Document: spc-doc_PL 20416-0229 change

• spc-doc_PL 00142-0357
• spc-doc_PL 20416-0229

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Minocycline Tablets BP 100 mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 115.85 mg of minocycline hydrochloride (dihydrate) equivalent to 100 mg of minocycline.

3    PHARMACEUTICAL FORM

The product is presented in the form of buff, biconvex, film coated tablet, engraved with company logo on one side and A494 on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Minocycline is a broad spectrum antibiotic employed for the treatment of infections caused by tetracycline-sensitive organisms. Some tetracycline-resistant strains of staphylococci are also sensitive.

It is indicated for the treatment of:

A.    Gonorrhoea, non-gonococcal urethritis, prostatitis.

B.    Acne vulgaris

C.    Acute and chronic bronchitis, bronchiectasis, lung abscess and Pneumonia.

D.    Ear, nose and throat infections.

E.    Urinary tract infections.

F.    Pelvic inflammatory disease e.g. salpingitis, oophoritis.

G.    Skin and soft tissue infections caused by minocycline sensitive organisms.

H.    Ophthalmological infections.

Nocardiosis.

J. Prophylactic treatment of asymptomatic meningococcal carriers.

4.2 Posology and method of administration

Route of administration: Oral

Dosage instructions Adults

Acne: 50 mg twice daily for a minimum of six weeks.

Gonorrhoea: Adult males: 200 mg initially followed by 100 mg every 12 hours for a minimum of 4 days with post-therapy cultures within 2-3 days.

Adult females may require more prolonged therapy.

Prophylaxis of asymptomatic meningococcal carriers: 100 mg twice daily for 5 days, usually followed by a course of rifampicin.

Routine antibiotic use: 200 mg daily in divided doses.

Children:    Over 12 years: 50 mg every twelve hours.

Under 12 years: Not recommended.

Elderly: Normal adult dose in elderly patients with mild to moderate renal impairment. Caution must be exercised in patients with severe renal impairment.

If, after six months, there is no satisfactory response minocycline should be discontinued. If minocycline is to be continued for longer than six months, patients should be monitored at least three monthly thereafter for signs and symptoms of hepatitis or SLE or unusual pigmentation (see Warning and Precautions).

4.3 Contraindications

Known hypersensitivity to tetracyclines or to any of the components of Minocycline Tablets.

Systemic lupus erythematosus.

Pregnancy

Lactation

Children under 12 years of age.

Complete renal failure

4.4 Special warnings and precautions for use

Caution should be exercised when administering to patients with hepatic dysfunction and in conjunction with alcohol or other potentially hepatotoxic drugs. It is recommended that alcohol consumption should remain within the Government's recommended limits.

Cross-resistance between tetracyclines may develop in micro-organisms and crosssensitisation in patients. Minocycline should be discontinued if there are signs/symptoms of overgrowth of resistant organisms, e.g. enteritis, glossitis, stomatitis, vaginitis, pruritus ani or Staphylococcal enteritis.

Minocycline may cause a yellow to brown discoloration of the teeth and enamel hypoplasia in the developing child. Therefore it should not be administered to children under twelve years of age.

Patients taking oral contraceptives should be warned that if diarrhoea or breakthrough bleeding occurs there is a possibility of contraceptive failure.

Clinical studies have shown that there is no significant drug accumulation in patients with renal impairment when they are treated with Minocycline in the recommended doses. In patients with severe renal impairment, dose reduction and monitoring of renal function may be required. The anti-anabolic action of the tetracyclines may cause an increase in serum urea. In patients with significantly impaired renal function, higher serum levels of tetracyclines may lead to uraemia, hyperphosphataemia 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.

Caution is advised in patients with myasthenia gravis as tetracyclines can cause weak neuromuscular blockade.

Rare cases of auto-immune hepatotoxicity and isolated cases of systemic lupus erythematosus (SLE) and also exacerbation of pre-existing SLE have been reported. If patients develop signs or symptoms of SLE or hepatotoxicity, or suffer exacerbation of pre-existing SLE, minocycline should be discontinued.

