Minocycline 100mg Film- Coated Tablets
1. NAME OF THE MEDICINAL PRODUCT
Minocycline 100 mg Film-coated Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 100 mg minocycline hydrochloride.
Excipient with known effect
Each tablet contains approximately 150 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 8.5 mm in diameter, marked ‘MN100’ 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
Adults
Routine antibiotic use: 200 mg daily in divided doses
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. 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 10, 50, 100, 250 and 500 tablets.
PVC/ Aluminium foil blister packs in packs of 10, 28 and 50 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 4569/0277
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 22 May 1995 Date of latest renewal: 21 May 2000