For the use only of a registered medical practitioner or a hospital or a laboratory.

 

Minocycline Hydrochloride Capsules USP 50 mg &100mg

CYNOMYCIN* 50

CYNOMYCIN* 100

Broad Spectrum Antimicrobial

 

COMPOSITION

                                                                       

Each CYNOMYCIN* 50 capsule contains: Minocycline hydrochloride U.S.P. equivalent to 50 mg minocycline

 

Each CYNOMYCIN* 100 capsule contains: Minocycline hydrochloride U.S.P. equivalent to 100 mg minocycline

 

PHARMACOLOGY

 

Minocycline is an anti infective, tetracycline class antibiotic.

Minocycline hydrochloride, a semisynthetic derivative of tetracycline, is 4-7,bis (dimethylamino)-l,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-l,11-dioxo-2-naphthacenecarboxamide monohydrochloride. Its structural formula is C₂₃H₂₇N₃O₇•HCl and its molecular weight is 493.94.

Minocycline hydrochloride is a yellow, crystalline powder; sparingly soluble or soluble in water, slightly soluble in alcohol; practically insoluble in chloroform and in ether; dissolves in solutions of alkali hydroxides and carbonates.

 

INDICATIONS

 

Minocycline hydrochloride is 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 Chlamydia psittaci.
• Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated, as judged by immunofluorescence.
• Inclusion conjunctivitis caused by Chlamydia trachomatis.
• Nongonococcal urethritis, endocervical or rectal infections in adults caused by Ureaplasma urealyticum or 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 species (in conjunction with streptomycin).
• Bartonellosis due to Bartonella bacilliformis.
• Granuloma inguinale caused by Calymmatobacterium granulomatis.

Minocycline hydrochloride 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 species.

Acinetobacter species.

Respiratory tract infections caused by Haemophilus influenzae.

Respiratory tract and urinary tract infections caused by Klebsiella species.

 

Minocycline hydrochloride is 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. (Note: Minocycline is not the drug of choice in the treatment of any type of staphylococcal infection.)

 

When penicillin is contraindicated, minocycline hydrochloride is an alternative drug in the treatment of the following infections:

• Uncomplicated urethritis in men due to Neisseria gonorrhoeae and for the treatment of other gonococcal infections.
• Infections in women caused by Neisseria gonorrhoeae.
• Meningitis due to Neisseria meningitidis.
• Syphilis caused by Treponema pallidum subspecies pallidum.
• Yaws caused by Treponema pallidum subspecies 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 species.

In acute intestinal amebiasis, minocycline hydrochloride may be a useful adjunct to amebicides.

 

In severe acne, minocycline may be useful adjunctive therapy.

 

Oral minocycline hydrochloride is indicated in the treatment of asymptomatic carriers of Neisseria meningitidis to eliminate meningococci from the nasopharynx. In order to preserve the usefulness of minocycline hydrochloride in the treatment of asymptomatic meningococcal carriers, diagnostic laboratory procedures, including serotyping and susceptibility testing, should be performed to establish the carrier state and the correct treatment. It is recommended that the prophylactic use of minocycline hydrochloride be reserved for situations in which the risk of meningococcal meningitis is high.

 

Oral minocycline hydrochloride 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.

DOSAGE AND ADMINISTRATION

 

The duration of therapy is guided by the severity of the infection and the patient’s clinical and bacteriological progress.

 

Adults: The usual oral dosage is 200 mg initially, followed by 100 mg every 12 hours.The total daily dose should not exceed 400 mg in 24 hours.

In the treatment of acne, the recommended dosage is 100 mg daily given twice a day.

In the treatment of uncomplicated gonococcal infections other than urethritis and anorectal infections in men, the initial oral dose is 200mg, followed by 100mg every 12 hours for a minimum of four days.

In the treatment of uncomplicated gonococcal urethritis in men, the recommended dose is 100mg every 12 hours for five days.

In the treatment of syphilis, the usual dosage of minocycline hydrochloride should be administered over a period of 10 to 15 days. 

In the treatment of meningococcal carrier state, the recommended dose is 100 mg every 12 hours for five days.

Mycobacterium marinum infections: Although optimal doses have not been established, 100 mg every 12 hours for 6 to 8 weeks has been used successfully in a limited number of cases.

