1. NAME OF THE MEDICINAL PRODUCT

Minocycline 50 mg Film-coated Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg minocycline hydrochloride.

Excipient with known effect

Each tablet contains approximately 75 mg lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

Round, biconvex, orange/brown film-coated tablets, approximately 6 mm in diameter, marked ‘MN50’ on one side with ‘G’ on the reverse.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

A broad spectrum antibiotic, indicated for oral administration, for the treatment of infections caused by tetracycline sensitive organisms and some tetracycline resistant strains of staphylococci.

Indications include: acne, skin and soft tissue infections, ophthamological infections, acute and chronic bronchitis, bronchiectasis, lung abscess, ear, nose and throat infections, pelvic inflammatory disease, nocardiosis, urinary tract infections, gonorrhoea, non-gonococcal urethritis and prostatitis.

Minocycline may also be used in prophylactic treatment of asymptomatic meningococcal carriers.

Also indicated in pre- and post operative prophylaxis of infection.

4.2    Posology and method of administration

Posology

Adults

Routine antibiotic use: 200 mg daily in divided doses Acne: 50 mg twice daily for at least 6 weeks.

Gonorrhoea: Males: 200 mg initially followed by 100 mg every 12 hours for a minimum of 4 days. Post therapy cultures within 2-3 days. Females: May require a more prolonged therapy.

Prophylaxis of asymptomatic meningococcal carriers: 100 mg twice daily for 5 days, followed by treatment with rifampicin.

If, after six months, there is no satisfactory response minocycline should be discontinued and other therapies considered. If minocycline is to be continued for longer than six months, patients should be monitored at least three monthly intervals thereafter for signs and symptoms of hepatitis or SLE (see section 4.4).

Renal impairment

As adults even in cases of mild to moderate renal impairment. However, caution is advised in patients with severe renal impairment.

Paediatric population

Minocycline is not recommended in children under 12 years.

Children over 12 years: 50 mg every 12 hours.

Method of administration

For oral administration.

To reduce the risk of ulceration and oesophageal irritation the tablets should be swallowed whole, with plenty of liquid, and whilst in an upright sitting or standing position. Unlike other tetracyclines, absorption of minocycline is not significantly impaired by food or moderate amounts of milk.

4.3    Contraindications

Hypersensitivity to the active substance, tetracyclines or to any of the excipients listed in section 6.1.

Minocycline is contraindicated in patients with systemic lupus erythematosus, pregnancy, lactation, complete renal failure and children under 12 years.

4.4    Special warnings and precautions for use

Breathing difficulties

Cases of breathing difficulties including dyspnoea, bronchospasm, exacerbation of asthma, pulmonary eosinophilia and pneumonitis (see section 4.8) have been reported with minocycline use. If patients develop breathing difficulties they should seek urgent medical advice and minocycline should be discontinued.

Paediatric population

All tetracyclines form a stable calcium complex in any bone forming tissue. An increase in the fibula growth rate has been observed in premature babies administered oral tetracyclines.

Tetracyclines are known to cause a yellow to brown discoloration of the teeth and enamel hypoplasia in the developing child or foetus.

Hepatic impairment

Minocycline should be used with caution in patients with hepatic dysfunction or in conjunction with potentially hepatotoxic drugs, including alcohol.

Auto-immune disorders

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

Renal impairment

Studies indicate there is no significant drug accumulation in patients with mild to moderate renal impairment when treated with the recommended dosages of minocycline. In cases of severe renal impairment a reduction of dosage and monitoring of renal function may be required.

Cross-sensitivities

Micro-organisms can develop cross resistance to tetracyclines and patients can develop cross sensitivity.

Minocycline should be discontinued there are signs/symptoms of overgrowth of resistant organisms, enteritis e.g. glossitis, stomatitis, vaginitis, if pruritus ani or staphylococcal enteritis.

Myasthenia Gravis

Tetracyclines can cause weak neuromuscular blockade-caution in Myasthenia Gravis.

Intracranial hypertension

As with other tetracyclines, bulging fontanelles 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.

Hyperpigmentation

As with other tetracyclines, minocycline may cause hyperpigmentation at various body sites (see also sections 4.2 and 4.8). 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. This is generally reversible on cessation of therapy.

Photosensitivity

Tetracyclines are known to cause photosensitivity reactions. Such patients should be warned to avoid direct exposure to natural or artificial sunlight and to discontinue therapy at the first sign of skin discomfort.

