PRODUCT MONOGRAPH

pms-MINOCYCLINE

(Minocycline Hydrochloride Capsules, USP) Antibiotic

ACTION

pms-MINOCYCLINE is a tetracycline with antibacterial activity against some Gram-negative and Gram-positive organisms. The action of pms-MINOCYCLINE is primarily bacteriostatic and it is thought to exert its antimicrobial effect by the inhibition of protein synthesis. The bioavailability study was performed on healthy volunteers using Gen-MINOCYCLINE 100 mg capsules. The rate and extent of absorption of Minocycline Hydrochloride after a single dose of 100 mg Gen-MINOCYCLINE and the marketed brand was measured and compared. The pharmacokinetic data are presented in the table below:

* for Tmax and T1/2 arithmetic mean (C.V. %) are presented.

* *the potency corrected ratio of means of the test product

CONTRAINDICATIONS

History of hypersensitivity to Minocycline Hydrochloride or any other tetracycline.

WARNINGS

Newborns. Infants and Children:

The use of tetracyclines, including pms-MINOCYCLINE during tooth development (last half of pregnancy, infancy and childhood under the age of thirteen years) has been shown to cause permanent tooth discolouration (yellow-grey-brown). This is more common during long-term use, but has been observed following short-term courses. Enamel hypoplasia has also been reported. All tetracyclines including pms-MINOCYCLINE form a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This appeared to be reversible when the drug was discontinued. Minocycline should not be used in such patients unless other drugs are ineffective or are contraindicated.

Pregnancy and Lactation:

Tetracyclines, including pms-MINOCYCLINE, are not recommended during pregnancy and lactation because of possible adverse effects on developing bones and teeth of the fetus and neonate. 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 also been noted in animals treated early in pregnancy. The safety of pms-MINOCYCLINE for use during pregnancy has not been established. Tetracyclines, including pms-MINOCYCLINE, are excreted in the milk of lactating women. It is advisable to avoid giving pms-MINOCYCLINE in conjunction with penicillin since some bacteriostatic drugs may interfere with the bactericidal action of penicillin. pms-MINOCYCLINE should not be used for the treatment of streptococcal diseases unless the organism is demonstrated to be sensitive, since most streptococci have been found to be resistant to tetracycline drugs. If it is deemed necessary that infection due to Group A beta-hemolytic streptococci be treated with pms-MINOCYCLINE, then such treatment should be continued for at least ten days. In the presence of significant renal impairment, usual oral doses may Iead to excessive systemic accumulations of pms-MINOCYCLINE and possible liver toxicity. Under such conditions, lower than usual doses may be indicated. After initial therapy, and if therapy is prolonged. serum level determinations of the drug are advisable. The anti-anabolic action of tetracyclines can also produce dose-related increases in BUN, consequently, in patients with significant renal impairment, elevated serum pms-MINOCYCLINE levels can lead to azotemia, hypophosphatemia and acidosis. Renal failure, including interstitial nephritis has been reported rarely. pms-MINOCYCLINE is capable of aggravating the symptoms associated with lupus erythematosus. Therefore, caution should be taken when administering the drug to patients with this disease. Minocycline Hydrochloride has been shown to depress plasma prothrombin activity. Therefore, patients who are on anticoagulant therapy should be monitored regularly and may require downward adjustment of their anticoagulant dosage. Interference with vitamin K synthesis by micro-organisms in the gut has been reported. Cross-sensitization among the various tetracyclines is extremely common. Pigmentation of skin, thyroid, bone and teeth have been reported occasionally in persons receiving Minocycline Hydrochloride for extended periods of time. The pigmentation may be irreversible. Reduced efficacy and increased incidence of breakthrough bleeding has been suggested with concomitant use of tetracycline and oral contraceptive preparations.