In the treatment of uncomplicated urethral, endocervical or rectal infection in adults caused by Chlamydia trachomatis or Ureaplasma urealyticum, the recommended dose is 100mg every 12 hours for at least seven days.

To reduce the risk of esophageal irritation and ulceration, capsules should be taken with adequate amounts of fluid (at least approximately one glass of water).

Absorption of minocycline hydrochloride may be impaired by aluminium, calcium, magnesium, iron-containing preparations, food, milk and other dairy products (see section Interactions).

 

Children above 8 years of age:

The initial dosage of minocycline hydrochloride is 4 mg/kg followed by 2 mg/kg every 12 hours.

 

Geriatric:

Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. (See Section Geriatric Use)

 

Patients with renal impairment:

In patients with renal impairment, the total daily dose should not exceed 200 mg in 24 hours. (See Section Precautions)

CONTRAINDICATIONS

 

Hypersensitivity to any of the tetracyclines or to any of the components of the product formulation.

 

SPECIAL WARNINGS

 

Rarely, anaphylactic/anaphylactoid reactions, including shock and fatalities have been associated with the administration of minocycline hydrochloride (see section Adverse Reactions).

 

Minocycline hydrochloride, like other tetracycline-class antibiotics, can cause fetal harm when administered to a pregnant woman (see section Pregnancy). 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 also has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline drugs should not be used during tooth development unless the expected benefits of therapy outweigh the risks.

PRECAUTIONS

Other very rare, serious events have occurred with minocycline hydrochloride including Stevens - Johnson syndrome and toxic epidermal necrolysis (see section Adverse Reactions). Minocycline hydrochloride should be discontinued if either of these serious skin reactions is suspected.

Pseudotumor cerebri (benign intracranial hypertension) has been reported with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. Bulging fontanels have been reported with the use of tetracyclines in infants. While both of these conditions and related symptoms usually resolve after discontinuation of the tetracycline, the possibility of permanent sequelae exists.

 

Photosensitivity has been observed in some individuals taking tetracyclines. Patients should be advised that an exaggerated sunburn reaction can occur with tetracycline drugs and should avoid direct sunlight.

Use in Patients with Hepatic Impairment

Hepatotoxicity has been associated with minocycline hydrochloride, therefore minocycline hydrochloride should be used with caution in patients with hepatic dysfunction and in conjunction with other hepatotoxic drugs.

 

Use in Patients with Renal Impairment

The anti-anabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN). In patients with significantly impaired renal function, higher serum levels of tetracyclines may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral and parenteral doses may lead to excessive systemic accumulations of the drug and possible liver toxicity (see section Dosage and Administration).

Laboratory Monitoring

Periodic laboratory evaluations of organ system function, including hematopoietic, renal and hepatic should be conducted.

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.

 

Minocycline hydrochloride, like other tetracycline-class antibiotics, crosses the placenta and may cause fetal harm when administered to a pregnant woman. If minocycline hydrochloride 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.

 

The use of tetracyclines during tooth development (last half of pregnancy) may cause permanent discoloration of the teeth. Enamel hypoplasia has also been reported (see section Special Warnings).

 

Tetracyclines administered during the last trimester form a stable calcium complex throughout the human fetal skeleton. A decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in the dose of 25 mg/kg every 6 hours. Changes in fibula growth rate were shown to be reversible when the drug was discontinued.

 

Congenital anomalies including limb reductions have been reported in post marketing experience.

 

LACTATION

 

Minocycline hydrochloride is excreted in human milk, therefore, a decision should be made whether to discontinue breast-feeding or to discontinue Minocycline (see section Special Warnings).

PEDIATRIC USE

 

Minocycline hydrochloride is not recommended for use in children below 8 years of age unless the expected benefits of therapy outweigh the risks (see section Special Warnings).

 

GERIATRIC USE

 

Clinical studies of minocycline hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. 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.

INTERACTIONS

 

Tetracyclines have been shown to depress plasma prothrombin activity. Concomitant anticoagulant therapy may require downward adjustment of anticoagulant dosage.  

 

Bacteriostatic drugs may interfere with the bactericidal action of penicillin.Avoid giving tetracycline-class drugs in conjunction with penicillin.

 

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium.  Absorption of minocycline hydrochloride is impaired by iron-containing preparations.  

 

Absorption of the standard oral formulations of minocycline is impaired by food, milk, and other dairy products. However, absorption of the pellet-filled capsules formulation is not significantly impaired by food or milk.

