MINOCIN- minocycline hydrochloride_capsule, coated pellets

CLINICAL PHARMACOLOGY
Following a single dose of two MINOCIN registered When MINOCIN registered registered max registered In previous studies with other minocycline dosage forms, the minocycline serum half-life ranged from 11 to 16 hours in 7 patients with hepatic dysfunction, and from 18 to 69 hours in 5 patients with renal dysfunction. The urinary and fecal recovery of minocycline when administered to 12 normal volunteers was one-half to one-third that of other tetracyclines.
Microbiology
Mechanism of Action The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including minocycline, have a similar antimicrobial spectrum of activity against a wide range of gram-positive and gram-negative organisms. Cross-resistance of these organisms to tetracycline is common. List of Microorganisms Minocycline has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE Gram-positive Bacteria Bacillus anthracis Listeria monocytogenes Staphylococcus aureus Streptococcus pneumoniae Gram-negative Bacteria Bartonella bacilliformis Brucella Klebsiella granulomatis Campylobacter fetus Francisella tularensis Haemophilus ducreyi Vibrio cholerae Yersinia pestis Acinetobacter Enterobacter aerogenes Escherichia coli Haemophilus influenzae Klebsiella Neisseria gonorrhoeae 1 Neisseria meningitidis 1 Shigella Other Microorganisms Actinomyces Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Clostridium Entamoeba Fusobacterium nucleatum fusiforme Mycobacterium marinum Mycoplasma pneumoniae Propionibacterium acnes Treponema pallidum pallidum Treponema pallidum pertenue Ureaplasma urealyticum
ANIMAL PHARMACOLOGY AND TOXICOLOGY
MINOCIN registered

MINOCIN registered Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox and tick fevers caused by rickettsiae. Mycoplasma pneumoniae Chlamydia trachomatis Chlamydophila psittaci Chlamydia trachomatis Chlamydia trachomatis Ureaplasma urealyticum Chlamydia trachomatis Borrelia recurrentis Haemophilus ducreyi Yersinia pestis Francisella tularensis Vibrio cholerae Campylobacter fetus Brucella Bartonella bacilliformis Klebsiella granulomatis Minocycline is indicated for the treatment of infections caused by the following gram-negative microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Escherichia coli. Enterobacter aerogenes. Shigella Acinetobacter Haemophilus influenzae. Klebsiella MINOCIN registered Upper respiratory tract infections caused by Streptococcus pneumoniae. Staphylococcus aureus. When penicillin is contraindicated, minocycline is an alternative drug in the treatment of the following infections: Uncomplicated urethritis in men due to Neisseria gonorrhoeae Neisseria gonorrhoeae Treponema pallidum pallidum Treponema pallidum pertenue Listeria monocytogenes Bacillus anthracis Fusobacterium fusiforme Actinomyces israelii Clostridium In acute intestinal amebiasis In severe acne Oral minocycline is indicated in the treatment of asymptomatic carriers of Neisseria meningitidis Oral minocycline is not indicated for the treatment of meningococcal infection. Although no controlled clinical efficacy studies have been conducted, limited clinical data show that oral minocycline hydrochloride has been used successfully in the treatment of infections caused by Mycobacterium marinum To reduce the development of drug-resistant bacteria and maintain the effectiveness of MINOCIN registered registered

THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF MINOCYCLINE DIFFERS FROM THAT OF THE OTHER TETRACYCLINES. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS. MINOCIN registered CLINICAL PHARMACOLOGY Ingestion of adequate amounts of fluids along with capsule and tablet forms of drugs in the tetracycline-class is recommended to reduce the risk of esophageal irritation and ulceration. The pellet-filled capsules should be swallowed whole. For Pediatric Patients Above 8 Years Of Age Usual pediatric dose: 4 mg/kg initially followed by 2 mg/kg every 12 hours, not to exceed the usual adult dose. Adults The usual dosage of MINOCIN registered Uncomplicated gonococcal infections other than urethritis and anorectal infections in men: 200 mg initially, followed by 100 mg every 12 hours for a minimum of 4 days, with post-therapy cultures within 2 to 3 days. In the treatment of uncomplicated gonococcal urethritis in men, 100 mg every 12 hours for 5 days is recommended. For the treatment of syphilis, the usual dosage of minocycline hydrochloride should be administered over a period of 10 to 15 days. Close follow-up, including laboratory tests, is recommended. In the treatment of meningococcal carrier state, the recommended dosage is 100 mg every 12 hours for 5 days. Mycobacterium marinum Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis Ureaplasma urealyticum Ingestion of adequate amounts of fluids along with capsule and tablet forms of drugs in the tetracycline-class is recommended to reduce the risk of esophageal irritation and ulceration. The pharmacokinetics of minocycline in patients with renal impairment (CL CR WARNINGS

