Clindamycin 75 mg/5 ml Granules for oral solution

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.

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

Posology

Adults

Moderately severe infection, 150 – 300 mg (10 ml-20 ml of the oral solution) every six hours; severe infection, 300 – 450 mg (20 ml-30 ml of the oral solution) every six hours.

Elderly patients

The half-life, volume of distribution and clearance, and extent of absorption after administration of clindamycin 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.

Paediatric population

The recommended dose is 15 mg/kg body weight per day, divided in 3 doses.

The maximum dose is 20 mg/kg/day, divided in 4 doses.

Table 1: Dosing table with the recommended posology for the paediatric population.

Dosage in renal/hepatic impairment

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

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

Method of administration

For oral use.

The oral solution should be taken no less than 30 minutes before lying down to avoid the possibility of oesophageal irritation.

A 10 ml graduated oral syringe with intermediate graduations of 0.5 ml and a “Press-In” Bottle Adapter (PIBA) are provided with the product.

For instructions on dilution of the product before administration and instructions for administration of the oral solution, see section 6.6.

Absorption of Clindamycin 75 mg/5 ml Granules for oral solution is not appreciably modified by the presence of food.

Clindamycin oral solution is contra-indicated in patients previously found to be sensitive to clindamycin, lincomycin or to any of the excipients listed in section 6.1.

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 generalised 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 oral solution 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 Clostridioides difficile) is the principal direct cause of antibiotic-associated colitis. These studies also indicate that this toxigenic clostridioides 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 Clostridioides difficile on selective media and assay of the stool specimen for the toxin(s) of C. difficile.

Clostridioides 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.

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.

Due to the risk of oesophagitis and oesophageal ulcer, it is important to ensure compliance with administration guidance (see Sections 4.2 and 4.8).

Precautions

Caution should be used when prescribing Clindamycin oral solution to individuals with a history of gastrointestinal 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.

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 (see section 4.8).

Prolonged administration of Clindamycin oral solution, 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 oral solution in atopic individuals.

Clindamycin oral solution contains sucrose and ethyl parahydroxybenzoate.

Sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicinal product contains 1.8 g of sucrose in each 5 ml of oral solution. This should be taken into account in patients with diabetes mellitus.

May be harmful to the teeth.

Ethyl parahydroxybenzoate

This medicinal product contains 0.6 mg ethyl parahydroxybenzoate in each 5 ml of oral solution.

May cause allergic reactions (possibly delayed).

Benzoate salts may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

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.

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.

Pregnancy

There was evidence of maternal toxicity and embryofetal toxicity in animal studies (see section 5.3).

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.

Clindamycin has no or negligible influence on the ability to drive and use machines.

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.

* ADR identified post-marketing.

‡ ADRs apply only to oral formulations.

# See section 4.4.

≠ Possible occurrence of oesophagitis and oesophageal ulcer, particularly if taken in a lying position.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Pharmacotherapeutic group: Lincosamide antibiotics, ATC code: 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. Lincosamides such as clindamycin bind to the 50S subunit of the bacterial ribosome similarly to macrolides such as erythromycin and inhibit 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.

Resistance

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

Breakpoints

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

EUCAST

Staphylococci: sensitive ≤ 0.25 resistant > 0.5

Streptococci ABCG and pneumoniae: sensitive ≤ 0.5 resistant > 0.5

Gram positive anaerobes: sensitive ≤ 4 resistant > 4

Gram negative anaerobes: ≤ 4 resistant > 4

PK/PD relationship

Efficacy is related to the ratio of the area of the concentration-time curve of unbound antibiotic to the MIC for the pathogen (fAUC/MIC).

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 pneumoniae

Streptococcus pyogenes

Viridans streptococci

Anaerobes

Bacteroides fragilis group

Prevotella formerly known as Bacteroides melaninogenicus

Bifidobacterium spp.

Clostridioides 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.

General characteristics of active substance

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.

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 foetal 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. 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.

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 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 for further information.

Obese paediatric patients aged 2 to less than 18 years and obese adults aged 18 to 20 years

An analysis of pharmacokinetic data in obese paediatric patients aged 2 to less than 18 years and obese adults aged 18 to 20 years demonstrated that clindamycin clearance and volume of distribution normalized by total body weight are comparable regardless of obesity.

None stated.

Sucrose

Ethyl parahydroxybenzoate (E214)

Poloxamer 188

Cherry flavour (including flavouring substances)

Simethicone 30% emulsion

Not applicable.

3 years

After first opening use the reconstituted oral solution within 2 weeks.

Store below 30 °C. Store in the original package in order to protect from light.

Do not refrigerate reconstituted solution.

Amber, type III glass bottle safely closed with a child resistant screw cap with tamper evident closure, containing 32 gr of granules (for pack size of 80 ml).

A 10 ml graduated oral syringe with intermediate graduations of 0.5 ml and a “press in” syringe/bottle adapter are also provided.

The preparation is delivered as a dry substance in sealed bottles to a pharmacy or healthcare facility, where the solution is prepared extempore. The granulate is dissolved in 60 ml of purified water, whereby 80 ml of oral solution is obtained in a concentration of 15 mg of clindamycin base per 1 ml.

Instructions for reconstitution:

To make the solution, add 30 ml of the water and shake vigorously; then add the remaining 30 ml of water and shake well for at least 2.5 min until the solution is uniform. Allow to settle and you will have a colourless to slightly yellowish, clear to slightly cloudy solution with characteristic cherry odour.

Instructions for administration of Clindamycin oral solution:

1. Open the bottle and at first use insert the “Press-In” Bottle Adapter (PIBA) (see pictures A-B).

2. Insert the syringe into the PIBA and draw out the required volume from the inverted bottle (see pictures C-D).

3. Remove the filled syringe from the bottle in the upright position (see picture E).

4. Discharge the syringe contents into the mouth. Repeat steps 2 to 4 as needed to achieve the required dose.

5. Replace the cap on the bottle (PIBA remains in place).

6. Rinse the syringe with water and allow to air dry.

If you are giving Clindamycin oral solution to a child:

- Make sure that the child is sitting up or standing.

- Put the syringe into the child's mouth, placing the barrel-opening in the area between the gums and the inside of the cheek (see picture F).

- Push the plunger slowly, giving the child time to swallow the medicine as it squirts out. Do not push the plunger too quickly as the medicine may come out too quickly and the child may choke.

- Give the child some water to drink in order to ensure that all the medicine is washed down.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.