Minocycline may cause hyperpigmentation at various body sites (see Administration and 4.8 Undesirable Effects). Hyperpigmentation may present regardless of dose or duration of therapy but develops more commonly during long term treatment. Patients should be advised to report any unusual pigmentation without delay and Minocycline should be discontinued.

If a photosensitivity reaction occurs, patients should be warned to avoid direct exposure to natural or artificial light and to discontinue therapy at the first signs of skin discomfort.

As with other tetracyclines, bulging fontanelleles in infants and benign intracranial hypertension in juveniles and adults have been reported. Presenting features were headache and visual disturbances including blurring of vision, scotoma and diplopia. Permanent vision loss has been reported. Treatment should cease if evidence of raised intracranial pressure develops.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in the elderly:

Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Laboratory monitoring:

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

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent administration of magnesium-containing laxatives with minocycline may result in the formation of non-absorbable complexes. In addition, concurrent use with antacids may result in decreased absorption of oral minocycline due to increased intragastric pH. Absorption of Minocycline is impaired by the concomitant administration of iron, calcium, magnesium, aluminium bismuth and zinc salts (interactions with specific salts, antacids, bismuth containing ulcer-healing drugs, quinapril which contains a magnesium carbonate excipient). It is recommended that any indigestion remedies, vitamins, or other supplements containing these salts are taken at least 3 hours before or after a dose of Minocycline. Unlike earlier tetracyclines, absorption of Minocycline is not significantly impaired by food or moderate amounts of milk.

Concurrent use of cholestyramine or colestipol may result in binding of oral minocycline, thus impairing their absorption; an interval of several hours between administration of cholestyramine or colestipol and oral minocycline is recommended.

Concurrent long-term use of oestrogen containing oral contraceptives with minocycline may result in reduced contraception reliability and increased incidence of breakthrough bleeding.

Concomitant use of minocycline with heparin may partially counteract the anticoagulant effect of heparin; heparin dosage adjustment may be required during and following concurrent use. Tetracyclines depress plasma prothrombin activity and reduced doses of concomitant anticoagulants may be necessary.

Diuretics may aggravate nephrotoxicity by volume depletion.

Concurrent use of methoxyflurane with minocycline may increase the potential for nephrotoxicity.

Being a bacteriostatic drug, minocycline may interfere with bactericidal effect of penicillins in the treatment of meningitis or in other situations where a rapid bactericidal effect is required. Concurrent therapy should, therefore, be avoided. Caution should be exercised during concurrent use of minocycline with other photosensitising medication, because of possible additive photosensitising effects.

Concomitant use of sodium bicarbonate with minocycline may result in decreased absorption of oral minocycline because of increased intragastric pH; patients should be advised not to take this medication within 1-2 hours of oral minocycline.

There is an increased risk of ergotism when ergot alkaloids or their derivatives are given with tetracyclines.

Administration of isotretinoin or other systemic retinoids or retinol should be avoided shortly before, during and shortly after minocycline therapy. Each of these agents alone has been associated with pseudotumor cerebri (benign intracranial hypertension) (see 4.4 Special warnings and precautions).

Interference with laboratory and other diagnostic tests:

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

4.6 Fertility, Pregnancy and lactation

Minocycline traverses the placental barrier. Use during the 2^nd half of pregnancy may cause permanent discoloration of teeth (yellow-grey-brown. This adverse reaction is more common during long term use of the drugs but has been observed following repeated short term courses), enamel hypoplasia and inhibition of skeletal growth in the foetus.

Results of animal studies indicate that tetracyclines cross the placenta, are found in foetal tissues and can have toxic effects on the developing foetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. Minocycline therefore, should not be used in pregnancy unless considered essential

In humans, Minocycline, like other tetracycline-class antibiotics, crosses the placenta and may cause foetal harm when administered to a pregnant woman. In addition, there have been post marketing reports of congenital abnormalities including limb reduction. If Minocycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the foetus.

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

In addition, fatty infiltration of the liver may occur in pregnant women.

Minocycline is excreted in breast milk. It may form unabsorbable complexes with breast milk calcium.