PRECAUTIONS

The administration of pms-MINOCYCLINE to children under 13 years of age is not recommended. Bulging fontanelles have been reported in young infants following full therapeutic dosage of tetracyclines including Minocycline Hydrochloride. Pseudotumor cerebri has been reported in adults. (See Adverse Reactions section). Patients should be warned to avoid exposure to direct sunlight and/or ultraviolet light while under treatment with pms-MINOCYCLINE or other tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema or discomfort. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Studies to date indicate that photosensitivity is rarely reported with Minocycline Hydrochloride. Patients treated with pms-MINOCYCLINE may suffer from headaches, light-headedness, dizziness or vertigo. Decreased hearing has been rarely reported in patients on Minocycline Hydrochloride. Administration of pms-MINOCYCLINE in excess of the recommended dosage can increase the frequency and severity of these CNS symptoms. Patients should be cautioned about driving vehicles or using hazardous machinery while on pms-MINOCYCLINE therapy. These symptoms may disappear during therapy and usually disappear rapidly when the drug is discontinued. As with other antibiotics, pms-MINOCYCLINE therapy may result in overgrowth of non-susceptible organisms (including fungi). If superinfection occurs, pms-MINOCYCLINE should be discontinued and appropriate therapy instituted. The development of cross-resistance to many antibiotics can develop rapidly in several species of micro-organisms. The clinician should bear this in mind if therapy with pms-MINOCYCLINE is not achieving expected results. The frequency of resistance to pms-MINOCYCLINE in hemolytic streptococci is highest in strains from infections of the ear, wounds and skin. Culture and sensitivity studies should be performed whenever feasible and routinely in suspected streptococcal infections. Since sensitivity reactions are more likely to occur in persons with a history of allergy, asthma, hay fever, or urticaria, pms-MINOCYCLINE should be used with caution in such individuals. Before treating patients with gonorrhea, a darkfield examination should be made from any lesion suggestive of concurrent syphilis. Serological tests for syphilis should be repeated monthly for at least 4 months. pms-MINOCYCLINE should be used with caution in patients with hepatic dysfunction and in conjunction with alcohol or other hepatotoxic drugs. ln long-term therapy with pms-MINOCYCLINE, periodic laboratory evaluation of organ systems including haematopoietic, renal and hepatic studies, should be performed. Minocycline Hydrochloride has been shown to depress plasma prothrombin activity. Therefore, patients who are on anticoagulant therapy should be monitored regularly and may require downward adjustment of their anticoagulant dosage. Interference with vitamin K synthesis by micro-organisms in the gut has been reported. Antacids containing aluminum, calcium or magnesium and oral iron preparations impair absorption and should not be given to patients taking oral pms-MINOCYCLINE. Dairy products can delay absorption. Studies to date have been indicated that the absorption of Minocycline Hydrochloride is not notably influenced by foods.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms and Signs:

Dizziness, nausea, vomiting, abdominal pain, intestinal hemorrhage, hypotension, lethargy, coma, acidosis, azotemia without a concomitant rise in creatinine.

Treatment:

Specific antidote: None. Pmseral antidotes: Antacids (e.g., calcium carbonate or lactate, milk of magnesia, aluminium hydroxide) which form relatively insoluble complexes with Pms- MINOCYCLINE. (Calcium Solution 5%: 50 Gm calcium carbonate or lactate dissolved in 1000 mL water, yields a 5% solution). Gastric lavage, if necessary.

DOSAGE AND ADMINISTRATION

Children 13 Years of Age or Older: The usual dosage of pms-MINOCYCLINE is 4 mg/kg initially followed by 2 mg/kg every 12 hours. Tetracyclines are not recommended in children under 13 years of age (see WARNINGS).

Adults:

The usual oral dosage of pms-MINOCYCLINE is 100 mg or 200 mg initially, followed by 100 mg every 12 hours. Alternatively, if more frequent doses are preferred, two or four 50 mg doses may be given initially, followed by one 50 mg dose every 6 hours. Therapy should be continued for 1 or 2 days beyond the time when characteristic symptoms or fever have subsided. For treatment of syphilis, pms-MINOCYCLINE therapy should be administered over a period of 10 or 15 days. Close followup, including laboratory tests, is recommended. Concomitant therapy: Antacids containing aluminum, calcium or magnesium and/or iron preparations impair absorption and should not be given to patients taking pms-MINOCYCLINE.

PHARMACEUTICAL INFORMATION

Chemistry: Trade Name: pms-MINOCYCLINE Proper Name: Minocycline Hydrochloride Chemical Name: 4, 7-Bis(dimethylamino)-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydro-3, 10,12, 12a-tetrahydroxy-1, 11 dioxo-2-naphthacenecarboxamide monohydrochloride. Structural Formula: Molecular Formula: C23H27N307. HCl Molecular Weight: 493.94

Description:

Minocycline hydrochloride is a yellow crystalline powder which is slightly hydroscopic and slightly sensitive to light and oxidation.

