tetracycline may render oral contraceptives less effective. To avoid contraceptive failure, female patients on low dose oral contraceptives should be advised to use second form of contraception during treatment with minocycline [see Drug Interactions (7.5)].oAutoimmune 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.oPatients should be counseled about discoloration of skin, scars, teeth or gums that can arise from minocycline therapy.oPhotosensitivity 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.oXimino 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.oPatients should be advised to swallow Ximino whole and not to chew, crush, or split the capsules.. oXimino should not be used by pregnant women or women attempting to conceive child [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].. oIt is recommended that Ximino not be used by men who are attempting to father child [see Nonclinical Toxicology (13.1)].. oPatients should be advised that pseudomembranous colitis can occur with minocycline therapy. If patients develop watery or bloody stools, they should seek medical attention.. oPatients 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.. oPatients 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.. oConcurrent use of tetracycline may render oral contraceptives less effective. To avoid contraceptive failure, female patients on low dose oral contraceptives should be advised to use second form of contraception during treatment with minocycline [see Drug Interactions (7.5)].. oAutoimmune 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.. oPatients should be counseled about discoloration of skin, scars, teeth or gums that can arise from minocycline therapy.. oPhotosensitivity 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.. oXimino 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.. oPatients should be advised to swallow Ximino whole and not to chew, crush, or split the capsules.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The mechanism of action of Ximino for the treatment of acne is unknown.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis-In 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 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 significantly increased incidence of neoplasms in either males or females.Mutagenesis-Minocycline was not mutagenic in vitro in 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 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 result of use of Ximino). 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 result of use of Ximino) adversely affected spermatogenesis. Effects observed at 300 mg/kg/day included 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 deleterious effect on spermatogenesis.Ximino should not be used by individuals of either gender who are attempting to conceive child.

NURSING MOTHERS SECTION.

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, 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)].

OVERDOSAGE SECTION.

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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL. PRINCIPAL DISPLAY PANEL. NDC 10631-330-30XiminoTM (minocycline hydrochloride)Extended-Release Capsules45 mgRx only 30 Capsules30s Bottle Label label1.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Ximino 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 have not been established.Use of tetracycline-class antibiotics below the age of is not recommended due to the potential for tooth discoloration [see Warnings and Precautions (5.1)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The pharmacodynamics of Ximino for the treatment of acne are unknown.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Ximino is not bioequivalent to immediate release minocycline products.Following administration of single dose of Ximino (135 mg) to 32 healthy male and female adult subjects, the mean (SD) AUC(0-) and Cmax were 17.90 (5.56) mcg hr/mL and 0.96 (0.32) mcg/mL, respectively, under fasting conditions. In separate trial, when single dose of Ximino (135 mg) was administered with high fat meal to 30 healthy male and female adult subjects, the mean (SD) AUC(0-) and Cmax were 17.16 (3.19) mcg hr/mL and 0.97 (0.25) mcg/mL, respectively.Minocycline is lipid soluble and distributes into the skin and sebum.

PREGNANCY SECTION.

8.1 Pregnancy. Teratogenic Effects: Pregnancy Category [see Warnings and Precautions (5.1)]Ximino 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 can cause fetal harm when administered to pregnant woman.Spontaneous reports of congenital anomalies including limb reduction have been reported with minocycline use in pregnancy in postmarketing 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 times and times, respectively, the systemic exposure to minocycline observed in patients as result of use of Ximino). Reduced mean fetal body weight was observed in studies in which minocycline was administered to pregnant rats at 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 Ximino).Minocycline was assessed for effects on peri- and post-natal development of rats in study that involved oral administration to pregnant rats from day 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 result of use of Ximino). 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).

SPL PATIENT PACKAGE INSERT SECTION.

