SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Dalacin C Phosphate Sterile Solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains clindamycin phosphate equivalent to 150mg clindamycin.

Excipients with known effect:

Each ml of solution contains 9.45mg of benzyl alcohol see sections 4.3 and 4.4.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for Injection.

Clear, colourless, sterile solution for intramuscular or intravenous use.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Antibacterial. 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 such as Bacteroides spp, Fusobacterium spp, Propionibacterium spp, Peptostreptococcus spp. and microaerophilic streptococci. Clindamycin does not penetrate the blood/brain barrier in therapeutically effective quantities.

4.2 Posology and method of administration

Parenteral (i.m. or IV. administration). Dalacin C Phosphate must be diluted prior to IV. administration and should be infused over at least 10-60 minutes.

Adults: Serious infections: 600 mg - 1.2 g/day in two, three or four equal doses.

More severe infections: 1.2-2.7 g/day in two, three or four equal doses.

Single i.m. injections of greater than 600 mg are not recommended nor is administration of more than 1.2 g in a single one-hour infusion.

For more serious infections, these doses may have to be increased. In life-threatening situations, doses as high as 4.8 g daily have been given intravenously to adults.

Alternatively, the drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV. infusion.

Children (over 1 month of age): Serious infections: 15-25 mg/kg/day in three or four equal doses.

More severe infections: 25-40 mg/kg/day in three or four equal doses. In severe infections it is recommended that children be given no less than 300 mg/day regardless of body weight.

Elderly patients: The half-life, volume of distribution and clearance, and extent of absorption after administration of clindamycin phosphate 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 should not be influenced, therefore, by age alone. See Precautions for other factors which should be taken into consideration.

Treatment for infections caused by beta-haemolytic streptococci should be continued for at least 10 days to guard against subsequent rheumatic fever or glomerulonephritis.

The concentration of clindamycin in diluent for infusion should not exceed 18mg per mL and INFUSION RATES SHOULD NOT EXCEED 30 MG PER MINUTE. The usual infusion rates are as follows:

Dose	Diluent	Time
300mg	50mL	10 min
600mg	50mL	20min
900mg	50-100mL	30min
1200mg	100mL	40 min

4.3 Contraindications

Dalacin C Phosphate is contra-indicated in patients previously found to be sensitive to clindamycin, lincomycin or to any component of the formulation particularly benzyl alcohol.

4.4 Special warnings and special precautions for use

Warnings

This product contains benzyl alcohol (9.45mg/ml as preservative). Intravenous administration of the preservative benzyl alcohol has been associated with serious adverse events, and death in paediatric patients including neonates characterized by central nervous system depression, metabolic acidosis, gasping respirations, cardio-vascular failure and haematological anomalies (“gasping syndrome”). Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Use only if it is necessary and if there are no alternatives possible. If given in high volumes, should be used with caution and preferably for short term treatment in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis) due to benzoic acid (a metabolite of benzyl alcohol).

Premature and low-birth weight infants may be more likely to develop toxicity.

Benzyl Alcohol containing products should not be used in pre-term or full-term neonates unless strictly necessary.

Benzyl alcohol can cross the placenta and clindamycin should only be used during pregnancy if clearly needed (see section 4.6).

Dalacin C Phosphate 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 125mg to 500mg 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 colestyramine 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 C. difficile on selective media and assay of the stool specimen for the toxin(s) of C. difficile.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C difficile. [134-147]

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. [134-147]

Precautions

Caution should be used when prescribing Dalacin C Phosphate 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. Safety and appropriate dosage in infants less than one month old have not been established.

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

Care should be observed in the use of Dalacin C Phosphate in atopic individuals.

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    Pregnancy and lactation: Pregnancy Code B1

Safety for use in pregnancy has not been established.

Benzyl alcohol can cross the placenta (sees section 4.4).

Clindamycin is excreted in human milk. Caution should be exercised when Dalacin C Phosphate is administered to a nursing mother. It is unlikely that a

nursing infant can absorb a significant amount of clindamycin from its gastrointestinal tract.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

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

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.

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.

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

Cardiac Disorders: Rare instances of cardiopulmonary arrest and hypotension have been reported following too rapid intravenous administration. (See Section 4.2 Posology and Method of Administration)

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

General Disorders and Administration Site Conditions: Local irritation, pain, abscess formation have been observed in conjunction with IM injection. These reactions can be minimized by deep IM injection and avoiding the use of an indwelling catheter.

Thrombophlebitis has been reported with IV injection.

4.9 Overdose

In cases of overdosage no specific treatment is indicated.

The serum biological half-life of lincomycin 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

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.

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.

5.2 Pharmacokinetic properties

General characteristics of active substance

Following parenteral administration, the biologically inactive clindamycin phosphate is hydrolysed to clindamycin. When the equivalent of 300 mg of clindamycin is injected intramuscularly, a mean peak plasma concentration of 6 microgram/ml is achieved within three hours; 600 mg gives a peak concentration of 9 microgram/ml. In children, peak concentration may be reached within one hour. When the same doses are infused intravenously, peak concentrations of 7 and 10 micrograms per ml respectively are achieved by the end of infusion.

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 preterm neonates and patients with severe renal impairment.

Clindamycin undergoes metabolism, 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

None stated

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzyl alcohol Disodium edetate Sterilised water for injections

6.2 Incompatibilities

Solutions of clindamycin salts have a low pH and incompatibilities may reasonably be expected with alkaline preparations or drugs unstable at low pH. Incompatibility has been reported with: ampicillin sodium, aminophylline, barbiturates, calcium gluconate, ceftriaxone sodium, ciprofloxacin, diphenylhydantoin, idarubicin hydrochloride, magnesium sulphate, phenytoin sodium and ranitidine hydrochloride.

Shelf life

24 months

6.4    Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze.

6.5    Nature and contents of container

Type 1 flint glass ampoule containing 2 ml or 4 ml sterile, aqueous solution, packed in cardboard carton, together with a leaflet.

6.6 Special precautions for disposal

Dalacin C Phosphate has been shown to be physically and chemically compatible for at least 24 hours in dextrose 5% water and sodium chloride injection solutions containing the following antibiotics in usually administered concentrations: Amikacin sulphate, aztreonam, cefamandole nafate, cephazolin sodium, cefotaxime sodium, cefoxitin sodium, ceftazidime sodium, ceftizoxime sodium, gentamicin sulphate, netilmicin sulphate, piperacillin and tobramycin.

The compatibility and duration of stability of drug admixtures will vary depending upon concentration and other conditions.

7    MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent

CT13 9NJ UK

8    MARKETING AUTHORISATION NUMBER

PL 00057/0959

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/12/1990

DATE OF REVISION OF THE TEXT

28/07/2014