This information is intended for use by health professionals

1. Name of the medicinal product

Clindamycin 150 mg Hard Capsule

2. Qualitative and quantitative composition

Each capsule contains clindamycin hydrochloride equivalent to 150 mg clindamycin.

Excipient(s) with known effect:

lactose.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Capsule, hard.

A capsule with a lavender body and maroon cap imprinted with CL 150 in white.

4. Clinical particulars
4.1 Therapeutic indications

In the treatment of serious infections due to gram-positive organisms, including 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.

4.2 Posology and method of administration

Posology

Method of administration

To be taken orally. Clindamycin Capsules should always be taken with a glass of water.

Absorption of Clindamycin Capsules is not appreciably modified by the presence of food.

Adults (including the elderly):

Moderately severe infection: 150 - 300 mg every six hours

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

Dosage in elderly

The dosage of clindamycin may require reduction in patients with renal impairment due to prolongation of the serum half-life of this drug. This is particularly important with parenteral dosage.

Pediatric population (over 1 month of age):

The usual daily dosage is 12 - 24 mg/kg in 4 divided doses.

In children under one year of age or weighing 10 kg or less, the minimum recommended dosage is 37.5 mg every eight hours.

Dosage in Renal Impairment:

Clindamycin dosage modification is not necessary in patients with renal insufficiency.

4.3 Contraindications

Clindamycin is contraindicated in patients previously found to be hypersensitive to clindamycin, lincomycin, or any of the excipients listed in section 6.1. Although cross-sensitisation to lincomycin has not been demonstrated, it is recommended that clindamycin is not used in patients who have demonstrated lincomycin sensitivity.

4.4 Special warnings and precautions for use

Severe hypersensitivity reactions, including severe skin reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving clindamycin therapy. If a hypersensitivity or severe skin reaction occurs, clindamycin should be discontinued and appropriate therapy should be initiated (see sections 4.3 and 4.8).

Clindamycin Capsules should only be used in the treatment of serious infections. In considering the use of this product the practitioner should bear in mind the type of infection and the potential hazard of the diarrhoea that may develop, since cases of colitis have been reported.

Studies indicate a toxin(s) produced by clostridia (especially Clostridium difficile) is the principal cause of antibiotic-associated colitis. These studies also indicate that this toxigenic clostridium is usually sensitive in vitro to vancomycin. When 125 - 500 mg of vancomycin is administered orally four times a day, there is a rapid observed disappearance of the toxin from faecal samples and a coincident recovery from the diarrhoea.

Treatment with antibacterial agents alters 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 diarrhoea (CDAD) and is a primary cause of “antibiotic-associated colitis”.

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.

Care should be observed in the use of Clindamycin Capsules in atopic individuals e.g. asthma and allergy.

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

If therapy is prolonged liver and kidney function tests and blood counts should be performed. Such monitoring is also recommended in neonates and infants. Safety and appropriate dosage in infants less than one month old have not been established.

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

Prolonged administration of an anti-infective may result in super-infection due to organisms resistant to the anti-infective.

Clindamycin Capsules should not be used in patients with diarrhoea or intestinal inflammatory disease.

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

Attention should also be paid to the possibility of cross resistance to macrolides and lincosamides for some individual bacterial strains (see section 5.1 Pharmacodynamic properties).

4.5 Interaction with other medicinal products and other forms of interaction

Clindamycin administered by injection 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.

Clindamycin Capsules should not be prescribed concurrently with erythromycin.

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 in humans. 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

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

≥ 1/1 000 to <1/100

Rare

≥ 1/10 000 to <1/1 000

Very

Rare

< 1/10 000

Not Known

(cannot be estimated From available data)

Infections and infestations

pseudomembranous colitis*#

clostridium difficile

colitis*,

Vaginal infection*

Blood and Lymphatic System Disorders

Agranulocytosis*

Leukopenia*,

Neutropenia*

Thrombocytopenia*

Eosinophilia

Immune System Disorders

Anaphylactic shock*,

Anaphylactoid

Reactions*, anaphylactic reaction*, hypersensitivity*

Nervous System Disorders

Dysgeusia

Gastrointestinal Disorders

Abdominal pain,

Diarrhoea

Nausea,

Vomiting

Oesophageal ulcer*‡

Oesophagitis*‡

Hepatobiliary Disorders

Jaundice*

Skin and Subcutaneous Tissue Disorders

Rash

maculopapular,

Urticaria

Toxic epidermal Necrolysis (TEN)*,

Steven Johnson syndrome (SJS)*,

drug reaction with eosinophilia and systemic symptoms (DRESS)*,

Acute generalized exanthematous pustulosis (AGEP*),

angioedema*,

Erythema multiforme*,

Dermatitis, exfoliative*,

Dermatitis bullous*,

Rash

Morbilliform*,

Pruritus

Investigations

Liver function test abnormal

* ADR identified post-marketing.

