SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL    PRODUCT

Clindamycin Hydrochloride 150mg Capsules, hard.

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each capsule contains Clindamycin hydrochloride equivalent to 150 mg of Clindamycin.

Excipients with known effect:

Each capsule contains 237 mg lactose monohydrate.

For full excipients see section 6.1

3    PHARMACEUTICAL FORM

Capsule, hard.

Hard capsule (white/white) with a marking 'C150 ' on the body.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Antibacterial.

Clindamycin is indicated for the treatment of serious infections caused by susceptible Gram-positive organisms, staphylococci (both penicillinase- and non-penicillinase-producing), streptococci (except Streptococcus faecalis) and pneumococci. It is also indicated in serious infections caused by susceptible anaerobic pathogens.

Also used for treating intra-abdominal infections, skin and soft tissue infections. As needed, clindamycin should be administered in conjunction with another antibacterial agent that is active against gram negative aerobic bacteria.

Tonsillitis

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

4.2    Posology and method of administration

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

Adults: Moderately severe infection, 150 - 300 mg every six hours; severe infection, 300 - 450 mg every six hours.

Elderly patients: 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 formulations in some cases.

Dosage in 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.

Note: In cases of beta-haemolytic streptococcal infection, treatment with Clindamycin should continue for at least 10 days to diminish the likelihood of subsequent rheumatic fever or glomerulonephritis.

4.3 Contraindications

Clindamycin is contra-indicated in patients previously found to be sensitive to Clindamycin, lincomycin or to any component of the formulation.

4.4 Special warnings and precautions for use

Warnings: Clindamycin should only be used in the treatment of serious infections. In considering the use of the product, the practitioner should bear in mind the type of infection and the potential hazard of the diarrhoea which may develop, since cases of colitis have been reported during, or even two or three weeks following, the administration of Clindamycin.

Studies indicate a toxin(s) produced by clostridia (especially Clostridium difficile) is the principal direct cause of antibiotic-associated colitis. These studies also indicate that this toxigenic clostridium is usually sensitive in vitro to vancomycin. When 125 mg to 500 mg of vancomycin are administered orally four times a day for 7-10 days, there is a rapid observed disappearance of the toxin from faecal samples and a coincident clinical recovery from the diarrhoea. (Where the patient is receiving cholestyramine in addition to vancomycin, consideration should be given to separating the times of administration).

Colitis is a disease which has a clinical spectrum from mild, watery diarrhoea to severe, persistent diarrhoea, leucocytosis, fever, severe abdominal cramps, which may be associated with the passage of blood and mucus. If allowed to progress, it may produce peritonitis, shock and toxic megacolon. This may be fatal.

The appearance of marked diarrhoea should be regarded as an indication that the product should be discontinued immediately. The disease is likely to follow a more severe course in older patients or patients who are debilitated. Diagnosis is usually made by the recognition of the clinical symptoms, but can be substantiated by endoscopic demonstration of pseudomembranous colitis. The presence of the disease may be further confirmed by culture of the stool for Clostridium difficile on selective media and assay of the stool specimen for the toxin(s) of C. difficile.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Clindamycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

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

Periodic liver and kidney function tests should be carried out during prolonged therapy. Such monitoring is also recommended in neonates and infants.

Prolonged administration of Clindamycin, as with any anti-infective, may result in super-infection due to organisms resistant to Clindamycin.

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

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 : Safety for use in pregnancy has not yet been established. Animal studies do not indicate reproductive toxicity (see section 5.3).

The use of Clindamycin capsules may be considered during pregnancy, if necessary.

Lactation : Clindamycin is excreted in human milk. Caution should be exercised when Clindamycin is administered to a nursing mother. It is unlikely that a nursing infant can absorb a significant amount of Clindamycin from its gastro-intestinal tract.

4.7    Effects on ability to drive and use machines

Clindamycin is not known to interfere with the ability to drive and operate machinery.

4.8    Undesirable effects

Blood and the Lymphatic System Disorders: Transient neutropenia (leucopenia), eosinophilia, agranulocytosis and thrombocytopenia have been reported. No direct aetiologic relationship to concurrent Clindamycin therapy could be made in any of the foregoing.

Immune System Disorders: A few cases of anaphylactoid reactions have been reported.

Gastro-intestinal Disorders: Oesophageal ulcers have been reported as serious adverse events; oesophagitis with oral preparations, nausea, vomiting, abdominal pain and diarrhoea (see Section 4.4 Special Warnings and Special Precautions for Use, Warnings).

Hepatobiliary Disorders: Jaundice and abnormalities in liver function tests have been observed during Clindamycin therapy.

