They derive from the antibacterial and pharmacokinetic characteristics of clindamycin. They are based on data obtained from clinical studies performed with the medicinal product and its place in the range of currently available antibacterial products.

Treatment of infections:

Clindamycin is indicated for the treatment of severe infections by susceptible micro-organisms causing namely:

·         Ears, nose and throat infections,

·         Bronchopulmonary infections,

·         Stomatological infections,

·         Skin infections,

·         Genital infections,

·         Osteoarticular infections,

·         Post-surgical abdominal infections,

·         Septicaemia.

Except for meningeal infections even if caused by susceptible micro-organisms, because the antibiotic does not diffuse into CSF in therapeutically effective quantities.

Prophylaxis:

Prophylaxis of infective endocarditis during dental care and upper respiratory tract procedures performed on an outpatient basis in patients allergic to beta lactams.

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

Posology

Treatment of infections:

Adults: 600 to 2,400 mg/24 hours in 2, 3 or 4 doses.

Prophylaxis:

Adults: 600 mg orally in the hour preceding the procedure.

Paediatric population

Avocin capsules are not suitable for children, who are unable to swallow them whole.

Use of the capsules may not be appropriate to provide the exact doses required in mg/kg to treat children.

Treatment of infections:

Children aged over 6 years: 8 to 25 mg/kg/24 hours, in 3 to 4 doses.

Prophylaxis:

Children aged over 6 years: 15 mg/kg orally in the hour preceding the procedure.

Method of administration:

Not applicable.

Antibiotic-associated colitis

Pseudomembranous colitis and antibiotic-associated colitis have been observed with use of nearly all antibacterial agents including clindamycin (see section 4.8); they may range in severity from mild to life threatening. Consequently, it is important to consider this diagnosis in the event of diarrhoea occurring during or after the administration of any antibiotic. If an antibiotic- associated colitis arises, clindamycin must be discontinued immediately; a doctor should be consulted and adequate treatment, including a specific treatment against Clostridium difficile should be initiated. Drugs inhibiting peristalsis are contraindicated in this situation.

Hypersensitivity

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 treatment. In cases of hypersensitivity or severe skin reaction occurs, clindamycin should be discontinued and appropriate medical treatment should be initiated (see sections 4.3 and 4.8).

Clindamycin should be used with caution in patients with a history of asthma or other allergies.

The occurrence early in treatment of generalised erythema with pyrexia and pustules would suggest acute generalised exanthematous pustulosis (see section 4.8); treatment must be discontinued and any further administration of clindamycin is contraindicated.

Hepatic insufficiency

Raised clindamycin serum levels and increased elimination half-life have been reported in cases of hepatic insufficiency.

If therapy is prolonged, liver functions tests should be performed. Long-term treatment

Long-term treatment should only be undertaken with close monitoring of blood counts, liver enzymes and renal function.

Antibiotic use, particularly for long periods, is associated with the emergence and selection of less susceptible bacteria or the development of fungi. Appropriate treatment must be initiated in the event of superinfection.

This drug must not be used in the treatment of meningitis since clindamycin does not diffuse adequately into cerebrospinal fluid (see section 4.1).

Lactose

This medicinal product contains lactose. Its use should be avoided in patients presenting with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases).

Acute kidney injury

Acute kidney injury, including acute renal failure, has been reported infrequently. In patients receiving prolonged therapy, suffering from pre-existing renal dysfunction or taking concomitant nephrotoxic drugs, monitoring of renal function should be considered (see section 4.8).

1.1      Combinations requiring precautions for use

+ Vitamin K antagonists:

Increased antivitamin K effect and/or bleeding,

More frequent INR monitoring. If necessary dose adjustment of antivitamin K during treatment with clindamycin and after treatment discontinuation.

+ Topical gastrointestinal agents, antacids and adsorbents

Topical gastrointestinal agents, charcoal and antacids (aluminium, calcium and magnesium salts), alone or combined with alginates, reduce the digestive absorption of certain other medicinal products taken simultaneously. Medicinal products for which a reduction in gastrointestinal absorption has been observed include acetylsalicylic acid, H2 blockers and lansoprazole, bisphosphonates, catioresins, certain classes of antibiotics (fluoroquinolones, tetracyclines, lincosamides) and some anti-tubercular agents, digitalis, glucocorticoids, thyroid hormones, phenothiazine neuroleptics, sulpiride, certain beta-blockers, penicillamine, ions (iron,

phosphorus, fluorine), chloroquine, ulipristal and fexofenadine.

As a precaution, these topical gastrointestinal agents or antacids should be taken some time apart from any other medicinal product (more than 2 hours, if possible).

+ Ciclosporin

Decrease in the blood concentrations of the immunosuppressive agent, associated with a risk of loss of immunosuppressive activity. Increase monitoring of ciclosporin blood levels and increase its dosage if required.