Composition: Each pms-MINOCYCLINE capsule contains: Lactose Monohydrate (Spray Dried), Starch Corn, Magnesium Stearate, Capsule #3 CS Med Orange OP "G"/Med Orange OP "M50" *, Capsule #2 CS Lavender OP "G"/Med Orange OP "M100" * *, ink * * *. * The capsule shell body (Medium Orange Opaque) contains: D&C Yellow #10, FD&C Red #40, Titanium Dioxide, Gelatin-NF. * * The capsule shell cap (Lavender Opaque) contains: FD&C Blue #1, FD&C Red #40, D&C Red #28, Titanium Dioxide, Gelatin-NF. * * * The ink contains: Pharmaceutical Glaze (Modified) in SD-45, Synthetic Black Iron Oxide, SDA- 3A Alcohol, FD&C Blue No.2 Aluminum Lake, FD&C Red No.40 Aluminum Lake, FD&C Blue No.1 Aluminum Lake, D&C Yellow No.10 Aluminum Lake, n-Butyl Alcohol and Propylene Glycol.

Stability and Storage Recommendations

: Store at 15-30 degC. Protect from light.

AVAILABILITY OF DOSAGE FORMS

Availability:

pms-MINOCYCLINE is available in 50 mg and 100 mg capsules. Potency is calculated in terms of minocycline base.

Description: 50 mg Capsules: Hard gelatin capsules with medium orange body and medium orange opaque cap. The body has "P" and the cap has "50" both printed in White ink. 100 mg Capsules: Hard gelatin capsules with medium orange body and lavender orange opaque cap. The body has "P" and the cap has "100" both printed in white ink.

Package Sizes: pms-MINOCYCLINE 50 mg Capsules: Bottles of 100. pms-MINOCYCLINE 100 mg Capsules: Bottles of 100.

MICROBIOLOGY

This survey of the in vitro activity of minocycline against clinical isolates was compiled from data presented in 130 articles published from 1967 to 1980. The MICs of minocycline against clinical isolates representing gram-positive, gram-negative, actinomycetes, acid-fast and anaerobic bacteria and mycoplasma, were recorded and entered into a computer data-base file. The percent of clinical isolates inhibited at various antibiotic concentrations was determined directly from the total number of isolates tested by a computer-assisted statistical analysis system program.

SUSCEPTIBILITY TESTING

Tube-Dilution Testing:

Microorganisms may be considered susceptible (likely to respond to minocycline therapy), moderately susceptible (harbouring partial resistance) or resistant (not likely to respond to minocycline therapy) depending on the minimum inhibitory concentration (M.I.C.) as follows:

Minocycline M.I.C. Interpretive Standards (mg/L) Susceptible Moderately Susceptible Resistant

< 4 8 > 16

Acceptable Quality Control Ranges of M.1.C. for Referenced Strains:

Plate Testing:

If the Kirby-Bauer method of susceptibility testing (using a 30 mcg tetracycline disc) gives a zone of 19 mm or greater, the bacterial strain is considered to be susceptible to any tetracycline. A zone of 14 mm or less is considered resistant.

For Staphylococcal species, minocycline powder may be used for additional susceptibility testing. Acceptable Quality Control Limits (Zone Diameter) for Disc Susceptibility testing of reference strains:

PHARMACOLOGY

Animal Pharmacology: Blood levels produced following oral dosing of Minocycline Hydrochloride to various animal species were: 21 mg/L at steady state monkeys administered 30 mg/kg, and 6.5 mg/L at 3 hours post-dose in rats given a single 25 mg/kg dose, Minocycline Hydrochloride was extensively distributed to all tissues examined in 14C-labelled drug studies in dogs.

Human Pharmacology:

Serum concentrations in normal adults given a single 200 mg capsule averaged 2.24 (0.74 - 4.45) mg/L at one hour and 1.25 (0.34 - 2.36) mg/L at 12 hours. After a single oral dose of 150 mg, Minocycline Hydrochloride has a serum half-life of about 16 hours. In a group of 5 healthy male volunteers, serum levels of 1.4 - 1.8 mg/L were maintained at 12 and 24 hours with doses of 100 mg every 12 hours for three days. When given 200 mg once daily for three days, the serum levels had fallen to approximately 1 mg/L at 24 hours. When Minocycline Hydrochloride tablets are administered with a meal including milk, the extent of absorption (AUC) is reduced by approximately 33 % while the peak serum concentrations are reduced by approximately 32% and delayed one hour. In previous studies with other dosage forms, the minocycline 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 is one half to one-third that of other tetracyclines.

