CLINJAB INJECTION

For the use of a Registered Medical Practitioner, Hospital or a Laboratory only

 CLINDAMYCIN INJECTION USP 150 mg/ml (For IM/IV Injection Use Only)

CLINJAB INJECTION

 COMPOSITION

Each ml contains:

Clindamycin Phosphate USP equ. to Clindamycin 150 mg

Benzyl Alcohol BP 9.45 mg (as preservative)

Water for Injections BP q.s.

DESCRIPTION

A clear, colourless to almost colorless solution.

 PHARMACODYNAMIC

Pharmacotherapeutic group: Lincosamides, ATC Code: J01FF01

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 clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin.

PHARMACOKINETICS

Absorption

Following parenteral administration, the biologically inactive clindamycin phosphate is hydrolyzed to clindamycin. When the equivalent of 300mg of clindamycin is injected intramuscularly, a mean peak plasma concentration of 6 microgram/ml is achieved within three hours; 600mg 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.

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 foetal 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. In vitro studies in human liver and intestinal microsomes indicated that clindamycin is predominantly oxidized by CYP3A4, with minor contribution from CYP3A5, to form clindamycin sulfoxide and a minor metabolite, N- desmethylclindamycin. The half-life is 2 to 3 hours, although this may be prolonged in pre-term neonates and patients with severe renal impairment.

Biotransformation

Clindamycin undergoes metabolism, to the active N-demethyl and sulphoxide metabolites and also some inactive metabolites.

Elimination

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.

THERAPEUTIC INDICATION

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 for the treatment of severe infections caused by susceptible anaerobic pathogens such as Bacteroides spp, Fusobacterium spp, Propionibacterium spp, Peptostreptococcus spp. and microaerophilic streptococci. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

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

 DOSAGE AND ADMINISTRATION

Parenteral (IM or IV administration) – ‘see Method of administration’ below.

Posology

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 IM 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.

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

Elderly: 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.

Paediatric population (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.

Method of administration

Parenteral (IM or IV administration). Clindamycin 150 mg/ml Solution for Injection and Infusion should be used undiluted for IM administration. Clindamycin 150 mg/ml Solution for Injection and Infusion must be diluted prior to IV administration and should be infused over at least 10-60 minutes.

Dilution for IV use and IV infusion rates

The concentration of clindamycin in diluent for infusion should not exceed 18 mg per ml and infusion rates should not exceed 30mg per minute. The usual infusion rates are as follows:

 OVERDOSE

Management:

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.

CONTRAINDICATION

Hypersensitivity to the active substance or to any of the excipients.

Clindamycin 150 mg/ml Solution for Injection and Infusion is contra-indicated in patients previously found to be sensitive to lincomycin.

 WARNING AND PRECAUTIONS

Warnings

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.

Clindamycin 150mg/ml Solution for Injection and Infusion 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.

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’. 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. 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 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.

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. 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. Drugs inhibiting peristalsis are contraindicated in this situation.

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.

Precautions

Caution should be used when prescribing Clindamycin 150mg/ml Solution for Injection and Infusion to individuals with a history of gastro-intestinal disease, especially colitis.

Since Clindamycin 150 mg/ml Solution for Injection and Infusion 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 should be performed. Acute kidney injury, including acute renal failure, has been reported infrequently. In patients suffering from pre-existing renal dysfunction or taking concomitant nephrotoxic drugs, monitoring of renal function should be considered. 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 150 mg/ml Solution for Injection and Infusion may result in the overgrowth of non-susceptible organisms particularly yeasts.

Prolonged administration of Clindamycin 150 mg/ml Solution for Injection and Infusion, 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 150 mg/ml Solution for Injection and Infusion in atopic individuals.

Clindamycin phosphate should not be injected intravenously undiluted as a bolus, but should be infused over at least 10-60 minutes as directed.

This medicine contains less than 1 mmol sodium (23 mg) per 2 ml ampoule, that is to say essentially ‘sodium-free’.

This medicinal product contains 26 mg sodium per 4 ml ampoule, equivalent to 1.3% of the WHO recommended maximum daily intake of 2 g sodium for an adult.”

PREGNANCY, LACTATION AND FERTILITY

Pregnancy

There was evidence of maternal toxicity and embryofetal toxicity in animal studies.

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 < 0.5 to 3.8 μg/ml. Clindamycin has the potential to cause adverse effects on the breastfed infant’s gastrointestinal flora such as diarrhoea or blood in the stool, or rash. If oral or intravenous clindamycin is required by a nursing mother, it is not a reason to discontinue breastfeeding, but an alternate drug may be preferred. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for clindamycin and any potential adverse effects on the breastfed child from clindamycin or from the underlying maternal condition.

Fertility

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

DRUG INTERACTION

Clindamycin administered by injection 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.

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.

Co-administration of clindamycin with inhibitors of CYP3A4 and CYP3A5

Clindamycin is metabolized predominantly by CYP3A4, and to a lesser extent by CYP3A5, to the major metabolite clindamycin sulfoxide and minor metabolite N desmethylclindamycin. Therefore, inhibitors of CYP3A4 and CYP3A5 may reduce clindamycin clearance and inducers of these isoenzymes may increase clindamycin clearance. In the presence of strong CYP3A4 inducers such as rifampicin, monitor for loss of effectiveness.

In vitro studies indicate that clindamycin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2E1 or CYP2D6 and only moderately inhibits CYP3A4. Therefore, clinically important interactions between clindamycin and co-administered drugs metabolized by these CYP enzymes are unlikely.

ADVERSE 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 of undesirable effects listed below 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.

^* ADR identified post-marketing.

^† ADRs apply only to injectable formulations.

^# Refer “Warning and Precautions”

• Rare instances have been reported following to rapid intravenous administration

PRESENTATION

CLINJAB Injections are supplied in 2 ml and 4 ml flint Type I USP ampoule.

STORAGE AND OTHER INFORMATION

Store in a cool and dry place. Protect from light.

Store at below 30°C temperature.

Caution: Not to be used if container is found leaking or solution is hazy or contain any visible solid particles.

Keep this medicine out of the sight and reach of children.