SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Clindamycin 600mg Hard Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 651.56 mg clindamycin hydrochloride equivalent to 600 mg clindamycin.

Excipient with known effect:

Each capsule contains 135.64 mg anhydrous lactose (see section 4.4).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Hard capsule

Size '00el' hard gelatin capsule with opaque white cap and opaque white body imprinted with 'A724' on cap with black ink.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Clindamycin is indicated for the treatment of severe infections (see sections 4.4 and 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

Moderately severe infection: 150 - 300 mg every six hours

Severe infection: 1200 - 1800 mg daily in divided doses given every six to eight

hours

Elderly

The half-life, volume of distribution and clearance, and extent of absorption after administration of clindamycin hydrochloride are not altered by increased age. Analysis of data from clinical studies has not revealed any age-related increase in toxicity. Dosage requirements in elderly patients, therefore, should not be influenced by age alone.

Children: 3 - 6 mg/kg every six hours depending on the severity of the infection.

Clindamycin capsules are not suitable for children who are unable to swallow them whole. The capsules do not provide exact mg/kg doses therefore it may be necessary to use an alternative formulation in some cases.

Renal impairment

No dose adjustment is necessary in patients with mild to moderate impairment of renal function. In patients with severe renal impairment or anuria, plasma concentration should be monitored. Depending on the results, this measure can make a reduction in dosage or an increase in the dose interval of 8 or even 12 hours necessary.

Hepatic impairment

In patients with moderate to severe hepatic impairment, elimination half-life of clindamycin is prolonged. A reduction in dosage is generally not necessary if clindamycin is administered every 8 hours. However, the plasma concentration of clindamycin should be monitored in patients with severe hepatic impairment. Depending on the results, this measure can make a reduction in dosage or an increase in the dose intervals necessary.

Method of Administration

Oral.Clindamycin capsules should always be swallowed whole with a full glass of water. Absorption of Clindamycin is not appreciably modified by the presence of food.

4.3 Contraindications

Clindamycin is contra-indicated in patients previously found to be sensitive to clindamycin, lincomycin or to any of the excipients listed in section 6.1. Clindamycin should not be used in patients with existing diarrhoea.

4.4 Special warnings and precautions for use

The choice of clindamycin should be based on factors such as severity of the infection, the prevalence of resistance to other suitable agents and the risk of selecting clindamycin-resistant bacteria.

Treatment with antibacterial agents can significantly alter the normal flora of the colon leading to overgrowth of Clostridium difficile. This has been reported with use of nearly all antibacterial agents, including clindamycin. Clostridium difficile produces toxins A and B which contribute to the development of Clostridium difficile associated diarrhea (CDAD) and is a primary cause of “antibiotic-associated colitis”.

It is important to consider the diagnosis of CDAD in patients who present with diarrhea subsequent to the administration of antibacterial agents. This may progress to colitis, including pseudomembranous colitis (see Section 4.8), which may range from mild to fatal colitis. If antibiotic-associated diarrhoea or antibiotic-associated colitis is suspected or confirmed, ongoing treatment with antibacterial agents, including clindamycin, should be discontinued and adequate therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in this situation.

Clindamycin does not penetrate the blood/brain barrier in therapeutically effective quantities.

Since clindamycin does not diffuse adequately into cerebrospinal fluid, the drug should not be used in the treatment of meningitis.

Caution should be used when prescribing clindamycin to individuals with a history of gastro-intestinal disease, especially colitis.

If therapy is prolonged, liver and kidney function tests should be performed.

The use of clindamycin may result in overgrowth of non-susceptible organisms, particularly yeasts.

Care should be observed in the use of clindamycin in atopic individuals.

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

4.5 Interaction with other medicinal products and other forms of interaction

Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. It should be used with caution, therefore, in patients receiving such agents.

Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance the two drugs should not be administered concurrently.

Vitamin K antagonists

Increased coagulation tests (PT/INR) and/or bleeding, have been reported in patients treated with clindamycin in combination with a vitamin K antagonist (e.g. warfarin, acenocoumarol and fluindione). Coagulation tests, therefore, should be frequently monitored in patients treated with vitamin K antagonists.

4.6 Fertility, pregnancy and lactation

Pregnancy

Oral and subcutaneous reproductive toxicity studies in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus due to clindamycin, except at doses that caused maternal toxicity. Animal reproduction studies are not always predictive of human response.

Clindamycin crosses the placenta. There are inadequate data regarding the safety of clindamycin in pregnancy. Therefore, clindamycin should only be administered to pregnant women if the potential benefit is considered to outweigh the possible risk to the foetus. After multiple doses, amniotic fluid concentrations were approximatley 30 % of maternal blood concentrations.

In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters has not been associated with an increased frequency of congenital abnormalities. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy.

Clindamycin should be used in pregnancy only if clearly needed.

Breastfeeding

Orally and parentally administered clindamycin has been reported to appear in human breast milk in ranges from 0.7 to 3.8 pg/mL. Because of the potential for serious adverse reactions in nursing infants, clindamycin should not be taken by nursing mothers.

Fertility

Fertility studies in rats treated orally with clindamycin revealed no effects on fertility or mating ability.

4.7 Effects on ability to drive and use machines

Clindamycin has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The table below lists the adverse reactions identified through clinical trial experience and post-marketing surveillance by system organ class and frequency.

