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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Lymecycline 408mg Capsules, hard

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each capsule contains 408mg of lymecycline equivalent to 300mg tetracycline base For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Capsule, hard

Hard gelatin capsule, blue cap and white body

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Lymecycline 408mg Capsules, hard is indicated for the treatment of the following infections caused by tetracycline sensitive organisms (please see section 4.4 and 5.1) including the following:

•    Moderate to severe acne

•    Acute sinusitis

•    Acute exacerbation of chronic bronchitis

•    Helicobacter pylori infection

•    Urogenital infections caused by Chlamydia trachomatis

•    Trachoma

•    Rickettsial fever

•    Soft tissue infection

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

4.2    Posology and method of administration

Posology

Adults:

The usual dosage for the chronic treatment of acne is 408 mg daily: treatment should be continued for at least 8 weeks.

For other infections, the usual dosage is 408 mg twice a day. If higher doses are required, 1224-1632 mg may be given over 24 hours.

The capsules should always be taken with a glass of water.

In the management of sexually transmitted disease both partners should be treated.

Older people :

As for other tetracyclines, no specific dose adjustment is required.

Paediatric population

Not recommended for children under the age of 12 years. For children over the age of 12 years the adult dosage may be given.

Method of administration

Lymecycline 408mg Capsules, hard is for oral administration

4.3 Contraindications

Lymecycline 408mg Capsules, hard is contraindicated in:

-    hypersensitivity to lymecycline or any other tetracycline or to any of the excipients listed in section 6.1.

-    patients with overt renal insufficiency

-    children less than 12 years.

-    pregnancy and during lactation in women breast feeding infants.

4.4 Special warnings and precautions for use

Prolonged use of an anti-infective may result in the development of infection due to micro-organisms resistant to the anti-infective.

Cross-resistance between tetracyclines may develop in micro-organisms, and cross sensitisation in patients.

Tetracyclines should only be used with caution in patients with hepatic dysfunction, lest accumulation occurs with increased toxicity. Careful monitoring of dosage by serum levels is necessary. High dosage of tetracyclines may be hepatotoxic and great care should be used with concurrent administration of other hepatotoxic drugs.

Tetracyclines may cause photosensitivity reactions; however, very rare cases have been reported with lymecycline.

May cause exacerbation of systemic lupus erythematosus.

Can cause weak neuromuscular blockade so should be used with caution in Myasthenia Gravis.

Tetracyclines are absorbed to some extent by developing bones and teeth and may produce staining and enamel hypoplasia.

4.5 Interaction with other medicinal products and other forms of interaction

The absorption of tetracyclines may be affected by the simultaneous administration of calcium, aluminium, magnesium, bismuth and zinc salts, antacids, bismuth containing ulcer-healing drugs, iron preparations and quinapril. These products should not be taken within two hours before or after taking Lymecycline 408mg Capsules, hard.

Unlike earlier tetracyclines, absorption of lymecycline is not significantly impaired by moderate amounts (e.g. a glass) of milk.

Concomitant use of oral retinoids should be avoided as this may increase the risk of benign intracranial hypertension.

An increase in the effects of anticoagulants may occur with tetracyclines. Concomitant use of diuretics should be avoided.

Concurrent use of barbiturates, phenytoin or carbamazepine may decrease plasma levels of tetracyclines.

Concurrent use with the anaesthetic methoxyflurane increases the risk of kidney failure and has been reported to result in fatal kidney failure.

4.6 Fertility, pregnancy and lactation

Pregnancy: Tetracyclines readily cross the placenta barrier.

Tetracyclines are selectively absorbed by developing bones and teeth and may cause dental staining and enamel hypoplasia. Therefore, lymecycline should not be administered to pregnant women (see section 4.3).

Lactation: Tetracyclines are distributed into milk.Therefore, lymecycline should not be administered to breast-feeding women (risk of enamel hypoplasia or dental dyschromia in the infant) (see section 4.3).

Fertility: In humans, the effect of lymecycline on fertility is unknown. However, tetracycline hydrochloride had no effect on fertility in male and female rats at a daily dose which is 25-fold higher than that proposed for humans.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed

4.8 Undesirable effects

The most frequently reported adverse events with lymecycline are gastrointestinal disorders of nausea, abdominal pain, diarrhoea and nervous system disorder of headache.

The most serious adverse events reported with lymecycline are Stevens Johnson syndrome, anaphylactic reaction, angioneurotic oedema and intracranial hypertension.

Adverse reactions are ranked by frequency, the most frequent first, using the following convention:

Very Common: (>1/10),

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).

System Organ Class	Frequency	Adverse Reaction
Blood and lymphatic system disorders	Not known	Neutropenia Thrombocytop enia
Eye disorders	Not known	Visual disturbance
Gastrointestinal disorders	Common	Nausea Abdominal pain Diarrhoea
	Not known	Epigastralgia Glossitis Vomiting Enterocolitis
General disorders and administration site conditions	Not known	Pyrexia
Hepatobiliary disorders	Not known	Jaundice
Immune system disorder	Not known	Anaphylactic reaction Hypersensitivity

General tetracyclines adverse events:

Benign intracranial hypertension and bulging fontanelles in infants were reported with tetracyclines with possible symptoms of headaches, visual disturbances including blurring of vision, scotomata, diplopia or permanent visual loss.

The following adverse effects were reported with tetracyclines in general and may occur with lymecycline:

dysphagia, oesophagitis, oesophageal, ulceration, pancreatitis, teeth discolouration, hepatitis, hepatic failure.