FDA-APPROVED PATIENT LABELING. PATIENT INFORMATIONXIMINO (Zi-min-o)(minocycline hydrochloride)Extended-Release CapsulesRead this Patient Information leaflet that comes with Ximino before you start taking it and each time you get refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment.What is XiminoXimino is tetracycline-class drug. Ximino is prescription medicine used to treat pimples and red bumps (non-nodular inflammatory lesions) that happen with moderate to severe acne vulgaris in people 12 years and older. Ximino is not effective for acne that is not red-looking (this means acne that is not inflammatory).It is not known if Ximino is:osafe for use longer than 12 weeks.osafe and effective for the treatment of infections.osafe and effective in children under the age of 12 years.Who should not take XiminoDo not take Ximino if you are allergic to tetracycline class medicines. Ask your doctor or pharmacist for list of these medicines if you are not sure.What should tell my doctor before taking XiminoBefore you take Ximino, tell your doctor if you:ohave kidney problems. Your doctor may prescribe lower dose of medicine for youohave liver problemsohave diarrhea or watery stoolsohave vision problemsoplan to have surgery with general anesthesiaohave any other medical conditionsoare male, and you and your female partner are trying to conceive baby. You should not take Ximino.oare pregnant or plan to become pregnant. Ximino may harm your unborn baby. Taking Ximino while you are pregnant may cause serious side effects on the growth of bone and teeth of your baby. Talk to your doctor before taking Ximino if you plan to become pregnant, or if you are already taking Ximino and plan to become pregnant. Stop taking Ximino and call your doctor right away if you become pregnant while taking Ximino.oare breastfeeding or plan to breastfeed. Ximino passes into your milk and may harm your baby. You and your doctor should decide if you will take Ximino or breastfeed. You should not do both.Tell your doctor about all the other medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Ximino may affect the way other medicines work, and other medicines may affect how Ximino works.Especially tell your doctor if you take:obirth control pills. Ximino may make your birth control pills less effective. You could become pregnant. You should use second form of birth control while taking Ximino.oa blood thinner medicine.oa penicillin antibiotic medicine. Ximino and penicillins should not be used together.oantacids that contain aluminum, calcium, or magnesium or iron-containing products.oan acne medication that contains isotretinoin. Ximino and isotretinoin should not be used together.Ask your doctor or pharmacist if you are not sure if your medicine is one that is listed above.Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.How should take XiminooTake Ximino exactly as your doctor tells you.oSkipping doses or not taking all doses of Ximino may:omake the treatment not work as well.oincrease the chance that the bacteria will become resistant to Ximino.oXimino can be taken with or without food. Taking Ximino with food may lower your chances of getting irritation or ulcers in your esophagus. Your esophagus is the tube that connects your mouth to your stomach.oSwallow Ximino whole. Do not chew, crush, or split the capsules.If you take too much Ximino, call your doctor or poison control center right away. Your doctor may do blood tests to check you for side effects during treatment with Ximino.What should avoid while taking XiminooAvoid sunlight, sunlamps, and tanning beds. Ximino can make your skin sensitive to the sun and the light from sunlamps and tanning beds. You could get severe sunburn.oWear loose-fitting clothes that protect your skin from sun exposure. Talk to your doctor about other ways to protect your skin while out in sunlight.oYou should not drive or operate dangerous machinery until you know how Ximino affects you. Ximino may cause you to feel dizzy or lightheaded, or have spinning feeling (vertigo).What are possible side effects of XiminoXimino may cause serious side effects, including:oHarm to an unborn baby. See What should tell my doctor before taking XiminooPermanent teeth discoloration. Ximino may permanently turn baby or childs teeth yellow-grey-brown during tooth development. Ximino should not be used during tooth development. Tooth development happens in the last half of pregnancy, and from birth to years of age. See What should tell my doctor before taking XiminooIntestine infection (pseudomembranous colitis). Pseudomembranous colitis can happen with most antibiotics, including Ximino. Call your doctor right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and fever. Pseudomembranous colitis can happen or more months after you have finished your medication. oSerious liver problems. Stop taking Ximino and call your doctor right away if you get any of the following symptoms of liver problems:oloss of appetiteotirednessodiarrheaoyellowing of your skin or the whites