TOXICOLOGY

Minocycline Hydrochloride has been tested in acute experiments in mice and rats, sub-chronic and chronic experiments in rats and dogs following oral and parenteral routes of administration. The LD50 of intravenous and intraperitoneal injections of minocycline in mice was 95 mg/kg and 280 mg/kg, respectively. The oral LD50 in mice was 3100 mg/kg. Minocycline Hydrochloride has been given orally each day to dogs for six months at doses of 0, 4, 20 and 60 mg/kg/day (100 mg/kg/day for the first month) equally divided each day. At 20 mg/kg/day, there were no apparent drug-related findings except yellow discolouration of the skeleton and teeth in some animals, occasional emesis and black discolouration of the thyroid gland. At a dose of 4 mg/kg/day, there were no drug related findings during the six month period, with the exception of discolouration of the thyroid gland and possibly some yellowing of the bones. Peak serum drug concentrations ranging from 8.5 to 100 mg/L were obtained with 60 and 100 mg/kg/day doses, 2.1 to 9.7 mg/L with the 20 mg/kg/day dose and 0.4 to 1.5 mg/L with the 4 mg/kg/day dose. Minocycline Hydrochloride was also given intravenously to dogs at doses of 5, 10, 20 and 40 mg/kg/day, a very similar dose range to that of the oral study, but administered for 1 month. Untoward findings such as body weight loss, reduced food consumption, erythema of the skin and of visible mucous membranes of varying duration, intensity and incidence, were associated primarily with the high dose (40 mg/kg/day). These findings were similar, except for erythema, to those obtained after the same dose of tetracycline. These drug-related findings with Minocycline Hydrochloride were associated with serum concentrations of 95 mg/L, three times those found with tetracycline (31 mg/L). Dogs that received 5, 10 and 20 mg/kg/day intravenously gave serum concentrations of 4, 12 and 38 mg/L, respectively, and were found essentially to be without toxicity. These serum values are in considerable excess of those necessary for therapeutic effectiveness in man. In these experiments, Minocycline Hydrochloride appeared to be tolerated as well intravenously as it was orally. Similar results were found following chronic oral administration of Minocycline Hydrochloride to rats for one year. These animals were given a drug diet containing 0.008, 0.04, 0.2 and 1.0% Minocycline Hydrochloride, which corresponded to ranges of 4.4 to 8.5, 21.3 to 44.0, 108 to 122 and 593 to 812 mg/kg/day drug intake; these doses gave early morning plasma drug concentrations of 0.07 to 0.16, 0.36 to 0.51, 2.9 to 6.5 and 17 to 50 mg/L respectively. With the exception of the discolouration of the teeth (dose 0.04% drug diet or greater), femur and thyroid gland, there were no significant drug-related signs of toxicity at doses less than 1 % drug diet. As with other tetracyclines, Minocycline Hydrochloride has been found to produce discolouration of the thyroid gland in the rat, dog, monkey and human but not in the mouse. There was no evidence, however, from these investigations that thyroid function or bone growth was affected. A 23-month carcinopmsicity study in the rat has shown that Minocycline Hydrochloride was not carcinopmsic and that the black pigment in the thyroid gland did not cause neoplastic changes. Biopsy specimens of thyroid tissue following the administration of Minocycline Hydrochloride and tetracycline to man revealed an intraepithelial lipofuscin deposition of both drugs, considered to be within normal variation. Thyroid function studies in man displayed a decrease within the normal range of thyroxine, indicating a tendency toward relative hypothyroidism. Other than the tooth and bone discolouration that also occurs with other tetracyclines and the thyroid pigmentation seen in rats, dogs and monkeys, toxic effects of Minocycline Hydrochloride were observed only where serum concentrations were in excess of the therapeutic concentrations. It is concluded from the chronic safety evaluation studies that Minocycline Hydrochloride has a good margin of safety between therapeutic blood concentrations and concentrations producing toxic effects. Reproduction studies performed in rats, rabbits and dogs have shown, as with other tetracyclines in animal studies, that Minocycline Hydrochloride crosses the placenta, is found in fetal tissues and can produce toxic effects on the developing embryo, fetus or neonate when present in sufficient amounts. The effects observed on the conceptus in rats and rabbits ranged from a low incidence of slight retardation of ossification and slight angulation of ribs at oral doses of 70 mg/kg/day in rats and 25 mg/kg/day in rabbits during pregnancy, to more extensive retardation of ossification and pmseralized morphologic changes and death at doses of 150 mg/kg/day and higher in the rat fetus. On other experiments, no deleterious effects were reported in rats or rabbits with oral doses as high as 100 and 75 mg/kg/day respectively. No adverse effects due to Minocycline Hydrochloride were seen in the newborn of 2 dogs given 20 mg/kg in 2 equally divided daily doses from days 35 to 62 of pregnancy.