Adverse reactions identified from post-marketing experience are included in italics. The frequency grouping is defined 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);

Not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class	Very Commo n > 1/10	Common > 1/100 to < 1/10	Uncommo n > 1/1,000 to < 1/100	Rare > 1/10,000 to < 1/1,000	Very Rare < 1/10,00 0	Not Known (cannot be estimated from available data)
Infections and infestations						Vaginal infection
Blood and Lymphatic System Disorders						Agranulocyt osis Leukopenia Neutropenia Thrombocyt openia Eosinophilia
Immune System Disorders						Anaphylactoi d reaction Drug reaction with eosinophilia and systemic symptom (DRESS)
Nervous System Disorders						Dysgeusia
Gastrointest inal Disorders		Abdomina l pain Diarrhoea Pseudome mbranous colitis (see section 4.4)	Nausea Vomiting			Oesophageal ulcer Oesophagitis
Hepatobiliar y Disorders		Liver function test abnormal				Jaundice

Skin and Subcutaneo us Tissue Disorders

Rash maculopa p ular Urticaria

Toxic epidermal necrolysis Stevens- Johnson syndrome Acute generalised exanthemato us pustulosis (AGEP) Erythema multiforme Dermatitis exfoliative Dermatitis bullous Rash morbilliform Pruritis

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

In cases of overdosage no specific treatment is indicated.

The serum biological half-life of clindamycin is 2.4 hours. Clindamycin cannot readily be removed from the blood by dialysis or peritoneal dialysis.

If an allergic adverse reaction occurs, therapy should be with the usual emergency treatments, including corticosteroids, adrenaline and antihistamines.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Lincosamides, ATC code: J01FF01 Mode of action

Clindamycin binds to the 50S subunit of the bacterial ribosome and inhibits protein synthesis. Clindamycin has a predominately bacteriostatic action.

Mechanism of resistance

Resistance to clindamycin usually occurs via macrolide-lincosamide-streptogramin B (MLS_b) type of resistance, which may be constitutive or inducible.

PK/PD relationship

The efficacy mainly depends on the duration of time during which the agent level is above the minimum inhibitory concentration (MIC) of the pathogen.

Breakpoints

The minimum inhibitory concentrations (MIC) breakpoints are as follows:

Staphylococci: sensitive < 0.5 resistant > 0.5

Streptococci ABCG and pneumoniae: sensitive < 0.5 resistant > 0.5

Gram positive anaerobes: sensitive < 4 resistant > 4

Gram negative anaerobes: < 4 resistant > 4

Susceptibility

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 local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

*Up to 50% of methicillin-susceptible S. aureus have been reported to be resistant to clindamycin in some areas. More than 90% of methicillin-resistant S.aureus (MRSA) are resistant to clindamycin and it should not be used while awaiting susceptibility test results if there is any suspicion of MRSA.

5.2 Pharmacokinetic properties

General characteristics of active substance

About 90% of a dose of clindamycin hydrochloride is absorbed from the gastrointestinal tract; concentrations of 2 to 3 micrograms per ml occur within one hour after a 150 mg dose of clindamycin, with average concentrations of about 0.7 micrograms per ml after 6 hours. After doses of 300 and 600 mg peak plasma concentrations of 4 and 8 micrograms per ml, respectively, have been reported. Absorption is not significantly diminished by food in the stomach but the rate of absorption may be reduced.

Clindamycin is widely distributed in body fluids and tissues including bone, but it does not reach the csf in significant concentrations. It diffuses across the placenta into the fetal circulation and has been reported to appear in breast milk. High concentrations occur in bile. It accumulates in leucocytes and macrophages. Over 90% of clindamycin in the circulation is bound to plasma proteins. The half-life is 2 to 3 hours, although this may be prolonged in pre-term neonates and patients with severe renal impairment.

Clindamycin undergoes metabolism, presumably in the liver, to the active N-demethyl and sulfoxide metabolites, and also some inactive metabolites. About 10% of a dose is excreted in the urine as active drug or metabolites and about 4% in the faeces; the remainder is excreted as inactive metabolites. Excretion is slow, and takes place over several days. It is not effectively removed from the blood by dialysis.

Characteristics in patients

No special characteristics. See section 4.4 "Special warnings and special precautions for use" for further information.

5.3 Preclinical safety data

There is no further preclinical data of relevance to the safety assessment beyond what has already been mentioned in this summary of product characteristics.

6.1 List of excipients

Capsule fill:

Anhydrous Lactose Com starch Talc

Magnesium stearate

Capsule cap and body: Titanium dioxide (E171) Gelatin Water

Sodium lauryl sulfate

Printing ink:

Shellac

Dehydrated alcohol Isopropyl alcohol Butyl alcohol Propylene glycol (E1520) Strong ammonia solution Black iron oxide (E172) Potassium hydroxide Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

No special storage conditions.

6.5 Nature and contents of container

Clindamycin 600 mg capsules are available in blister packs (clear PVC/Aclar film / aluminium foil)

Pack sizes: 12, 15, 16, 20, 24, 30, 32, 40, 100 and 104 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7    MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.

Reykjavikurvegi 76-78 220 Hafnarfjordur Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0678

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/02/2016

10    DATE OF REVISION OF THE TEXT

12/02/2016