of your eyesounexplained bleedingoconfusionosleepiness oCentral nervous system effects. See What should avoid while taking Ximino Central nervous system effects such as light headedness, dizziness, and spinning feeling (vertigo) may go away during your treatment with Ximino or if treatment is stopped. Call your doctor if you get headaches that do not go away or blurred vision.oBenign intracranial hypertension, also called pseudotumor cerebri. This is condition where there is high pressure in the fluid around the brain. This swelling may lead to vision changes and permanent vision loss. Stop taking Ximino and tell your doctor right away if you have blurred vision, vision loss, or unusual headaches.oImmune system reactions including lupus-like syndrome, hepatitis, and inflammation of blood or lymph vessels (vasculitis). Using Ximino for long time to treat acne may cause immune system reactions. Tell your doctor right away if you get fever, rash, joint pain, or body weakness. Your doctor may do tests to check your blood for immune system reactions.oSerious rash and allergic reactions. Ximino may cause serious rash and allergic reactions that may affect parts of your body such as your liver, lungs, kidneys and heart. Sometimes these can lead to death.oStop taking Ximino and get medical help right away if you have any of these symptoms:oskin rash, hives, sores in your mouth, or your skin blisters and peelsoswelling of your face, eyes, lips, tongue, or throatotrouble swallowing or breathingoblood in your urineofever, yellowing of the skin or the whites of your eyes, dark colored urineopain on the right side of the stomach area (abdominal pain)ochest pain or abnormal heartbeatsoswelling in your legs, ankles, and feetodarkening of your nails, skin, eyes, scars, teeth, and gumsThe most common side effects of Ximino include:oheadacheotirednessodizziness or spinning feelingoitchingCall your doctor if you have side effect that bothers you or that does not go away. Your doctor may do tests to check you for side effects during treatment with Ximino.These are not all the side effects with Ximino. Ask your doctor or pharmacist for more information.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store XiminooStore Ximino at room temperature between 68o to 77o (20o to 25o C).oKeep Ximino in the container that it comes in and keep the container tightly closed.oKeep Ximino dry.Keep Ximino and all medicines out of the reach of children.General information about XiminoMedicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use Ximino for condition for which it was not prescribed. Do not give Ximino to other people, even if they have the same symptoms you have. It may harm them.This Patient Information leaflet summarizes the most important information about Ximino. If you would like more information, talk to your doctor. You can ask your doctor or pharmacist for information about Ximino that is written for health professionals.What are the ingredients in XiminoActive Ingredient: minocycline HCl, USP.Inactive Ingredients: colloidal silicon dioxide, D&C Yellow 10 (in 45 mg strength), FD&C Blue 1, FD&C Yellow (in 45 mg and 135 mg strength), gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, and titanium dioxide.The 45 mg, 90 mg, and 135 mg capsules also contain Opadry Clear which contains hypromellose, polyethylene glycol 400, polyethylene glycol 6000, and talc.Ximino also contains black ink which contains black iron oxide, potassium hydroxide, propylene glycol, and shellac.This Patient Information has been approved by the U.S. Food and Drug Administration.XIMINO trademark is the property of Sun Pharmaceutical Industries Limited.Manufactured by:Ohm Laboratories Inc.New Brunswick, NJ 08901Distributed by:Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512 April 2017FDA-11. osafe for use longer than 12 weeks.. osafe and effective for the treatment of infections.. osafe and effective in children under the age of 12 years.. ohave kidney problems. Your doctor may prescribe lower dose of medicine for you. ohave liver problems. ohave diarrhea or watery stools. ohave vision problems. oplan to have surgery with general anesthesia. ohave any other medical conditions. oare male, and you and your female partner are trying to conceive baby. You should not take Ximino.. oare pregnant or plan to become pregnant. Ximino may harm your unborn baby. Taking Ximino while you are pregnant may cause serious side effects on the growth of bone and teeth of your baby. Talk to your doctor before taking Ximino if you plan to become pregnant, or if you are already taking Ximino and plan to become pregnant. Stop taking Ximino and call your doctor right away if you become pregnant while taking Ximino.. oare breastfeeding or plan to breastfeed. Ximino passes into your milk and may harm your baby. You and your doctor should decide if you will take Ximino or breastfeed. You should not do both.. obirth control pills. Ximino may make your birth control pills less effective. You could become pregnant. You