 

The concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective.

 

Administration of isotretinoin or other systemic retinoids or retinol should be avoided shortly before, during and shortly after minocycline therapy. Each of these agents used alone has been associated with pseudotumor cerebri (see section Precautions).

 

Increased risk of ergotism when ergot alkaloids or their derivatives are given with tetracyclines.

 

INTERFERENCE WITH LABORATORY AND OTHER DIAGNOSTIC TESTS

 

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

 

EFFECTS ON ACTIVITIES REQUIRING CONCENTRATION AND PERFORMANCE

 

Patients should use caution when driving a vehicle or using hazardous machinery while on minocycline hydrochloride therapy. Central nervous system side effects, including light-headedness, dizziness, or vertigo have been reported with minocycline hydrochloride therapy. These symptoms may disappear during therapy and usually disappear when the drug is discontinued.

 

ADVERSE REACTIONS

 

Adverse reactions are listed in the Table in CIOMS frequency categories under MedDRA system/organ classes:

 

Common:                                  > 1%

Uncommon:                              > 0.1% and < 1%

Rare:                                        > 0.01% and <0.1%

Very rare:                                 < 0.01%

System Organ Class               Adverse Reaction

 

Blood and Lymphatic System Disorders

Rare:                                        Eosinophilia, leukopenia, neutropenia, thrombocytopenia

Very rare:                                 Hemolytic anemia, pancytopenia

Frequency undetermined:           Agranulocytosis

 

Cardiac Disorders

Very rare:                                 Myocarditis, pericarditis

 

Ear and Labyrinth Disorders

Rare:                                        Impaired hearing, tinnitus

 

 

Endocrine Disorders

Very rare:                                 Abnormal thyroid function, brown-black discoloration of thyroid

 

Gastrointestinal Disorders

Rare:                                       Diarrhea, nausea, stomatitis, discoloration of teeth (including adult tooth discoloration), vomiting

Very rare:                                 Dyspepsia, dysphagia, enamel hypoplasia, enterocolitis,

esophagitis, esophageal ulceration, glossitis, pancreatitis, pseudomembranous colitis

Frequency Undetermined:          Oral cavity discoloration (including tongue, lip and gum)

 

General Disorders and Administration Site Conditions

Uncommon:                              Fever

Very rare:                                 Discoloration of secretions

 

Hepatobiliary Disorders

Rare:                                        Increased liver enzymes, hepatitis

Very rare:                                 Hepatic cholestasis, hepatic failure (including fatalities),

                                                hyperbilirubinemia, jaundice

Frequency undetermined:           Autoimmune hepatitis

 

Immune System Disorders

Rare:                                        Anaphylaxis/anaphylactoid reaction (including shock)

including fatalities (see section Special Warnings)

Frequency undetermined:           Hypersensitivity

Infections and Infestations

Very rare:                                 Oral and anogenital candidiasis, vulvovaginitis

 

Metabolism and Nutrition Disorders

Rare:                                        Anorexia

 

Musculoskeletal, Connective Tissue, and Bone Disorders

Rare:                                        Arthralgia, lupus-like syndrome, myalgia

Very rare:                                 Arthritis, bone discoloration, exacerbation of systemic lupus erythematosus (SLE), joint stiffness, joint swelling

 

Nervous System Disorders

Common:                                  Dizziness (light headedness)

Rare:                                        Headache, hypesthesia, paresthesia, pseudotumor cerebri, vertigo

Very rare:                                 Bulging fontanel

Frequency Undetermined:          Convulsions, sedation

 

Renal and Urinary Disorders

Rare:                                        Increased BUN

Very rare:                                 Acute renal failure, interstitial nephritis

 

Reproductive System and Breast Disorders

Very rare:                                 Balanitis

 

Respiratory, Thoracic, and Mediastinal Disorders

Rare:                                        Cough, dyspnea

Very rare:                                 Bronchospasm, exacerbation of asthma, pulmonary eosinophilia

Frequency undetermined:           Pneumonitis

 

Skin and Subcutaneous Tissue Disorders

Rare:                                        Alopecia, erythema multiforme, erythema nodosum, fixed drug eruption; hyperpigmentation of skin, photosensitivity, pruritus, rash, urticaria

Very rare:                                 Angioedema, exfoliative dermatitis, hyperpigmentation of nails, Stevens-Johnson Syndrome, toxic epidermal necrolysis (see section Precautions), vasculitis

 

In the post marketing setting, there have been reports of thyroid carcinoma in patients receiving minocycline therapy. A casual relationship between minocycline use and thyroid carcinoma has not been established.