‡ ADRs apply only to oral formulations.

# See section 4.4.

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 UK Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

In cases of overdosage no specific treatment is indicated. The serum biological half-life of clindamycin is 2.4 hours. Haemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.

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: Anti-infectives for treatment of acne,

ATC Code: D10AF01.

Mechanism of action

Clindamycin is a lincosamide antibiotic with a primarily bacteriostatic action against Gram-positive aerobes and a wide range of anaerobic bacteria. 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.

Although Clindamcyin is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin. At usual doses, clindamycin exhibits bacteriostatic activity in vitro.

Pharmacodynamic effects

The efficacy is related to the area under the concentration-time curve of the unbound fraction the agent that exceeds the minimum inhibitory concentration (MIC) of the pathogen (fAUC/MIC).

Resistance

Resistance to clindamycin is most often due to mutations at the rRNA antibiotic binding site or methylation of specific nucleotides in the 23S RNA of the 50S ribosomal subunit. These alterations can determine in vitro cross resistance to macrolides and streptogramins B (MLSB phenotype). Resistance is occasionally due to alterations in ribosomal proteins. Resistance to clindamycin may be inducible by macrolides in macrolide-resistant bacterial isolates.

Inducible resistance can be demonstrated with a disk test (D-zone test) or in broth. Less frequently encountered resistance mechanisms involve modification of the antibiotic and active efflux. There is complete cross resistance between clindamycin and lincomycin. As with many antibiotics, the incidence of resistance varies with the bacterial species and the geographical area. The incidence of resistance to clindamycin is higher among methicillin-resistant staphylococcal isolates and penicillin-resistant pneumococcal isolates than among organisms susceptible to these agents.

Most Gram-negative aerobic bacteria, including the Enterobacteriaceae, are resistant to Clindamycin. Clindamycin demonstrates cross-resistance with lincomycin. When tested by in vitro methods, some staphylococcal strains originally resistant to erythromycin rapidly developed resistance to Clindamycin. The mechanisms for resistance are the same as for erythromycin, namely methylation of the ribosomal binding site, chromosomal mutation of the ribosomal protein and in a few staphylococcal isolates enzymic inactivation by a plasmid-mediated adenyltransferase.

Antimicrobial activity

Clindamycin has been shown to have in vitro activity against isolates of the following organisms:

Aerobic bacteria

Gram-positive bacteria

Staphylococcus aureus; (methicillin-susceptible isolates)

Coagulase-negative staphylococci (methicillin-susceptible isolates)

Streptococcus pneumoniae (penicillin-susceptible isolates)

Beta-hemolytic streptococci groups A, B, C, and G

• Viridans group streptococci

Corynebacterium spp.

Gram-negative bacteria

Chlamydia trachomatis

Anaerobic bacteria

Gram-positive bacteria

Actinomyces species.

Clostridium spp. (except Clostridium difficile).

Eggerthella (Eubacterium) spp.

Peptococcus species;

Peptostreptococcus species;.

Propionibacterium acnes

Gram-negative bacteria

Bacteroides spp

Fusobacterium spp.

Gardnerella vaginalis

Prevotella spp.

Species for which acquired resistance may be a problem

Aerobic bacteria

Gram-positive bacteria

Staphylococcus aureus (methicillin-susceptible isolates)

Coagulase-negative staphylococci (except methicillin-resistant isolates)

Streptococcus pneumoniae (except penicillin-resistant isolates)

Gram-negative bacteria

Moraxella catarrhalis

Anaerobic bacteria

Gram-negative bacteria

Bacteroides fragilis

Inherently resistant organisms

Aerobic bacteria

Gram-positive bacteria

Coagulase-negative staphylococci (methicillin-resistant isolates)

Enterococcus faecalis

Enterococcus faecium

Gram-negative bacteria

Haemophilus influenzae

Anaerobic bacteria

Gram-positive bacteria

Clostridium difficile

Breakpoints

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. Particularly in severe infections or therapy failure microbiological diagnosis with verification of the pathogen and its susceptibility to clindamycin is recommended.