should use second form of birth control while taking Ximino.. oa blood thinner medicine.. oa penicillin antibiotic medicine. Ximino and penicillins should not be used together.. oantacids that contain aluminum, calcium, or magnesium or iron-containing products.. oan acne medication that contains isotretinoin. Ximino and isotretinoin should not be used together.. oTake Ximino exactly as your doctor tells you.. oSkipping doses or not taking all doses of Ximino may:omake the treatment not work as well.oincrease the chance that the bacteria will become resistant to Ximino.. omake the treatment not work as well.. oincrease the chance that the bacteria will become resistant to Ximino.. oXimino can be taken with or without food. Taking Ximino with food may lower your chances of getting irritation or ulcers in your esophagus. Your esophagus is the tube that connects your mouth to your stomach.. oSwallow Ximino whole. Do not chew, crush, or split the capsules.. oAvoid sunlight, sunlamps, and tanning beds. Ximino can make your skin sensitive to the sun and the light from sunlamps and tanning beds. You could get severe sunburn.. oWear loose-fitting clothes that protect your skin from sun exposure. Talk to your doctor about other ways to protect your skin while out in sunlight.. oYou should not drive or operate dangerous machinery until you know how Ximino affects you. Ximino may cause you to feel dizzy or lightheaded, or have spinning feeling (vertigo).. oHarm to an unborn baby. See What should tell my doctor before taking Ximino. oPermanent teeth discoloration. Ximino may permanently turn baby or childs teeth yellow-grey-brown during tooth development. Ximino should not be used during tooth development. Tooth development happens in the last half of pregnancy, and from birth to years of age. See What should tell my doctor before taking Ximino. oIntestine infection (pseudomembranous colitis). Pseudomembranous colitis can happen with most antibiotics, including Ximino. Call your doctor right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and fever. Pseudomembranous colitis can happen or more months after you have finished your medication. oSerious liver problems. Stop taking Ximino and call your doctor right away if you get any of the following symptoms of liver problems:oloss of appetiteotirednessodiarrheaoyellowing of your skin or the whites of your eyesounexplained bleedingoconfusionosleepiness oloss of appetite. otiredness. odiarrhea. oyellowing of your skin or the whites of your eyes. ounexplained bleeding. oconfusion. osleepiness. oCentral nervous system effects. See What should avoid while taking Ximino Central nervous system effects such as light headedness, dizziness, and spinning feeling (vertigo) may go away during your treatment with Ximino or if treatment is stopped. Call your doctor if you get headaches that do not go away or blurred vision.. oBenign intracranial hypertension, also called pseudotumor cerebri. This is condition where there is high pressure in the fluid around the brain. This swelling may lead to vision changes and permanent vision loss. Stop taking Ximino and tell your doctor right away if you have blurred vision, vision loss, or unusual headaches.. oImmune system reactions including lupus-like syndrome, hepatitis, and inflammation of blood or lymph vessels (vasculitis). Using Ximino for long time to treat acne may cause immune system reactions. Tell your doctor right away if you get fever, rash, joint pain, or body weakness. Your doctor may do tests to check your blood for immune system reactions.. oSerious rash and allergic reactions. Ximino may cause serious rash and allergic reactions that may affect parts of your body such as your liver, lungs, kidneys and heart. Sometimes these can lead to death.. oStop taking Ximino and get medical help right away if you have any of these symptoms:oskin rash, hives, sores in your mouth, or your skin blisters and peelsoswelling of your face, eyes, lips, tongue, or throatotrouble swallowing or breathingoblood in your urineofever, yellowing of the skin or the whites of your eyes, dark colored urineopain on the right side of the stomach area (abdominal pain)ochest pain or abnormal heartbeatsoswelling in your legs, ankles, and feetodarkening of your nails, skin, eyes, scars, teeth, and gums. oskin rash, hives, sores in your mouth, or your skin blisters and peels. oswelling of your face, eyes, lips, tongue, or throat. otrouble swallowing or breathing. oblood in your urine. ofever, yellowing of the skin or the whites of your eyes, dark colored urine. opain on the right side of the stomach area (abdominal pain). ochest pain or abnormal heartbeats. oswelling in your legs, ankles, and feet. odarkening of your nails, skin, eyes, scars, teeth, and gums. oheadache. otiredness. odizziness or spinning feeling. oitching. oStore Ximino at room temperature between 68o to 77o (20o to 25o C).. oKeep Ximino in the container that it comes in and keep the container tightly closed.. oKeep Ximino dry.. April 2017FDA-11.