Use of minocycline during lactation is not recommended due to the possibility of permanent discoloration of teeth, enamel hypoplasia, inhibition of linear skeletal growth, photosensitivity reactions and oral and vaginal thrush in infants. In addition vestibular disturbances may occur with minocycline.

Minocycline should only be administered if considered essential to pregnant or lactating women.

4.7 Effects on ability to drive and use machines

Treatment with minocycline may cause lightheadedness, dizziness, headache, tinnitus and vertigo (more common in women) and, rarely, impaired hearing have occurred. Patients should be warned about the possible hazards of driving or operating machinery during treatment. These symptoms may disappear during therapy and usually disappear when the drug is discontinued.

4.8 Undesirable effects

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%

Infections and Infestations

Very Rare: Oral and anogenital candidiasis, vulvovaginitis.

Unknown: Infrequently, superinfection with resistant organisms may cause black hairy tongue, oral and vaginal moniliasis and staphylococcal enteritis.

Blood and Lymphatic System Disorders

Rare: Eosinophilia, leucopenia, neutropenia, thrombocytopenia.

Very Rare: Haemolytic anaemia, pancytopenia.

There are also reports of: Agranulocytosis

Immune System Disorders

Rare: Anaphylaxis /anaphylactoid reaction (including shock), including fatalities.

There are also reports of: Hypersensitivity, pulmonary infiltrates, anaphylactoid purpura.

Endocrine Disorders

Very Rare: Abnormal thyroid function, brown-black discolouration of the thyroid.

Metabolism and Nutrition Disorders Rare: Anorexia.

Nervous System Disorders Common: Dizziness (light-headedness).

Rare: Headache, hypaesthesia, paraesthesia, intracranial hypertension. (Treatment should cease if evidence of raised intracranial pressure develops), vertigo. Dizziness and vertigo are more common in women.

Very Rare: Bulging fontanelle.

There are also reports of: convulsions, sedation.

Ear and Labyrinth Disorders Rare: Impaired hearing, tinnitus.

Cardiac Disorders

Rare: Myocarditis, pericarditis.

Respiratory, Thoracic and Mediastinal Disorders Rare: Cough, dyspnoea.

Very Rare: Bronchospasm, exacerbation of asthma, pulmonary eosinophilia.

There are also reports of: Pneumonitis.

Gastrointestinal Disorders

Rare: Diarrhoea, nausea, stomatitis, discolouration of teeth (including adult tooth discolouration), vomiting.

Very Rare: Dyspepsia, dysphagia, enamel hypoplasia, enterocolitis, oesophagitis, oesophageal ulceration, glossitis, pancreatitis, pseudomembranous colitis.

There are also reports of: Oral cavity discolouration (including tongue, lip and gum).

Hepatobiliary Disorders

Rare: Increased liver enzymes, hepatitis, autoimmune hepatoxicity. (See Section 4.4 Special warnings and precautions for use).

Very Rare: Hepatic cholestasis, hepatic failure (including fatalities), hyperbilirubinaemia, jaundice.

Rarely liver damage has been reported.

There are also reports of: Autoimmune hepatitis.

Skin and Subcutaneous Tissue Disorders

Rare: Alopecia, erythema multiforme, erythema nodosum, fixed drug eruption, hyperpigmentation of skin, photosensitivity, pruritis, rash, Maculopapular and erythematous rashes, urticaria, vasculitis.

Very Rare: Angioedema, exfoliative dermatitis, hyperpigmentation of nails, Stevens-Johnson Syndrome, toxic epidermal necrolysis.

Musculoskeletal, Connective Tissue and Bone Disorders Rare: Arthralgia, lupus-like syndrome, myalgia.

Very Rare: Arthritis, bone discolouration, cases of or exacerbation of systemic lupus erythematosus (SLE) (See Section 4.4 Special warnings and precautions for use), joint stiffness, joint swelling.

Renal and Urinary Disorders

Rare: Increased serum urea, acute renal failure, interstitial nephritis.

Reproductive System and Breast Disorders Very Rare: Balanitis.

