MINOCYCLINE HYDROCHLORIDE- minocycline hydrochloride_capsule

Following a single dose of two minocycline hydrochloride capsules, 100 mg administered to 18 normal fasting adult volunteers, maximum serum concentrations were attained in 1 to 4 hours (average 2.1 hours) and ranged from 2.1 to 5.1 µg/mL (average 3.5 µg/mL). The serum half-life in the normal volunteers ranged from 11.1 to 22.1 hours (average 15.5 hours). When minocycline hydrochloride capsules were given concomitantly with a high-fat meal, which included dairy products, the extent of absorption of minocycline hydrochloride capsules was unchanged compared to dosing under fasting conditions. The mean T max 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. Antimicrobial Activity Minocycline has been shown to be active against most strains of the following microorganisms, both in vitro 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 Rickettsiae Treponema pallidum pallidum Treponema pallidum pertenue Ureaplasma urealyticum Susceptibility Test Methods When available, the clinical microbiology laboratory should provide cumulative reports 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 a b Species Minimal Inhibitory Concentration ( mcg / mL ) Zone Diameter ( mm ) Agar Dilution ( mcg / mL ) S I R S I R S I R Enterobacteriaceae a Acinetobacter a Tetracycline <= 4 8 >=16 >=15 12 to 14 <= 11 Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus a Vibrio a Neisseria b Bacillus b Francisella b Yersinia pestis A report of Susceptible Intermediate Resistant 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 Escherichia coli Haemophilus influenzae Neisseria gonorrhoeae Staphylococcus aureus Staphylococcus aureus Streptococcus pneumoniae ATCC 49619

Minocycline hydrochloride capsules, USP are indicated in the treatment of the following infections due to susceptible strains of the designated microorganisms: Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox and tick fevers caused by rickettsiae. Respiratory tract infections caused by Mycoplasma pneumoniae Lymphogranuloma venereum caused by Chlamydia trachomatis Psittacosis (Ornithosis) due to Chlamydophila psittaci Trachoma caused by Chlamydia trachomatis Inclusion conjunctivitis caused by Chlamydia trachomatis Nongonococcal urethritis, endocervical, or rectal infections in adults caused by Ureaplasma urealyticum Chlamydia trachomatis Relapsing fever due to Borrelia recurrentis Chancroid caused by Haemophilus ducreyi Plague due to Yersinia pestis Tularemia due to Francisella tularensis Cholera caused by Vibrio cholerae. Campylobacter fetus infections caused by Campylobacter fetus Brucellosis due to Brucella Bartonellosis due to Bartonella bacilliformis. Granuloma inguinale caused by 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 Respiratory tract infections caused by Haemophilus influenzae Respiratory tract and urinary tract infections caused by Klebsiella Minocycline hydrochloride capsules, USP are indicated for the treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Upper respiratory tract infections caused by Streptococcus pneumoniae Skin and skin structure infections caused by 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 Infections in women caused by Neisseria gonorrhoeae Syphilis caused by Treponema pallidum pallidum Yaws caused by Treponema pallidum pertenue Listeriosis due to Listeria monocytogenes Anthrax due to Bacillus anthracis Vincent's infection caused by Fusobacterium fusiforme Actinomycosis caused by Actinomyces israelii Infections caused by 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 minocycline hydrochloride capsules, USP and other antibacterial drugs, minocycline hydrochloride capsules, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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 en dash General Other Tooth discoloration in children less than 8 years of age (See WARNINGS Oral cavity discoloration (including tongue, lip, and gum) has been reported. Tinnitus and decreased hearing have been reported in patients on minocycline hydrochloride. 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 and lymphadenopathy. Eosinophilia may be present. To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharmaceuticals Inc. at 1-269-544-2299 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
Risk Summary 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). Minocycline hydrochloride capsules (50 mg, 75 mg and 100 mg) do not contain sodium.

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.

WARNINGS
Tooth Development Minocycline hydrochloride, 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 antianabolic 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 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 minocycline hydrochloride. 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 minocycline hydrochloride 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 (i.e., adrenal and pituitary tumors). Likewise, although mutagenicity studies of minocycline have not been conducted, positive results in in vitro
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. DOSAGE AND ADMINISTRATION 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. Minocycline hydrochloride capsules may be taken with or without food (See 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 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 minocycline hydrochloride capsules is 200 mg initially followed by 100 mg every 12 hours. Alternatively, if more frequent doses are preferred, two or four 50 mg capsules may be given initially followed by one 50 mg capsule 4 times daily. 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
REFERENCES
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard- Tenth Edition; CLSI Document M07- A10, Vol. 2, January, 2015. Clinical and Laboratory Standards, 940 West Valley Rd. , Suite 2500, Wayne, PA 19087-1898. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard- Twelfth Edition; CLSI Document M02- A12, Vol. 1, January, 2015. , Suite 2500, Wayne, PA 19087-1898, 3. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-sixth Informational Supplement. Document M100-S26, Vol. 3, January, 2016. , Suite 2500, Wayne, PA 19087-1898, For further product information, call Torrent Pharmaceuticals Inc. at 1-269-544-2299. Manufactured by Ohm Laboratories Inc. , North Brunswick, NJ 08902. 8064276 Revised May 2017 Manufactured by WellSpring Pharma Services Inc. , OakVille ON, L6H 1M5 CANADA N4525B Revised November 2017 Manufactured for TORRENT PHARMA INC. , Basking Ridge, NJ 07920.

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