Minocycline contains lactose and sunset yellow

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

This medicinal product contains sunset yellow which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Anticoagulants

Plasma prothrombin activity is depressed by tetracyclines. Reduced doses of any concomitant anticoagulants may be necessary.

ACE inhibitors, antacids and adsorbants

Tetracyclines bind to di-/tri-valent cations. Absorption from the gastrointestinal tract is impaired by the concomitant administration of iron, calcium, aluminium, magnesium, bismuth and zinc salt (interactions with specified salts, antacids, kaolin, bismuth containing ulcer-healing drugs, quinapril which contains a magnesium carbonate excipient). Dosages should be maximally separated.

Absorption of tetracyclines is not significantly impaired by food, milk and milk products.

Diuretics

Diuretics may aggravate nephrotoxicity by volume depletion.

Antibacterials

Minocycline should not be used with penicillins.

Ergotamine and ergometrine There is an increased risk of ergotism.

Oral contraceptives

Both can induce hyperpigmentation.

Retinoids

Administration of isotretinoin should be avoided shortly before, during and shortly after minocycline therapy. Each drug alone has been associated with pseudotumor cerebri (benign intracranial hypertension) (see section 4.4).

Laboratory tests

Minocycline may affect urinary urobilinogen excretion tests by reducing bacterial converters of bilirubin to urobilinogen. Minocycline may also produce an interference fluorescence in the Hungarty methods for measuring urinary catecholamines.

4.6    Fertility, pregnancy and lactation

Minocycline use during pregnancy and lactation is contraindicated.

Pregnancy

Animal studies have indicated that tetracyclines cross the placenta. Tetracyclines have been found in foetal tissues and can have toxic effects on the developing foetus (related to retardation of skeletal development). Studies on animals treated during early pregnancy also indicate embryotoxicity. The use of tetracyclines during the last half of pregnancy, when the teeth are developing, may cause permanent discolouration of teeth (more common with long term or repeated short term use). Enamel hypoplasia has also been reported.

Breast-feeding

Tetracyclines have been detected in the milk of lactating women. Permanent tooth discolouration may occur in the developing infant and enamel hypoplasia has been reported.

4.7    Effects on ability to drive and use machines

Dizziness, vertigo, headache, light-headedness, visual disturbances, tinnitus and impaired hearing (rarely) have occurred following administration of Minocycline. Patients should be warned of these effects and the possible hazard of driving or operating machinery, if affected.

4.8    Undesirable effects

Adverse reactions are listed in the Table in CIOMS frequency categories under MedDRA system/organ classes. The frequency of adverse reactions is defined using the following convention: common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to 1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data)

MedDRA system organ class	Adverse drug reaction
Infections and infestations
Very rare	Oral and anogenital candidiasis, vulvovaginitis
Blood and lymphatic system disorders
Rare	Eosinophilia, leucopenia, neutropenia, thrombocytopenia
Very rare	Haemolytic anaemia, pancytopenia

Not known	Agranulocytosis
Immune system disorders
Rare	Anaphylaxis/anaphylactoid reaction (including shock and fatalities)
Not known	Hypersensitivity, pulmonary infiltrates, anaphylactoid purpura, polyarteritis nodosa
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, vertigo
Very rare	Bulging fontanelle
Not known	Convulsions, sedation
Ear and labyrinth disorders
Rare	Impaired hearing, tinnitus
Cardiac disorders
Rare	Myocarditis, pericarditis
Respiratory, thoracic mediastinal disorders
Rare	Cough, dyspnoea
Very rare	Bronchospasm, exacerbation of asthma, pulmonary eosinophilia
Not known	Pneumonitis
Gastrointestinal disorders
Rare	Diarrhoea, nausea, stomatitis, discolouration of teeth, vomiting
Very rare	Dyspepsia, dysphagia, enamel hypoplasia, enterocolitis, oesophagitis, oesophageal ulceration, glossitis, pancreatitis, pseudomembranous colitis
Hepatobiliary disorders
Rare	Increased liver enzymes, hepatitis, autoimmune hepatotoxicity (see section 4.4)
Very rare	Hepatic cholestatis, hepatic failure (including fatalities), hyperbilirubinaemia, jaundice
Not known	*Autoimmune hepatitis
Skin and subcutaneous tissue disorders
Rare	Alopecia, erythema multiforme, erythema nodosum, fixed drug eruption, hyperpigmentation of the skin, photosensitivity, pruritis, rash, urticaria, vasculitis
Very rare	Angioedema, exfoliative dermatitis, hyperpigmentation of nails, Stevens-Johnson syndrome, toxic epidermal necrolysis
Not known	Drug reaction with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders
Rare	Arthralgia, lupus-like syndrome, myalgia
Very rare	Arthritis, bone discolouration, cases of systemic

	lupus erythematous (SLE) (see section 4.4), 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

* Autoimmune hepatitis: See section 4.4.