General Disorders and Administration Site Conditions Uncommon: Fever.

Very Rare: Discolouration of secretions.

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 recognised, 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.

Hyperpigmentation of various body sites including the skin, nails, teeth, oral mucosa, bones, thyroid, eyes (including sclera and conjunctiva), breast milk, lacrimal secretions and perspiration has been reported. This blue/black/grey or muddy-brown discolouration may be localised or diffuse. The most frequently reported site is in the skin. Pigmentation is often reversible on discontinuation of the drug, although it may take several months or may persist in some cases. The generalised muddy-brown skin pigmentation may persist, particularly in areas exposed to the sun.

4.9 Overdose

Dizziness, nausea and vomiting are the adverse effects most commonly seen with overdose. In cases of overdose, discontinue medication, treat symptomatically with appropriate supportive measures. Minocycline is not removed in significant quantities by haemodialysis or peritoneal dialysis. There is no specific antidote. Gastric lavage and appropriate supportive measures should be carried out.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Minocycline is a broad spectrum antimicrobial agent. It interferes with bacterial protein synthesis by reversibly binding to bacterial 30 S ribosomal subunit, thus preventing the binding of aminoacyl transfer RNA to the messenger RNA ribosome complex.

Minocycline is more active against many species than tetracycline hydrochloride. In addition it is reported to be effective in-vitro against some tetracycline resistant staphylococci, streptococci and certain strains of tetracycline-resistant escherichia coli and haemophilus SPP.

5.2 Pharmacokinetic properties

Minocycline is readily and almost completely absorbed from the gastrointestinal tract after oral intake.

The absorption is not significantly affected by the presence of food or milk, although, absorption is impaired by the concomitant administration of iron salts, or antacids containing calcium, magnesium or aluminium salts. Normal doses of 200 mg followed by 100 mg every 12 hours produces plasma concentrations within the range of 1 to 4 aeg per ml.

Minocycline is more lipid-soluble than doxycycline and the other tetracyclines and is widely distributed in body tissues and fluids, including the cerebrospinal fluid. Highest levels are attained in bile, liver, duodenum, thyroid and lung. A higher ratio of CSF to blood concentrations has been reported with minocycline than with doxycycline. It crosses the placenta and small quantities diffuse into the milk of nursing mothers.

Concentration of minocycline is higher in sputum as compared to oxytetracycline or doxycycline. About 76% of minocycline is bound to plasma proteins. It has a lower renal clearance than doxycycline and its plasma halflife ranges from 11-23 hours. The prolonged half-life may be a function of protein binding.

Minocycline is partly metabolised to inactive substances. Compared with other tetracycline analogues, only a small proportion of a single dose is excreted in the urine. The urinary recovery of biologically active substances is about 5% in 24 hours and 11% in 96 hours.

Minocycline is effective in the treatment of urinary tract infection despite relatively low urinary concentrations (10-20 aeg/ml).

About 20-34% of a single oral dose is recovered in microbiologically active form in the faeces.

5.3 Preclinical safety data

None stated

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose

Microcystalline Cellulose Starch 1500 Stearic Acid Magnesium Stearate Colloidal Silicon Dioxide

Film coating materials

Component of Opadry® film coating system 03B86981 BROWN

Titanium dioxide

Iron Oxide Yellow (E172)

Iron Oxide Red (E172)

Iron Oxide Black (E172)

Macrogol

Hypromellose

6.2 Incompatibilities

None

6.3 Shelf life

3 years

6.4    Special precautions for storage

Store below 25^oC. Protect from light and moisture. Keep out of the reach of children.

6.5    Nature and contents of container

The pack sizes for this product are 28, 50,100, 250, 500 and 1000 tablets.

The product is packed in opaque plastic containers comprising of polypropylene tubes and polyethylene made tamper-evident closures.

6.6 Special precautions for disposal

No special instructions for use/handling

7 MARKETING AUTHORISATION HOLDER

Crescent Pharma Ltd

Units 3 and 4, Quidhampton Business Units

Polhampton Lane

Overton

Hampshire

RG25 3ED