Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Sandoz SA (Pty) Ltd<sup>1</sup>, Waterfall 5-lr, Magwa Crescent West, Waterfall City, Jukskei View, 2090 1 Company Reg. No.: 1990/001979/07
Cross-resistance has been demonstrated between lincomycin hydrochloride and clindamycin.
Antagonism has been demonstrated with erythromycin.
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, CLINDAHEXAL should be discontinued and appropriate therapy should be initiated (see sections 4.3 and 4.8).
The choice of clindamycin should be based on factors such as severity of the infection, the prevalence of resistance to other suitable medicines and the risk of selecting clindamycinresistant bacteria. CLINDAHEXAL should only be used in the treatment of serious infections. When considering the use of CLINDAHEXAL, 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 CLINDAHEXAL.
Treatment with antibacterial agents can significantly alter 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). 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 mucous. 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 CLINDAHEXAL should be discontinued immediately.
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 Clostridium difficile.
Clostridium Difficile Associated Diarrhoea (CDAD) has been reported with the 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 Clostridium difficile. Clostridium difficile produces toxins A and B which contribute to the development of (CDAD).
Hypertoxin producing strains of Clostridium 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.
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. Medicines inhibiting peristalsis are contraindicated in this situation.
Caution is advised when using CLINDAHEXAL in patients with a history of gastro-intestinal disease, especially colitis.
Clindamycin does not penetrate the blood/brain barrier in therapeutically effective quantities. Since CLINDAHEXAL does not diffuse adequately into cerebrospinal fluid, it should not be used in the treatment of meningitis.
Periodic liver and kidney function tests should be carried out during prolonged therapy.
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 CLINDAHEXAL may result in super-infection due to organisms resistant to clindamycin.
Care should be observed in the use of CLINDAHEXAL in atopic individuals.
Treatment with clindamycin is possibly an alternative treatment in case of penicillin allergy (penicillin hypersensitivity). An allergic cross-reaction between clindamycin and penicillin is not known and not expected because of the structural differences of both substances. However, (in isolated cases) anaphylaxis has been observed after clindamycin treatment for patients with existing penicillin allergy. This should be taken into consideration before treating penicillin allergic patients with CLINDAHEXAL
Porphyria: There is no evidence that CLINDAHEXAL cannot be used in porphyria.
CLINDAHEXAL contains lactose. Patients with rare hereditary problems of galactose intolerance, e.g. galactosaemia the Lapp lactase deficiency or glucose-galactose malabsorption or fructose intolerance should not take CLINDAHEXAL.
CLINDAHEXAL contains lactose which may have an effect on the gylcaemic control of patients with diabetes mellitus.
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 medicines.
Antagonism in vitro has been observed between clindamycin and erythromycin. Due to possible clinical significance the two CLINDAHEXAL should not be administered concurrently.
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.
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 medicines metabolized by these CYP enzymes are unlikely.
Oral and subcutaneous reproductive toxicity studies in rats and rabbits revealed no evidence of impaired fertility or harm to the foetus 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.
CLINDAHEXAL should be used in pregnancy only if a safer alternative is not available.
Orally and parentally 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 breastfed infants, CLINDAHEXAL should not be taken by mothers who are breastfeeding their infants. Mothers taking CLINDAHEXAL should not breastfeed.
Fertility studies in rats treated orally with clindamycin revealed no effects on fertility or mating ability. The effect on human fertility is unknown.
CLINDAHEXAL has no or negligible influence on the ability to drive and use machines.
The evaluation of side effects is based on the following information on frequencies: Frequent, less frequent and not known (cannot be estimated from available data):
Frequent: Pseudomembranous colitis (see section 4.4).
Not known: Clostridium difficile, colitis, vaginal infection.
Not known: Agranulocytosis, leukopenia, neutropenia, thrombocytopenia, eosinophilia.
Not known: Anaphylactic shock, anaphylactoid reaction, anaphylactic reaction, hypersensitivity.
Not known: Dysgeusia.
Frequent: Abdominal pain, diarrhoea.
Less frequent: Nausea, vomiting.
Not known: Oesophageal ulcer, oesophagitis.
Not known: Jaundice.
Not known: Acute kidney Injury.
Less frequent: Rash maculopapular, urticaria.
Not known: 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, rash morbilliform, pruritus.
Frequent: Liver function test abnormal.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.
Suspected side effects can also be reported directly to the HCR via Patientsafety.sacg@novartis.com.
Not applicable.
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