Due to oral minocycline's virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines. Body as a whole Gastrointestinal DOSAGE AND ADMINISTRATION Genitourinary Hepatic toxicity PRECAUTIONS Skin WARNINGS Respiratory Renal toxicity WARNINGS Musculoskeletal Hypersensitivity reactions Blood Central Nervous System PRECAUTIONS - General Other Tooth discoloration in children less than 8 years of age (see WARNINGS Oral cavity discoloration (including tongue, lip, and gum) have been reported. Tinnitus and decreased hearing have been reported in patients on MINOCIN. The following syndromes have been reported. In some cases involving these syndromes, death has been reported. As with other serious adverse reactions, if any of these syndromes are recognized, the drug should be discontinued immediately: Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis. Fever and lymphadenopathy may be present. Lupus-like syndrome consisting of positive antinuclear antibody; arthralgia, arthritis, joint stiffness, or joint swelling; and one or more of the following: fever, myalgia, hepatitis, rash, and vasculitis. Serum sickness-like syndrome consisting of fever; urticaria or rash; and arthralgia, arthritis, joint stiffness, or joint swelling. Eosinophilia may be present. To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines or to any of the components of the product formulation.

Pregnancy
Teratogenic Effects: Pregnancy Category D WARNINGS All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. There are no adequate and well-controlled studies on the use of minocycline in pregnant women. Minocycline, like other tetracycline-class antibiotics, 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 in post-marketing experience. Only limited information is available regarding these reports; therefore, no conclusion on causal association can be established. If minocycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Nonteratogenic Effects WARNINGS
Nursing Mothers
Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from the tetracyclines, 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
Pediatric Use
Minocycline is not recommended for the use in children below 8 years of age unless the expected benefits of therapy outweigh the risks. (See WARNINGS
Geriatric Use
Clinical studies of oral minocycline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 of concomitant disease or other drug therapy. (See WARNINGS DOSAGE AND ADMINISTRATION MINOCIN registered