Dental dyschromia and/or enamel hypoplasia may occur if the product is administered in children younger than 8 years of age

As with all antibiotics overgrowth of non-susceptible organisms may cause candidiasis, pseudomembranous colitis (Clostridium Difficile overgrowth), glossitis, stomatitis, vaginitis or staphyloccocal enterocolitis.

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; website: www.mhra.gov.uk/yellowcard

4.9 Overdose

There is no specific treatment, but gastric lavage should be performed as soon as possible. Supportive measure should be instituted as required and a high fluid intake maintained.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Tetracyclines ATC code: J01AA04

Mechanism of action

Tetracyclines provide bacteriostatic action at the available plasma and tissue concentrations and are effective against intracellular and extracellular organisms. Their mechanism of action is based on an inhibition of ribosomal protein synthesis. Tetracyclines block the access of the bacterial aminoacyl-tRNA to the mRNA-ribosome complex by binding to the 30S subunit of the ribosome, thus preventing the addition of amino acids to the growing peptide chain in protein synthesis. When given at therapeutically attainable concentrations their toxic effect is limited to the bacterial cells.

The exact mechanisms by which tetracyclines reduce lesions of acne vulgaris have not been fully elucidated; however, the effect appears to result in part from the antibacterial activity of the drugs. Following oral administration, the drugs inhibit the growth of susceptible organisms (mainly Propionibacterium acnes) on the surface of the skin and reduce the concentration of free fatty acids in sebum. The reduction in free fatty acids in sebum may be an indirect result of the inhibition of lipase-producing organisms which convert triglycerides into free fatty acids or may be a direct result of interference with lipase production in these organisms. Free fatty acids are comedogenic and are believed to be a possible cause of the inflammatory lesions, e.g. papules, pustules, nodules, cysts, of acne. However, other mechanisms also appear to be involved because clinical improvement of acne vulgaris with oral tetracycline therapy does not necessarily correspond with a reduction in the bacterial flora of the skin or a decrease in the free fatty acid content of sebum.

Mechanism of resistance

Tetracycline resistance in propionibacteria is usually associated with a single point mutation within the gene encoding 16S rRNA. Clinical isolates resistant to tetracycline were found to have cytosine instead of guanine at a position cognate with Escherichia coli base 1058. There is no evidence that ribosome mutations can be transferred between different strains or species of propionibacteria, or between propionibacteria and other skin commensals.

Resistance to the tetracyclines is associated with mobile resistance determinants in both staphylococci and coryneform bacteria. These determinants are potentially transmissible between different species and even different genera of bacteria.

In all three genera, cross-resistance with the macrolide-lincosamide-streptogramin group of antibiotics cannot be ruled out.

Strains of propionibacteria resistant to the hydrophilic tetracyclines are cross-resistant to doxycycline and may or may not show reduced susceptibility to minocycline.

Breakpoints

Clinical minimal inhibitory concentration (MIC) breakpoints established by (EUCAST) for lymecycline (based on sensitivities for tetracycline) are:

Staphylococcus species: Streptococcus A, B, C, G: Streptococcus pneumoniae: Haemophilus influenzae: Moraxella catarrhalis: Neisseria gonorrhoeae: Neisseria meningitides:

sensitive <1, resistant >2 sensitive <1, resistant >2 sensitive <1, resistant >2 sensitive <1, resistant >2 sensitive <1, resistant >2 sensitive <0.5, resistant >1 sensitive <1, resistant >2

Susceptibility table

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Susceptibility to tetracyclines of species relevant to the approved indication_

Commonly susceptible species

Gram-positive aerobes

None of relevance Gram-negative aerobes None of relevance Anaerobes

Propionbacterium acnes (clinical isolates)*

Other

None of relevance

Species for which acquired resistance may be a problem (defined as >10% resistant within any European country)

Gram-positive aerobes

S. aureus (methicillin susceptible)

S. aureus (methicillin resistant) +

Coagulase-negative staphylococci (methicillin susceptible)

Coagulase-negative staphylococci (methicillin resistant) +

Corynebacterium spp

Species for which acquired resistance may be a problem (defined as >10% resistant within any European country)

Gram-negative aerobes

None of relevance Anaerobes

Propionibacterium acnes (isolates from acne)* +

Other (microaerophile)

None of relevance Inherently resistant species

However, even if resistance to cutaneous propionibacteria is detected, this does not automatically translate into therapeutic failure, since the antiinflammatory activity of the tetracyclines is not compromised by resistance in the target bacteria.

5.2 Pharmacokinetic properties

After oral dosing it is absorbed readily with or without the presence of food.

Lymecycline is more readily absorbed from the gastro-intestinal tract than tetracycline, with a peak serum concentration of approximately 2mg/L after 3 hours following a 300 mg dose. In addition, similar blood concentrations are achieved with small doses. When the dose is doubled an almost correspondingly higher blood concentration has been reported to occur.

The serum half-life of lymecycline is approximately 10 hours.

5.3 Preclinical safety data

There are no non-clinical data of relevance to the prescriber which are additional to that already included in other sections of this SmPC

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Silica colloidal, hydrated Magnesium stearate

Capsule Body:

Titanium dioxide (E171) Gelatine

Capsule Cap:

Indigo carmine FD&C Blue (E132) Black iron oxide (E172)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Gelatine

6.2 Incompatibilities

Not applicable

6.3    Shelf life

15 months

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

Al/Al blister strip

Blister: 16, 20, 28, 56 and 100 capsules.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal and other handling

No special requirements for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.

Reykjavikurvegi 76-78 220 HafnarfjorQur Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0367

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 10/08/2012

DATE OF REVISION OF THE TEXT

11/07/2016