Resistance is usually defined by susceptibility interpretive criteria (breakpoints) established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for systemically administered antibiotics.

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints are presented below.

Table 1. EUCAST Susceptibility Interpretive Criteria for Clindamycin

MIC breakpoints

(mg/L)

Organism

S≤

R >

Staphylococcus spp.

0.25

0.5

Streptococcus

Groups A, B, C and G

0.5

0.5

Streptococcus pneumoniae

0.5

0.5

Viridans group streptococci

0.5

0.5

Gram-positive anaerobes

4

4

Gram-negative anaerobes

4

4

Corynebacterium spp.

0.5

0.5

5.2 Pharmacokinetic properties

Serum level studies with a 150mg oral dose of clindamycin in 24 normal adult volunteers showed that clindamycin was rapidly absorbed after oral administration. An average peak serum level of 2.5 mcg/mL was reached in 45 minutes: serum levels averaged 1.51 mcg/mL at 3 hours and 0.70 mcg/mL at 6 hours. Absorption of an oral dose is virtually complete (90%) and the concomitant administration of food does not appreciably modify the serum concentrations; serum levels have been uniform and predictable from person to person and dose to dose. Serum levels studies following multiple dose of clindamycin for up to 14 days show no evidence of accumulation or altered metabolism of drug. Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function. Haemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Concentrations of clindamycin in the serum increased linearly with increased dose. Serum levels exceed the MIC (minimum inhibitory concentrations) for most indicated organisms for at least six hours following administration of the usually recommended doses.

Clindamycin is widely distributed in body fluids and tissues (including bones). The average biological half-life is 2.4 hours. Approximately 10% of the bioactivity is excreted in the urine and 3.6% in the faeces; the remainder is excreted as bioinactive metabolites. Doses of up to 2 grams of clindamycin per day for 14 days have been well tolerated by healthy volunteers, except that the incidence of gastrointestinal side effects is greater with the higher doses. No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges.

Pharmacokinetic studies in elderly volunteers (61-79 years) and younger adults (18-39 years) indicate that age alone does not alter clindamycinpharmakinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentrations time curve) after IV administration of clindamycin phosphate. After oral administration of clindamycin, elimination half-life is increased to approximately 4.0 hours (range 3.4-5.1 h) in the elderly compared to 3.2 hours (range 2.1-4.2 h)in younger adults. The extent of absorption however, is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function.

5.3 Preclinical safety data

There is no evidence of teratogenic effect in animals, nor to date in man.

Carcinogenesis:

Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential.

Mutagenesis:

Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative.

Impairment of Fertility:

Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.1 times the highest recommended adult human dose based on mg/m2) revealed no effects on fertility or mating ability.

In oral embryo foetal development studies in rats and subcutaneous embryo foetal development studies in rats and rabbits, no developmental toxicity was observed except at doses that produced maternal toxicity.

6. Pharmaceutical particulars
6.1 List of excipients

Capsule Contents

Lactose Monohydrate

MaizeStarch

Magnesium Stearate

Purified Talc

Capsule Body

Gelatin

Erythrosin (E127)

Indigo carmine FD&C Blue (E132)

Capsule Cap

Gelatin

Erythrosin (E127)

Indigo carmine FD&C Blue (E132)

Titanium dioxide (E171)

Printing ink

Shellac

propylene Glycol (E1520)

titanium dioxide (E171)

ethanol

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

No special precautions for storage.

6.5 Nature and contents of container

Blister packs composed of PVC / PE /PVdCaluminium foil; pack sizes: 4, 8, 16, 20, 24, 30, 32, 40 and 100. Polypropylene containers with polyethylene tamper evident lids; pack size: 100.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Chanelle Medical, Loughrea, Co. Galway, Ireland

8. Marketing authorisation number(s)

PL 13931/0061

9. Date of first authorisation/renewal of the authorisation

21/08/2009

10. Date of revision of the text

3th May 2019