Drug Interactions
Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. Administration of isotretinoin should be avoided shortly before, during, and shortly after minocycline therapy. Each drug alone has been associated with pseudotumor cerebri. (See PRECAUTIONS Increased risk of ergotism when ergot alkaloids or their derivatives are given with tetracyclines.
Drug/Laboratory Test Interactions
False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro Dilution techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tetracycline (class) or minocycline powder 1,2 Diffusion techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method 2,3 Table 1: Susceptibility Test Interpretive Criteria for Minocycline and Tetracycline Species Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL) S I R S I R S I R Enterobacteriaceae Organisms that are susceptible to tetracycline are also considered susceptible to minocycline. However some organisms that are intermediate or resistant to tetracycline may be susceptible to minocycline. Minocycline <= 4 8 >=16 >=16 13 - 15 <=12 Tetracycline <= 4 8 >=16 >=15 12 - 14 <=11 Acinetobacter Minocycline <=4 8 >=16 >=16 13 - 15 <=12 Tetracycline <=4 8 >=16 >=15 12 - 14 <=11 Haemophilus influenzae Tetracycline <=2 4 >=8 >=29 26 - 28 <=25 Streptococcus pneumoniae’ Tetracycline <=1 2 >=4 >=28 25 - 27 <=24 Staphylococcus aureus Minocycline <=4 8 >=16 >=19 15 - 18 <=14 Tetracycline <=4 8 >=16 >=19 15 - 18 <=14 Vibrio cholerae Minocycline <=4 8 >=16 >=16 13 - 15 <=12 Tetracycline <=4 8 >=16 >=19 15 - 18 <=14 Neisseria meningitidis The current absence of resistance isolates precludes defining any result other than “susceptible”. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. Minocycline -- -- -- > -- -- <=2 -- -- Bacillus anthracis Tetracycline <=1 -- -- Francisella tularensis Tetracycline <=4 -- -- Yersinia pestis Tetracycline <=4 8 >=16 Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test 1,2,3 Table 2: Acceptable Quality Control Ranges for Minocycline and Tetracycline Species Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL) Enterococcus faecalis Minocycline 1 en dash 4 -- -- Tetracycline 8 en dash 32 -- -- Escherichia coli Minocycline 0.25 en dash 1 19 en dash 25 -- Tetracycline 0.5 en dash 2 18 en dash 25 -- Haemophilus influenzae Tetracycline 4 en dash 32 14 en dash 22 -- Neisseria gonorrhoeae Tetracycline -- 30 en dash 42 0.25 en dash 1 Staphylococcus aureus Minocycline 25 en dash 30 -- Tetracycline 24 en dash 30 -- Staphylococcus aureus Minocycline 0.06 en dash 0.5 -- Tetracycline 0.12 en dash 1 -- Streptococcus pneumoniae Tetracycline 0.06 en dash 0.5 27 en dash 31 --
WARNINGS
Tooth Development Minocin, like other tetracycline-class antibiotics, can cause fetal harm when administered to a pregnant woman. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline drugs, therefore, should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated. Skeletal Development All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued. Use in Pregnancy Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has been noted in animals treated early in pregnancy. Dermatologic Reaction Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) including fatal cases have been reported with minocycline use. If this syndrome is recognized, the drug should be discontinued immediately. Antianabolic Action The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis. Under such conditions, monitoring of creatinine and BUN is recommended, and the total daily dosage should not exceed 200 mg in 24 hours. (See DOSAGE AND ADMINISTRATION Photosensitivity Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. This has been reported with minocycline. Central Nervous System 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 rapidly when the drug is discontinued. Clostridium difficile Clostridium difficile registered C. difficile C. difficile C. difficile If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile C. difficile Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including Minocin. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and Minocin should be avoided because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Dietary administration of minocycline in long term tumorigenicity studies in rats resulted in evidence of thyroid tumor production. Minocycline has also been found to produce thyroid hyperplasia in rats and dogs. In addition, there has been evidence of oncogenic activity in rats in studies with a related antibiotic, oxytetracycline (ie, adrenal and pituitary tumors). Likewise, although mutagenicity studies of minocycline have not been conducted, positive results in in vitro mammalian cell assays (ie, mouse lymphoma and Chinese hamster lung cells) have been reported for related antibiotics (tetracycline hydrochloride and oxytetracycline). Segment I (fertility and general reproduction) studies have provided evidence that minocycline impairs fertility in male rats.
Labor and Delivery
The effect of tetracyclines on labor and delivery is unknown.
OVERDOSAGE
The adverse events more commonly seen in overdose are dizziness, nausea, and vomiting. No specific antidote for minocycline is known. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures. Minocycline is not removed in significant quantities by hemodialysis or peritoneal dialysis.
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Ninth Edition; CLSI Document M07-A9, Vol. 32, No. 2, January, 2012. Clinical and Laboratory Standards, 940 West Valley Rd., Suite 2500, Wayne, PA 19087-1898. 2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-Eleventh Edition; CLSI Document M02-A11, Vol. 32, No. 1, January, 2012. Clinical and Laboratory Standards, 940 West Valley Rd., Suite 2500, Wayne, PA 19087-1898. 3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement. Document M100-S24, Vol. 32, No. 3, January, 2014. Clinical and Laboratory Standards, 940 West Valley Rd., Suite 2500, Wayne, PA 19087-1898. Manufactured for: Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA By: Patheon Pharmaceuticals Inc., Cincinnati, OH 45237 Minocin is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates. copyright 9438600 Rev. 04
PATIENT INFORMATION
MINOCIN registered Pellet-Filled Capsules, 50 mg, 75 mg and 100 mg Read the Patient Information that comes with MINOCIN registered What is MINOCIN registered MINOCIN registered registered registered Sometimes other germs, called viruses cause infections. The common cold is a virus. MINOCIN registered Who should not use MINOCIN registered Do not take MINOCIN registered Ask your doctor or pharmacist for a list of these medications if you are not sure. See the end of this leaflet for a complete list of ingredients in MINOCIN registered MINOCIN registered MINOCIN registered MINOCIN registered What should I tell my doctor before starting MINOCIN registered Tell your doctor about all of your medical conditions, including if you: have liver or kidney problems are pregnant or planning to become pregnant. registered Stop taking MINOCIN registered are breast feeding. registered registered Tell your doctor about all the medicines you are taking including prescription and non-prescription medications, vitamins, and herbal supplements. MINOCIN registered birth control pills. registered a blood thinner medicine. a penicillin antibiotic medicine. registered Migraine medicines called ergot alkaloids An acne medicine called isotretinoin (Accutane, Amnesteem, Claravis, Sotret). Antacids that contain aluminum, calcium, or magnesium, or iron-containing products. Know the medicines you take, keep a list of them to show your doctor and pharmacist each time you get a new medicine. How should I take MINOCIN registered Take MINOCIN registered registered Decrease the effectiveness of the treatment Increase the chance that bacteria will develop resistance to MINOCIN registered Take MINOCIN registered registered MINOCIN registered registered If you take too much MINOCIN registered What are the possible side effects of MINOCIN registered MINOCIN registered registered watery diarrhea bloody stools stomach cramps unusual headaches blurred vision fever rash joint pain feeling very tired MINOCIN registered central nervous system effects. sun sensitivity (photosensitivity). registered registered These are not all the side effects with MINOCIN registered CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store MINOCIN registered Store MINOCIN registered Throw away any MINOCIN registered Keep MINOCIN registered General advice about MINOCIN registered Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use MINOCIN registered registered This Patient Information leaflet summarizes the most important information about MINOCIN registered If you would like more information, talk with your doctor. Your doctor or pharmacist can give you information about MINOCIN registered What are the ingredients in MINOCIN registered Active ingredient: Inactive ingredients: Manufactured for: Valeant Pharmaceuticals North America LLC By: Patheon Pharmaceuticals Inc. 9438600 03/2015 Rev. 04

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MINOCIN- minocycline hydrochloride_capsule, coated pellets Product manual source documgent