Document: spc-doc_PL 04416-0429 change

• spc-doc_PL 00057-0957
• spc-doc_PL 04416-0429

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Clindamycin 150mg Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains clindamycin hydrochloride equivalent to 150 mg clindamycin.

Excipient with known effect:

Also contains lactose.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Capsules, hard.

Hard capsule coloured lavender/maroon and marked ‘CL150’.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Clindamycin is indicated for the treatment of severe infections caused by susceptible Gram-positive aerobic organisms, staphylococci (penicillinase / and non- penicillinase producing), streptococci (with the exception of Streptococcus faecalis) and pnuemonicocci or by susceptible anaerobic organisms.

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

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

4.2    Posology and method of administration

Clindamycin Capsules should always be taken orally with a glass of water with or without food.

Adults: The usual dose is 150 - 300 mg every six hours; depending on the severity of the infection your doctor may prescribe 300 - 450 mg every six hours.

Older people: 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 shown any age-related increase in toxicity. Dosage requirements in elderly patients should not be influenced by age alone. See section 4.4 for other factors which should be taken into consideration.

Paediatric population: The usual dose is 3 - 6 mg/kg every six hours depending on the severity of the infection. (not to exceed the adult dose).

Children under one year of age and/or under 10 kg may require a lower dose.

Neonates (0-28 days), especially if premature, require special attention to dose reductions and/or extended dose intervals due to the prolonged elimination half-life.

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 the parenteral formulation in some cases.

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

4.3 Contraindications

Clindamycin is contraindicated in patients previously found to be sensitive to Clindamycin, lincomycin, or to any excipient listed in Section 6.1 (List of excipients).Clindamycin should not be used in patients with existing diarrhoea.

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 diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

It is important to consider the diagnosis of CDAD in patients who present with diarrhoea 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.

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

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

Clindamycin 150mg Capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

4.5    Interaction with other medicinal products and other forms of interaction

Muscle relaxants:

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

Antibacterial agents:

Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Due to possible clinical significance, the two drugs should not be administered concurrently and therefore clindamycin should not be given in combination with macrolides or streptogramin antibacterial agents.

Neostigmine and pyridostigmine:

Clindamycin antagonises the effects of the above anticholinesterases. Oestrogens:

Clindamycin possibly reduces the contraceptive effect of oestrogen. Though the risk is small, additional contraceptive precautions are recommended during concomitant use and for 7 days after discontinuing clindamycin.

Vaccines:

Oral typhoid vaccine is inactivated by concomitant administration of antibacterials. Thus, clindamycin should be avoided for 3 days before and after oral typhoid vaccination.

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 foetus 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 approximately 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.

Breast-feeding

Clindamycin is excreted in human milk. If possible, mothers should stop breastfeeding during therapy. Diarrhoea, fungus infection of the mucous membranes or other serious adverse events could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility of sensitivity should be borne in mind.

Orally and parenterally administered clindamycin has been reported to appear in human breast milk in ranges from 0.7 to 3.8pg/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.

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); and 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 Common > 1/10	Common > 1/100 to < 1/10	Uncommon >1/1000 to <1/100	Rare > 1/1000 0 to <1/1000	Very Rare < 1/1000	Not Known (cannot be estimated from available data)
Infections and infestatio						Vaginal infection
Blood and Lymphatic System Disorders						Agranulocytosis Leukopenia Neutropenia Thrombocytopeni a Eosinophilia
Immune System Disorders						Anaphylactoid reaction Drug reaction with eosinophilia and systemic symptom (DRESS)
Nervous System Disorders						Dysgeusia
Gastrointestinal Disorders		Abdominal pain Diarrhoea Pseudomemb ranous colitis (see section 4.4)	Nausea Vomiting			Oesophageal ulcer Oesophagitis
Hepatobiliary Disorders		Liver function test abnormal				Jaundice
Skin and Subcutaneous Tissue Disorders			Rash maculo- papular Urticaria			Toxic epidermal necrolysis Stevens- Johnson syndrome Acute generalised exanthematous pustulosis (AGEP) Erythema multiforme Dermatitis exfoliative Dermatitis bullous Rash morbilliform Pruritus Anaphylaxis
Musculoskeletal Disorders						polyarthritis

Diarrhoea occurs in up to 20% of patients; it may commence during treatment or may be delayed until some time after therapy has been completed. This may progress to colitis, including pseudomembraneous colitis, which may have life-threatening complications. Fatalities have been reported.