+ Cytochrome P450 (CYP) 3A4 inducers

Clindamycin is mainly metabolised by CYP3A4, and to a lesser extent by CYP3A5, to form the major metabolite, clindamycin sulphoxide, and the minor metabolite, N-desmethylclindamycin. Therefore, CYP3A4 and CYP3A5 inhibitors may reduce clindamycin clearance, and the inducers of these isoenzymes may increase clindamycin clearance. In the presence of potent CYP3A4 inducers such as rifampicin, monitoring of loss of efficacy is required.

In vitro studies indicate that clindamycin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2E1 or CYP2D6, and only moderately inhibits CYP3A4. Therefore, clinically significant interactions between clindamycin and coadministered medicinal products metabolised by these cytochromes are unlikely.

+ Tacrolimus

Decrease in the blood concentrations of the immunosuppressive agent, associated with a risk of loss of immunosuppressive activity. Increase monitoring of tacrolimus blood levels and increase its dosage if required.

Specific problems related to changes in the INR

Several cases of increases in the activity of antivitamin K have been reported in patients receiving antibiotics. Risk factors include the degree of severity of infection or inflammation and the patient’s age and general condition. In such cases, it is difficult to discern whether the infection or the treatment is responsible for the change in INR. However, certain classes of antibiotics are more implicated than others, namely fluoroquinolones, macrolides, cyclins, cotrimoxazole and certain cephalosporins.

Pregnancy

In embryo foetal development studies (see section 5.3) no toxicity was observed on the development except at doses that caused toxicity in the mother.

Clindamycin crosses the placenta.

Exposure data of clindamycin by systematic or topical route in pregnant woman during the first trimester are limited.

Available data of exposure during the second and third trimesters, are numerous and an increased foetal risk has not been reported.

Thus, taken into account the available data, it is preferable as a precaution not to use clindamycin during the first trimester of pregnancy.

During the second and third trimesters of pregnancy, clindamycin can be used if necessary. Breast-feeding

The excretion of clindamycin in human breast milk is low and the quantities ingested are much lower than paediatric therapeutic doses after systemic use.

Therefore, breast-feeding is possible whilst taking this antibiotic. However, in cases of diarrhoea, blood in stools, candidiasis or cutaneous rash in the infant, the continuation of breast-feeding (or off taking the medicine) must be reviewed.

Fertility

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

Avocin capsules have 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.

Following the organ classification system, the adverse reactions are listed below in order of decreasing frequency and then of clinical severity 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 Frequency not known (cannot be estimated from the available data).

* see section 4.4

# post-marketing data

# See section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing 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 according to their local country requirements.

To Report any side effects:

Saudi Arabia:

Other GCC States:

Haemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.

Pharmacotherapeutic class: lincosamides, ATC code: J01FF01. Clindamycin is an antibiotic from the lincosamide family.

Mechanism of action

Clindamycin inhibits the synthesis of bacterial proteins by bonding to the 50S sub-unit of the bacterial ribosome. At normal doses, clindamycin has a bacteriostatic activity in vitro.

Pharmacokinetic-pharmacodynamic relationship

The percentage of time during which the concentration of the antibiotic is above the minimum inhibitory concentration (MIC) of the bacteria between two administrations (%T>MIC) is the most predictive parameter for the efficacy of clindamycin.

Resistance

Clindamycin resistance is most often caused by mutations of the site where the antibiotic bonds to the rRNA or methylation of 23S RNA specific nucleotides of the 50S ribosome sub- unit. These changes can determine in vitro cross-resistance to macrolides and B streptogramins (MLSB phenotype).

Resistance mechanisms can also be due to active efflux.

Clindamycin resistance can be induced by macrolides in macrolide-resistant bacteria strains. Full cross-resistance between clindamycin and lincomycin is possible.

The incidence of clindamycin resistance is higher among methicillin-resistant staphylococcus strains and penicillin-resistant pneumococcal strains.

Critical concentrations

According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), critical concentrations for clindamycin that separate susceptible strains (S) from resistant strains

(R) are as follows:

Antibacterial spectrum of activity

The prevalence of acquired resistance may vary geographically and with time for certain species. Therefore, local information on the prevalence of resistance is useful, particularly for severe infections. If required, it is desirable to have a specialist opinion, mainly when the benefit of some medicinal products for certain infections can be questioned due to the level of prevalence of local resistance.

Anti-parasitic activity

Clindamycin shows in vitro and in vivo activity against Toxoplasma gondii.

General characteristics of active substance

About 90% of a dose of clindamycin hydrochloride is absorbed from the gastro-intestinal 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.

In oral embryo foetal development studies in rats and in subcutaneous embryo foetal development studies in rats and rabbits, no developmental toxicity was observed except at doses that produced maternal toxicity.

Genotoxicity studies haven’t shown a genotoxic activity. No cancerogenesis studies have been conducted with clindamycin.

Lactose monohydrate, Maize starch, Talc, Magnesium Stearate, Hard Gelatin Capsule.

Clindamycin is physicochemically incompatible with the following medicinal products: ampicillin, phenytoin, barbiturates, aminophylline, calcium gluconate, magnesium sulphate.

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

Store below 30°C.

Avocin 150 mg and 300 mg capsules are available in blister packs of 20 Capsules.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.