BIBLIOGRAPHY

1. Frisk AR and Tunevall G. Minocycline: clinical evaluation, abstract of papers. Eighth Interscience Conference on Antimicrobial Apmsts and Chemotherapy. New York (Oct.) 1968 p.49

2. Graber CD, Jervey LP, Martin F and Boltjes BH. In Vitro and ~ Vivo sensitivity of staphylococci and selected bacteria to minocycline and doxycycline. Abstracts of Papers. Eighth Interscience Conference on Antimicrobial Apmsts and Chemotherapy. New York (Oct.) 1968 p.49.

3. Steigbigel NH, Reed CW and Finland M. Absorption and excretion of five tetracycline analogues in normal young men. Amer J Med Sci 255: 296-312 (May) 1968.

4. Fedorke J, Katz S and Allnoch H. In Vitro activity of minocycline, a new tetracycline. Amer J Med Sci 255: 252-258 (Apr.) 1968.

5. Jao RL and Finland M. Susceptibility of mvcoplasma pneumoniae to 21 antibiotics In Vitro. Amer J Med Sci 253:639-650 (June) 1967.

6. Redin GS. Antibacterial activity in mice of minocycline, a new tetracycline. Antimicrob Ag Chemother p. 371-376 1966.

7. Renzini G, Bevilacqua RL, Boemi G and Ravagnan L. Antimicrobial In Vitro and In Vivo activity of a new tetracycline, CL 59, 806. Antibiotica 5: 241-261. (Dec.) 1967.

8. Steigbigel NH, Reed CW and Finland M. Susceptibility of common pathopmsic bacteria to seven tetracycline antibiotics In Vitro. Amer J Med Sci 255: 179-195 (Mar.) 1968.

9. Steigbigel NH, McCall CE, Reed CW and Finland M. Antibacterial action of "Broad Spectrum" Penicillins, cephalosporins and other antibiotics against gram-negative bacilli isolated from bacteremic patients. Ann N Y Acad Sci 145: 224-236 (Sept. 27) 1967.

10. Noble JF, Kanegis LA and Hallesy DW. Short-term toxicity and observations on certain aspects of the pharmacology of a unique tetracycline - minocycline. Toxicol Apol Pharmacol 11: 128-149 1967.

11. Kelly RG and Kanegis LA. Metabolism and tissue distribution of radioisotopically labelled minocycline. Toxicol Appl Pharmacol 11: 171-183, 1967.

12. Bevelander G and Cohlan SQ. The effect on the rat fetus of transplacentally acquired tetracyclines. Bio Neonatorum 4: 365-370, 1962.

13. Boucher D and Delast P. Developpement post natal de la souris apres traitement de la mere gestante et des descendants par les tetracyclines. Compt Rend Soc Biol 161: 30~305, 1967.

14. Pellagali GV and d'Angelo A. Effetto della tetracycline cloridrato sulla comparsa dei nuclei di ossificazione di embrioni di ratto. Bull Soc Ital Sper 40: 1321-1324, 1964.

15. Steiner G, Bradford W and Craig JM. Tetracycline-induced abortion in the rat. Lab Invest 14: 1456-1463, 1965.

16. Cohlan SQ. Bevelander G and Timsic T. Growth inhibition of prematures receiving tetracyclines. Am J Dis Child 105: 453-461, 1963.

17. Halme J and Aes J. Inhibition of collapms synthesis and bone calcification in foetal rat by tetracycline. Scand J Clin Lab Invest 21: 4 (Suppl. 101), 196B.

18. Saxen L. Effect of tetracycline on osteopmsesis In Vitro. J Exper Zool 162: 269-294, 1966.

19. Grove Donald C and Randall WA. Assav methods of antibiotics: A laboratorv manual. New York, 1955 Med Encyclopedia (Follow the method for chlortetracycline.)

20. McHenry MC, Gavan TL, Vidt DG, Jameson S and Wagner JG. Minocycline in renal failure. Clinical Pharmacology and Therapeutics 13 : 146, 1972.

21. Kuck NA, Redin GS and Forbes M. Activity of minocycline and other tetracyclines against tetracycline-sensitive and resistant staphylococci. Pro Soc Exp Biol Med 136: 479-481, 1971.

22. Bach MC, Zinner SH, Wilcox C and Finland M. Efficacy of standard disc diffusion test as applied to susceptibility of Staphvlococcus Aureus to tetracycline and minocycline. J Lab Clin Med 77(2), 1972.

23. Macdonald H et al. Pharmacokinetic studies on minocycline in man. Clin Pharm Ther 14: 5, 852, 861. 1973.