SPL UNCLASSIFIED SECTION.

1.1 Indication. Ximino is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older.To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, Ximino should be used only as indicated [see Warnings and Precautions (5.11)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oMinocycline like other tetracycline-class drugs can cause fetal harm when administered to pregnant woman. (5.1, 8.1). oMinocycline like other tetracycline-class drugs can cause fetal harm when administered to pregnant woman. (5.1, 8.1). 8.1 Pregnancy. Teratogenic Effects: Pregnancy Category [see Warnings and Precautions (5.1)]Ximino 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 can cause fetal harm when administered to pregnant woman.Spontaneous reports of congenital anomalies including limb reduction have been reported with minocycline use in pregnancy in postmarketing 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 times and times, respectively, the systemic exposure to minocycline observed in patients as result of use of Ximino). Reduced mean fetal body weight was observed in studies in which minocycline was administered to pregnant rats at 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 Ximino).Minocycline was assessed for effects on peri- and post-natal development of rats in study that involved oral administration to pregnant rats from day 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 result of use of Ximino). 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, 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. Ximino 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 have not been established.Use of tetracycline-class antibiotics below the age of 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oThe use of Ximino during tooth development (last half of pregnancy, infancy, and childhood up to the age of years) may cause permanent discoloration of the teeth (yellow-gray-brown). (5.1)oIf pseudomembranous colitis occurs, discontinue Ximino. (5.2)oIf liver injury is suspected, discontinue Ximino. (5.3)oIf renal impairment exists, Ximino doses may need to be adjusted to avoid excessive systemic accumulations of the drug and possible liver toxicity. (5.4)oMinocycline may cause central nervous system side effects including light-headedness, dizziness, or vertigo. Advise patients. (5.5)oMinocycline may cause pseudotumor cerebri (benign intracranial hypertension) in adults and adolescents. Discontinue Ximino if symptoms occur. (5.6)oMinocycline has been associated with autoimmune syndromes; discontinue Ximino immediately if symptoms occur. (5.7)oMinocycline has been associated with anaphylaxis, serious skin reactions, erythema multiforme, and DRESS syndrome. Discontinue Ximino immediately if symptoms occur. (5.9). oThe use of Ximino during tooth development (last half of pregnancy, infancy, and childhood up to the age of years) may cause permanent discoloration of the teeth (yellow-gray-brown). (5.1). oIf pseudomembranous colitis occurs, discontinue Ximino. (5.2). oIf liver injury is suspected, discontinue Ximino. (5.3). oIf renal impairment exists, Ximino doses may need to be adjusted to avoid excessive systemic accumulations of the drug and possible liver toxicity. (5.4). oMinocycline may cause central nervous system side effects including light-headedness, dizziness, or vertigo. Advise patients. (5.5). oMinocycline may cause pseudotumor cerebri (benign intracranial hypertension) in adults and adolescents. Discontinue Ximino if symptoms occur. (5.6). oMinocycline has been associated with autoimmune syndromes; discontinue Ximino immediately if symptoms occur. (5.7). oMinocycline has been associated with anaphylaxis, serious skin reactions, erythema multiforme, and DRESS syndrome. Discontinue Ximino immediately if symptoms occur. (5.9). 5.1 Teratogenic Effects. A. Minocycline, like other tetracycline-class drugs, can cause fetal harm when administered to 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.Ximino should not be used during pregnancy or by individuals of either gender who are attempting to conceive child [see Nonclinical Toxicology (13.1) and 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 years) may cause permanent discoloration of the 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. Enamel hypoplasia has also been reported. Tetracycline drugs, therefore, should not be used during tooth development.C. All tetracyclines form stable calcium complex in any bone-forming tissue. decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every hours. The decrease in fibula growth rate 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 and 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 of C. difficile, and surgical evaluation should be instituted as clinically indicated.. 5.3 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.. 5.4 Metabolic Effects. The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline-class drugs may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy is prolonged, serum level determinations of the drug may be advisable.. 5.5 Central Nervous System Effects. Central nervous system side effects including light-headedness, dizziness or vertigo have been reported with minocycline therapy. Patients who experience these symptoms should be cautioned about driving vehicles or using hazardous machinery while on minocycline therapy. These symptoms may disappear during therapy and usually disappear when the drug is discontinued.. 5.6 Benign Intracranial Hypertension. Pseudotumor cerebri (benign intracranial hypertension) in adults and adolescents has been associated with the use of tetracyclines. Minocycline has been reported to cause or precipitate pseudotumor cerebri, the hallmark of which is papilledema. Clinical manifestations include headache and blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. Although signs and symptoms of pseudotumor cerebri resolve after discontinuation of treatment, the possibility for permanent sequelae such as visual loss that may be severe exists. Patients should be questioned for visual disturbances prior to initiation of treatment with tetracyclines. If visual disturbance occurs during treatment, patients should be checked for papilledema. Concomitant use of isotretinoin and minocycline should be avoided because isotretinoin, systemic retinoid, is also known to cause pseudotumor cerebri.. 5.7 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. In symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use of all tetracycline-class drugs should be discontinued immediately.. 5.8 Photosensitivity. 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.. 5.9 Serious Skin/Hypersensitivity Reaction. 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, the drug should be discontinued immediately.. 5.10 Tissue Hyperpigmentation. Tetracycline-class antibiotics are known to cause hyperpigmentation. Tetracycline therapy 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.. 5.11 Development of Drug-Resistant Bacteria. Bacterial resistance to the tetracyclines may develop in patients using Ximino, therefore, the susceptibility of bacteria associated with infection should be considered in selecting antimicrobial therapy. Because of the potential for drug-resistant bacteria to develop during the use of Ximino, it should be used only as indicated.. 5.12 Superinfection. As with other antibiotic preparations, use of Ximino may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, Ximino should be discontinued and appropriate therapy instituted.. 5.13 Laboratory Monitoring. Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic studies should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated.