4.1. Therapeutic indications

Clindamycin is indicated for the treatment of:

Serious infections caused by anaerobic bacteria, including intra-abdominal infections, skin and soft tissue infections. As needed, clindamycin should be administered in conjunction with another antibacterial agent that is active against gram negative aerobic bacteria.

- Tonsillitis

- Dental infection

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

4.2. Posology and method of administration

Posology

Adults:

Moderately severe infection, 150-300 mg every six hours; severe infection, 300-450 mg every six hours.

Elderly patients:

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 revealed any age-related increase in toxicity. Dosage requirements in elderly patients, therefore, should not be influenced by age alone.

Paediatric population:

Clindamycin hydrochloride capsules should only be used for children who are able to swallow capsules.

Clindamycin should be dosed based on total body weight regardless of obesity.

Doses of 12-25 mg/kg/day six hourly depending on the severity of the infection.

The use of whole capsules may not be suitable to provide the exact mg/kg doses required for the treatment of children.

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 Clindamycin should continue for at least 10 days to diminish the likelihood of subsequent rheumatic fever or glomerulonephritis.

Method of administration

Oral. Clindamycin capsules should always be swallowed whole and washed down with a full glass of water while in an upright position and no less than 30 minutes before lying down to avoid the possibility of oesophageal irritation. Absorption of Clindamycin capsules is not appreciably modified by the presence of food.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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), acute generalised exanthematous pustulosis (AGEP), and Kounis syndrome 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 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 diarrhea 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)

If therapy is prolonged, liver and kidney functions 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 (see section 4.8).

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 capsules, as with any anti-infective, may result in super–infection due to organism resistant to clindamycin.

Care should be observed in the use of Clindamycin capsules in atopic individuals.

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

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. Therefore, it should be used with caution, in patients receiving such agents.

Vitamin K antagonists

Increased coagulation tests (PT/INR) and/or bleeding, has 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.

4.6. Fertility, pregnancy and lactation

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 3.8μg/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.

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.

Adverse reactions identified from post-marketing experience are included in italics.

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);

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*,

neutropenia*,

thrombocytopenia*,

leukopenia*,

eosinophilia

Immune System Disorders

anaphylactic shock*,

anaphylactoid reaction*,

anaphylactic reaction*,

Kounis syndrome*,

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)*,

Stevens- Johnson Syndrome (SJS)*,

Drug reaction with eosinophilia And systemic symptoms (DRESS)*,

Acute generalised exanthematous pustulosis (AGEP)*,

angioedema*,

Erythema multiforme

Dermatitis Exfoliative *,

Dermatitis bullous*,

Cutaneous vasculitis*,

Rash

Morbilliform,

Pruritus,

Symmetrical drug-related intertriginous and flexural exanthema*

Investigations

liver function test abnormal

Renal and urinary disorders

Acute kidney injury#

* 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 and/or with a small amount of water.

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.

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.