 

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, 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, vasculitis.

·   Serum sickness-like syndrome consisting of fever; urticaria or rash; and arthralgia, arthritis, joint stiffness, or joint swelling. Eosinophilia may be present.

PHARMACODYNAMICS, CLINICAL EFFICACY

 

Microbiology

The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including minocycline hydrochloride, have similar antimicrobial spectra of activity against a wide range of gram-positive and gram-negative organisms.

 

Cross-resistance of gram-positive and gram-negative organisms to tetracyclines is common. Almost all S. pyogenes strains are resistant to minocycline hydrochloride. Therefore, minocycline hydrochloride should not be used for streptococcal disease unless the organism has been demonstrated to be susceptible.

 

Because many strains of gram-positive and gram-negative organisms have been shown to be resistant to tetracyclines (see section Indications), culture and susceptibility tests are recommended.

 

PHARMACOKINETICS

Absorption

Minocycline hydrochloride is quickly and almost completely absorbed from the gastrointestinal tract following oral administration.

 

Following a single dose of two 100 mg tablets of minocycline hydrochloride, maximum serum concentrations were attained in 2 to 4 hours and ranged from 2.6 to 4.17 μg/mL (average 3.52 µg/mL).

Following a single dose of two 100 mg capsules of minocycline hydrochloride, maximum serum concentrations averaged 3.64 µg/mL.

 

Distribution

Minocycline hydrochloride distributes largely to all tissues due to its high degree of lipophilicity.

Studies have shown that minocycline hydrochloride is found in high concentration in lung tissue and mucus in man.

 

Serum levels of 1.4-1.8 µg/mL were maintained at 12 and 24 hours with intravenous doses of 100 mg every 12 hours for 3 days. Following 200 mg intravenous doses given once daily for 3 days, the serum levels had fallen to approximately 1 µg/mL at 24 hours.

 

Metabolism

Minocycline hydrochloride is extensively metabolized in humans.

 

Minocycline hydrochloride is mainly excreted in the bile and a small amount is recovered in the urine as active form.  The amount of active drug recovered in the feces after oral administration ranges from 20-34%.

 

Elimination

The mean serum half-life is approximately 16 hours for oral and intravenous administration.

 

Effect of Food

Absorption of the standard oral formulations of minocycline is impaired by food, milk, and other dairy products.

Special Populations

In patients with hepatic dysfunction, the minocycline hydrochloride serum half-life ranged from 10.7 to 16.9 hours.

 

The majority of studies in patients with varying degrees of renal impairment showed no significant difference in pharmacokinetics parameters as compared to healthy subjects.

 

PRECLINICAL SAFETY DATA

 

Dietary administration of minocycline hydrochloride in long-term tumorigenicity studies in rats resulted in evidence of thyroid tumor production. In the rat, chronic treatment with minocycline hydrochloride has resulted in goiter accompanied by elevated radioactive iodine uptake and evidence of thyroid tumor production. Minocycline hydrochloride has been observed to cause a dark discoloration of the thyroid in animals (rats, mice, dogs, and monkeys). Minocycline hydrochloride 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 hydrochloride have not been conducted, positive results in in vitro mammalian cell assays (i.e., 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 hydrochloride impairs fertility in male rats.

 

OVERDOSAGE

 

The adverse events more commonly seen in overdose are dizziness, nausea, and vomiting.

 

No specific antidote for minocycline hydrochloride is known.

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

 

STORAGE

 

Store at controlled room temperature 20ºC-25ºC (68ºF-77ºF)

 

PRESENTATION

 

100 mg capsules - Strip of 4

50 mg capsules - Strip of 6

 

Keep out of reach of children

 

Manufactured by:

Medreich Limited

49 B, Bommasandra Industrial area, Anekal Taluk,

Bangalore 560 099

 

Marketed in India by:

Wyeth Limited

Level 6 & 7, Platina ,

Plot No C-59, 'G' Block,

Bandra - Kurla Complex,

Bandra ( E ),

Mumbai 400 098

 

* Registered Trade Mark                                                                                               

 

 

Rev. 000/CDS 10.0/July 2009