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. Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Dizziness, nausea and vomiting are the adverse effects most commonly seen in overdose. Gastric lavage plus appropriate supportive treatment. Antacids and calcium salts will reduce absorption of minocycline but there is no specific antidote. Minocycline is not removed in significant quantities by haemodialysis or peritoneal dialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, tetracyclines, ATC code: J01AA08.

Minocycline is a tetracycline compound with bacteriostatic activity. In common with other tetracyclines, Minocycline is thought to exert antibacterial activity by inhibition of protein synthesis. Minocycline is active against a wide range of gram negative and gram positive organisms, known to be sensitive to tetracyclines and against some tetracycline resistant strains of Staphylococcus.sps.

Organisms may be considered susceptible (infection likely to respond to minocycline therapy) if the Minimum Inhibitory Concentration is not more than 4 pg/ml. Organisms may be considered to harbour partial resistance if the Minimum Inhibitory Concentration is 4 - 12.5 pg/ml and resistant if the Minimum Inhibitory Concentration is greater than 12.5 pg/ml.

If the Kirby-Bauer method of susceptibility testing gives a zone of 18 mm or greater than the bacterial strain is considered susceptible.

5.2    Pharmacokinetic properties

Absorption

Minocycline is readily absorbed from the gastrointestinal tract and is not as significantly affected by the presence of food or moderate amounts of milk as other tetracyclines. Absorption may be 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 produced plasma concentrations within the range of 1-4 pg/ml.

Distribution

Minocycline is reported to be more lipid soluble than doxycycline and the other tetracyclines and to be widely distributed in body tissues and fluids. High concentrations being achieved in the hepatobiliary tract, lungs, sinuses and tonsils, as well as in tears, saliva, and sputum. Penetration into cerebrospinal fluid is relatively poor, although a higher ratio of cerebrospinal fluid to blood concentrations has been reported with minocycline than with doxycycline. It crosses the placenta and diffuses into the milk of nursing mothers.

About 75% of minocycline in the circulation is bound to plasma proteins. The plasma half-life tends to be prolonged in patients with severe renal impairment. It has a lower renal clearance than doxycycline and its plasma half-life ranges from 11-23 hours.

Biotransformation

In contrast to most tetracyclines, minocycline appears to undergo some metabolism in the liver, mainly to 9-hydroxyminocycline. It is also excreted in bile.

Elimination

About a third of the drug may be excreted unchanged and although figures vary widely, about a third of this unchanged drug may appear in the urine and two thirds in the faeces.

5.3    Preclinical safety data

Studies have indicated that minocycline hydrochloride, the active ingredient of Minocycline 50 mg Tablets is a poison by the intravenous and intraperitoneal routes. Acute toxicity studies indicate an LD₅₀ in the rat by the oral route of 2,380 mg/kg and an LD₅₀ by the oral route of 3,600 mg/kg in the mouse.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose

Sodium starch glycolate Povidone

Microcrystalline cellulose Sodium laurilsulfate

Magnesium stearate

Film coating:

Carnauba wax

Printing ink: Hypromellose Titanium dioxide Macrogol 400 Quinoline yellow (E104) Sunset yellow (E110) Indigo carmine (E132)

6.2    Incompatibilities

Tetracyclines can chelate metal cations to produce insoluble complexes. Also incompatibility has been reported with solutions containing calcium, magnesium, aluminium and iron.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Store below 25°C. Store in the original package in order to protect from light.

6.5    Nature and contents of container

Polypropylene container with polyethylene cap (with optional polyethylene ullage filler) in packs of 50, 100, 250 and 500 tablets.

PVC/ Aluminium foil blister packs in packs of 20, 28, 50 and 84 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal No special requirements.

7. MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

8.    MARKETING AUTHORISATION NUMBER

PL 4569/0276

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 May 1995 Date of latest renewal: 21 May 2000

10 DATE OF REVISION OF THE TEXT

22/08/2016