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: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In cases of overdosage no specific treatment is indicated.

Features: Antibiotics cause very little effect when taken in acute overdosage. There may be nausea and vomiting. Skin rashes may occur if the patient is already allergic to the antibiotic.

Management: The serum biological half-life of clindamycin is 2.4 hours. Clindamycin cannot readily be removed from the blood by dialysis or peritoneal dialysis. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.

Gastric decontamination is not necessary. Give oral fluids for severe vomiting and diarrhoea if required. Other measures should be taken as indicated by the patient’s clinical condition. If an allergic reaction occurs therapy should be with the usual emergency treatments, including corticosteroids, adrenaline and antihistamines.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

General properties:

Pharmacotherapeutic group: Antibacterials for Systemic Use.

ATC Code: J01 FF

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. Clindamycin binds to the 50S subunit of the bacterial ribosome and inhibits the early stages of protein synthesis. The action of clindamycin is predominately bacteriostatic, though high concentrations may be slowly bactericidal against sensitive strains.

Breakpoints:

The following MICs have been proposed to separate susceptible from intermediately susceptible and resistant organisms.

Susceptible: < 1.6 p,g/ml Intermediate: >1.6 - < 4.8 p,g/ml Resistant: > 4.8 p,g/ml

The BSAC-recommended breakpoints for staphylococci are S: < 0.5 pg/ml; R: > 1.0 pg/ml

Susceptibility:

The following table lists organisms according to their inherent susceptibility to clindamycin. 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.

Resistance:

Resistance to clindamycin usually occurs via macrolide-lincosamide-streptograminB (MLS_b) type of resistance, which may be constitutive or inducible. This is mediated by a variety of acquired genes that encode methylases targeted at the peptidyl transferase center of 23S ribosomal RNA. Methylation impedes binding of antibacterials to the ribosome and gives rise to cross-resistance to macrolides (all macrolides when constitutive), lincosamides (clindamycin and lincomycin) and type B streptogramins, but not to type A streptogramins

5.2    Pharmacokinetic properties

Absorption

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.

Distribution

Clindamycin is widely distributed in body fluids and tissues including bone, but it does not reach the cerebrospinal fluid in significant concentrations. It diffuses across the placenta into the fetal circulation and appears 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.

Elimination

Clindamycin undergoes metabolism, presumably in the liver, to the active N-demethyl and sulphoxide metabolites and also some inactive metabolites. About 10% of the drug 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 evidence of teratogenic effect in animals nor to date in man.

6 PHARMACEUTICAL PARTICULARS

List of excipients

Lactose Monohydrate Maize Starch Magnesium Stearate Purified Talc

The capsule shells contain: Gelatin

Azorubine E122 Indigo carmine E132

Printing ink:

Shellac

Titanium dioxide (E171) Propylene Glycol (E1520) Ethanol

6.2    Incompatibilities

Not applicable.

6.3    Shelf-life

3 years.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5    Nature and contents of container

Packs of 24 and 100 capsules.

24’s: Blister packs composed of white PVC / PE / PVdC 250.25.90 micron and plain 20 pm hard tempered aluminium foil, one side coated with Heatseal Laquer, reverse side primed for printing. Each blister contains 8 capsules. 100’s: Polypropylene container with low density polyethylene tamper evident lids.

Not all pack sizes may be marketed.

6.6    Instructions for use/handling

None stated.

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR,

United Kingdom.

8. MARKETING AUTHORISATION NUMBER(S)

PL 4416/0429

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/02/2009

10 DATE OF REVISION OF THE TEXT 20/05/2015

1

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 clindamycin should not be used while awaiting susceptibility test results if there is any suspicion of

MRSA.