Skin and Subcutaneous Tissue Disorders: Maculopapular rash and urticaria have been observed during drug therapy. Generalised mild to moderate morbilliform-like skin rashes are the most frequently reported reactions. Rare instances of erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with Clindamycin.

Pruritus, vaginitis and rare instances of exfoliative and vesiculobullous dermatitis have been reported. Serious cutaneous adverse reaction (SCAR) and rare cases of toxic epidermal necrolysis have been reported during post-marketing surveillance.

Nervous System Disorders: Frequent cases of Dysgeusia have been observed upon systemic administration of Clindamycin using injectables (IM or IV), capsules, or oral granulate solutions, which include a few (non-frequent) serious adverse events.

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

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 classification: J01FF01

Mode of action: Clindamycin is a lincosamide antibiotic with a primarily bacteriostatic action against Gram-positive aerobes and a wide range of anaerobic bacteria. Most Gram-negative aerobic bacteria, including the Enterobacteriaceae, are resistant to Clindamycin. Lincosamides such as Clindamycin bind to the 50S subunit of the bacterial ribosome similarly to macrolides such as erythromycin and inhibit the early stages of protein synthesis. The action of Clindamycin is predominantly bacteriostatic although high concentrations may be slowly bactericidal against sensitive strains.

Mechanism of resistance

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

Breakpoints

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

Eucast

Staphylococci: sensitive < 0.5 resistant > 0.5

Streptococci ABCG and pneumoniae : sensitive < 0.5 resistant > 0.5

Gram positive anaerobes : < 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.

Species

Susceptible

Gram-positive aerobes

Staphylococcus aureus *

Staphylococcus epidermidis Streptococcus pneumonia

Streptococcus pyogenes Streptococcus viridans

Anaerobes

Bacteriodes fragilis group

Bacteroides melaninogenicus Bifidobacterium spp.

Clostridium perfringens Eubacterium spp Fusobacterium spp.

Peptococcus spp.

Peptostreptococcus spp. Propionibacterium spp.

Veillonella spp.

Resistant

Clostridia spp.

Enterococci Enterobacteriaceae

*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

Absorption: About 90% of a dose of Clindamycin hydrochloride is absorbed from the gastro-intestinal 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. The peak plasma concentration is achieved within approximately 45 minutes after oral administration. The bioavailability is non-linear and decreases with increasing doses. Following a 600 mg dose the absolute bioavailability is 53±14%.

Distribution: 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. 68 -93 % of clindamycin in the circulation is bound to plasma proteins. Clindamycin is distributed very highly intracellular due to the lipophilic properties. The intracellular concentrations are 10-50 times higher than the extracellular concentrations.

Metabolism: Clindamycin undergoes metabolism, presumably in the liver, to the active N-demethyl and sulphoxide 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 : Half-life is approximately two and a half hour- in children and approximately 3 hours in adults. Clindamycin is excreted as biological active and biological inactive metabolites in faeces, urine and bile. Faecal excretion is predominant. About 101% of the drug is excreted in the urine as active drug and about 4% in the faeces; the remainder is excreted as inactive metabolites.

Characteristics in patients

Elderly: The half-life, volume of distribution and clearance, and extent of absorption after administration of clindamycin phosphate are not altered by increased age

Patients with renal impairment: In the presence of renal impairment, elimination halflife is prolonged; however, a dosage reduction is unnecessary in the event of mild to moderate impairment of renal function.

Patients with hepatic impai1ment: In patients with moderate to severe hepatic impairment the half life is prolonged, but when giving the dose every 8 hour accumulation is rarely seen. Dose reduction is normally not necessary in patients with hepatic impairment.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on studies of repeat dose toxicity, reproductive toxicity or genotoxicity. Carcinogenicity studies have not been conducted.

In dogs, repeated high oral doses produced ulceration of the mucosa of the stomach and gall bladder.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Monohydrate

Pregelatinised Starch Purified Talc Magnesium stearate

Capsule shell:

Gelatin

Titanium dioxide (E171) Water

Printing ink:

Shellac

Propylene Glycol Black Iron Oxide (E172) Potassium Hydroxide

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

24 months

6.4    Special precautions for storage

Do not store above 25°C.

6.5    Nature and contents of container

Clindamycin Capsules 150 mg are available in blister packs (aluminium foil/PVC) of 24 and 100 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

None stated.

7 MARKETING AUTHORISATION HOLDER

Strandhaven Limited t/a Somex Pharma Ilford, Essex.

IG3 8BS.UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 15764/0109

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/02/2016

10    DATE OF REVISION OF THE TEXT

30/03/2016