MINOCYCLINE TABLETS BP 50 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Minocycline Tablets BP 50mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Minocycline Hydrochloride equivalent to 50mg anhydrous minocycline.

Excipients with known effect:

Each 50mg tablet contains 114.00 mg lactose.

For the full list of excipients, see section 6.1.

Beige film-coated tablets.

Beige, circular, biconvex film-coated tablets, impressed “C” on one face and the identifying letters “MI” on the reverse.

4.1 Therapeutic indications

Minocycline is indicated for the treatment of the following infections:

1) Gonorrhoea.

2) Non-gonococcal urethritis.

3) Prostatitis.

4) Moderate to severe acne; use in moderate acne only if topical treatment is ineffective, if acne is extensive or hard to reach and if there is a high risk of scarring.

5) Acute and chronic bronchitis.

6) Bronchiectasis.

7) Lung abscess.

8) Pneumonia.

9) Ear, nose and throat infections.

10) Urinary tract infections.

11) Pelvic inflammatory disease (eg salpingitis, oophoritis).

12) Skin and soft tissue infections caused by minocycline sensitive organisms.

13) Ophthalmic infections.

14) Nocardiosis.

15) Prophylactic treatment of asymptomatic meningococcal carriers.

16) Pre and post-operative prophylaxis of infection.

For sensitive organisms, see section 5.1.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

Adults:

Routine antibiotic use: 200mg daily in divided doses.

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

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

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

Special populations

Renal impairment:

Minocycline may be used at the normal recommended dosage in mild to moderate renal impairment, however caution is advised in patients with severe renal impairment.

Hepatic impairment:

Minocycline should be used with caution in patients with hepatic impairment.

Elderly:

Care is required if Minocycline is given to 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.

Paediatric population:

Children over 12 years: 50mg every 12 hours.

Children under 12 years: Not recommended.

Method of Administration

For oral administration. To reduce the risk of oesophageal irritation and ulceration, the tablets should be swallowed whole with plenty of fluid, while sitting or standing. Unlike earlier tetracyclines, absorption of minocycline is not significantly impaired by food or moderate amounts of milk.

4.3 Contraindications

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

Systemic Lupus Erythematosus

Pregnancy and lactation

Children under 12 years

Complete renal failure.

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) and also exacerbation or pre-existing SLE have been reported. If patients develop signs or symptoms of SLE or hepatotoxicity, or suffer exacerbation or pre-existing SLE, 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 if there are signs/symptoms of overgrowth of resistant organisms, enteritis e.g. glossitis, stomatitis, vaginitis, pruritus ani or staphylococcal enteritis.

Myasthenia Gravis

Tetracyclines can cause weak neuromuscular blockade – use with 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 light and to discontinue therapy at the first sign of discomfort.

Excipients

Lactose

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

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 salts (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 discoloration of the 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 discoloration 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)

Not known (cannot be estimated from the available data)

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Dizziness, nausea and vomiting are the adverse effects most commonly seen with 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: J01A A08

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

Minocycline should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

Mechanism of action

Minocycline inhibits protein synthesis in susceptible bacteria. In common with other tetracyclines it is primarily bacteriostatic and has a similar spectrum of activity to other tetracyclines.

Breakpoints

The general MIC breakpoint to identify organisms susceptible to minocycline is < 0.5 mg/l. All organisms for which the MIC of minocycline is > 1 mg/l are considered resistant (European Committee on Antimicrobial Susceptibility Testing (EUCAST)).

EUCAST Recommendations

1 Isolates susceptible to tetracycline are also susceptible to doxycycline and minocycline, but some resistant to tetracycline may be susceptible to minocycline and/or doxycycline. An MIC method should be used to test doxycycline susceptibility of tetracycline resistant isolates if required.

2 Tetracycline can be used to predict susceptibility to minocycline for prophylaxis against N. meningitidis infections.

Susceptibility testing for Enterobacterales, Pseudomonas spp., Enterococcus spp. and Viridans group streptococci is not recommended as the species is a poor target for therapy with the agent. Isolates may be reported as R without prior testing.

For Acinetobacter spp. Neisseria gonorrhoeae and PK-PD (Non-species related) breakpoints there is insufficient evidence that the organism or group is a good target for therapy with the agent. An MIC with a comment but without an accompanying S, I or R categorisation may be reported.

For anaerobic bacteria there is clinical evidence of activity in mixed intraabdominal infections, but no correlation between MIC values, PK-PD data and clinical outcome. Therefore no breakpoints for susceptibility testing are given.

Susceptibility

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable. Minocycline is usually active in vitro against Propionibacterium acnes, which is implicated in the pathogenesis of acne.

Resistance

Bacterial resistance to the tetracyclines is now common in some species and usually involves cross-resistance between the different tetracyclines.

5.2 Pharmacokinetic properties

Absorption

Minocycline is readily absorbed from the GI tract and is not 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 200mg followed by 100mg every 12 hours produced plasma concentrations within the range of 1–4L.lg/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 CSF to blood concentrations has been reported with minocycline than with doxycycline. It crosses the placenta and diffuses into milk of nursing mothers. About 75% of minocycline in the circulation is bound to plasma proteins. The plasma halflife 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

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The tablets also contain:

Hydroxypropyl­cellulose (E463)

Maize starch Magnesium stearate Lactose

The coating contains:

Hypromellose (E464)

Propylene Glycol

Purified Talc

Red Iron Oxide (E172)

Black Iron Oxide (E172)

Yellow Iron Oxide (E172)

Titanium Dioxide (E171)

6.2 Incompatibilities

None known

6.3 Shelf life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/recon­stitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special precautions for storage

Store below 25°C in a dry place.

Protect from light.

6.5 Nature and contents of container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps and polyfoam wad or cotton wool.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250^m white rigid PVC. (ii) Surface printed 20^m hard temper aluminium foil with 5–6g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28’s, 30’s, 50’s, 56’s, 60’s, 84’s, 90’s, 100’s, 112’s, 120’s, 168’s, 180’s, 500’s, 1000’s

Not all pack sizes may be marketed.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6 Special precautions for disposal and other handling

Not applicable.

Accord-UK Ltd (Trading style: Accord) Whiddon Valley Barnstaple

Devon

EX32 8NS

8 MARKETING AUTHORISATION NUMBER

PL 00142/0356

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

21/07/1993 / 14/11/2003