Cilapen 500 500 mg. Powder for injection

CILAPEN 500 is indicated for the treatment of the following infections caused by susceptible strains of the designated micro-organisms in the conditions listed below:

• Intra-abdominal infections Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Staphylococcus epidermidis, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii*, Proteus species, Pseudomonas aeruginosa, Bifidobacterium species, Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species*, Bacteroides species including B. fragilis, Fusobacterium species.
• Lower respiratory tract infections Staphylococcus aureus (penicillinase-producing strains), Acinetobacter species, Enterobacter species, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae*, Klebsiella species, Serratia marcescens.
• Gynaecological infections Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococcus), Enterobacter species*, Escherichia coli, Gardnerella vaginalis, Klebsiella species*, Proteus species, Bifidobacterium species*, Peptococcus species*, Peptostreptococcus species*, Propionibacterium species*, Bacteroides species including B. fragilis.
• Septicaemia Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species*, Bacteroides species including B. fragilis.
• Genito-urinary tract infections (complicated and uncomplicated) Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa.
• Bone and joint infections Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter species, Pseudomonas aeruginosa.
• Skin and soft tissue infections Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus vulgaris, Providencia rettgeri*, Pseudomonas aeruginosa, Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis, Fusobacterium species*.
• Endocarditis Staphylococcus aureus (penicillinase-producing strains)* CILAPEN 500 is indicated for the treatment of mixed infections caused by susceptible strains of aerobic and anaerobic bacteria.

The majority of these mixed infections are associated with contamination by faecal flora or flora originating from the vagina, skin and mouth. In these mixed infections, Bacteroides fragilis is usually susceptible to CILAPEN 500. CILAPEN 500 has demonstrated efficacy against many infections caused by aerobic and anaerobic Gram-positive and Gram-negative bacteria resistant to other antibiotics. In the treatment of infections caused by Pseudomonas aeruginosa, an aminoglycoside should be administered concomitantly. CILAPEN 500 is not indicated for the treatment of meningitis.

Prophylaxis To reduce the risk of wound sepsis in adult patients after colorectal surgery. *Efficacy of this organism in this organ system was studied in fewer than 10 infections.

The dosage recommendations for CILAPEN 500 represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. The total daily dosage and route of administration of CILAPEN 500 should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s), renal function and body mass.

Intravenous infusion Treatment: Adult dosage schedule for patients with normal renal function Doses cited in Table I are based on a patient with normal renal function (creatinine clearance of greater than 70 ml/min/1,73 m2) and a body weight of greater than or equal to 70 kg. A reduction in dose must be made for a patient with a creatinine clearance less than or equal to 70 ml/min/1,73 m2 (see Table 2 and 3) and/or a body weight less than 70 kg. The reduction for body weight is especially important for patients with much lower body weights and/or moderate/severe renal insufficiency. Most infections respond to a daily dose of 1-2 g administered in 3-4 divided doses. For the treatment of moderate infections a 1 g twice daily dosage regimen may be used in infections due to less susceptible organisms, the daily dosage of CILAPEN 500 may be increased to a maximum of 4 g/day or 50 mg/kg/day, whichever is lower. Each dose of less than or equal to 500 mg of CILAPEN 500 should be given by intravenous infusion over 20 to 30 minutes. Each dose greater than 500 mg should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Table 1- Dosage schedule for adults with normal renal function and body weight greater than or equal to 70 kg

Type or Severity of Infection

• A Fully susceptible organisms including gram-positive and gram-negative aerobes and anaerobes
• B Moderately susceptible organisms, primarily some strains of P. aeruginosa

Mild 250 mg 6 hourly (Total Daily Dose = 1,0 g) 500 mg 6 hourly (Total Daily Dose = 2,0 g)

Moderate 500 mg 8 hourly (Total Daily Dose = 1,5 g) or 500 mg 6 hourly 500 mg 6 hourly (Total Daily Dose = 2,0 g) or 1 g 8 hourly (Total Daily Dose = 3,0 g)

Severe, life threatening only 500 mg 6 hourly (Total Daily Dose = 2,0 g) 1 g 8 hourly (Total Daily Dose = 3,0 g) or 1 g 6 hourly (Total Daily Dose = 4,0 g)

Uncomplicated urinary tract infection 250 mg 6 hourly (Total Daily Dose = 1,0 g) 250 mg 6 hourly (Total Daily Dose = 1,0 g)

Complicated urinary tract infection 500 mg 6 hourly (Total Daily Dose = 2,0 g) 500 mg 6 hourly (Total Daily Dose = 2,0 g)

It is recommended that the maximum total daily dosage does not exceed 50 mg/kg/day or 4 g/day whichever is lower. However, cystic fibrosis patients with normal renal function may be treated with CILAPEN 500 at doses up to 90 mg/kg/day in divided doses, not exceeding 4 g/day. CILAPEN 500 may be used successfully as monotherapy in immunocompromised cancer patients for confirmed or suspected infections such as sepsis.

Treatment: Adult dosage schedule for patients with impaired renal function To determine the reduced dose for adults with impaired renal function: 1. The total daily dose is chosen from Table 1 based on infection characteristics. 2. From Table 2 and 3 the appropriate reduced dosage regimen is selected based on the daily dose from Table 1 and the patientu2019s creatinine clearance category. (For infusion times, see Treatment: Adult dosage schedule for patients with normal renal function).

• Hypersensitivity to any other carbapenem antibacterial medicine, imipenem, cilastatin or to any of the excipients listed in section 6.1
• Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial medicine (e.g. penicillins or cephalosporins)
• Meningitis
• Pregnancy and lactation (see section 4.6)

Meningitis CILAPEN 500 is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used (see section 4.3). CILAPEN 500 may be used in children with sepsis as long as they are not suspected of having meningitis.

Granulocytopenic patients Substance-related nausea and/or vomiting appear to occur more frequently in granulocytopenic patients than in non-granulocytopenic patients treated with CILAPEN 500.

Hypersensitivity There is some clinical and laboratory evidence of partial cross-allerginicity between CILAPEN 500 and other beta-lactam antibiotics, penicillin and cephalosporins. Several reactions (including anaphylaxis) have been reported with most beta-lactam antibiotics such as imipenem. Before therapy with CILAPEN 500, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. If an allergic reaction to CILAPEN 500 occurs, the medicine should be discontinued and approximate measures undertaken. Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous reactions) have been reported in patients on penicillin therapy. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8).

Hepatic Hepatic function should be closely monitored during treatment with CILAPEN 500 due to the risk of hepatic toxicity (such as increase in transaminases, hepatic failure and fulminant hepatitis). Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with CILAPEN 500. There is no dose adjustment necessary.

Haematology A positive direct or indirect Coombs test may develop during treatment with CILAPEN 500.

Pseudomembranous colitis Pseudomembranous colitis can range from mild to life-threatening in severity. CILAPEN 500 should therefore be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. It is important to consider a diagnosis of pseudomembranous colitis in patients who develop diarrhoea in association with CILAPEN 500 use. While studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibiotic-associated colitis, other causes should also be considered.

Paediatric use Clinical data are insufficient to recommend the use of CILAPEN 500 in children under 3 months of age, or paediatric patients with impaired renal function (serum creatinine greater than 0,1768 mmol/l). (See also Treatment: Paediatric dosage schedule (3 months or older)).

Renal impairment CILAPEN 500 accumulates in patients with reduced kidney function. CNS adverse reactions may occur if the dose is not adjusted to the renal function, see sections 4.2 and 4.4 u201cCentral nervous systemu201d in this section.

Central nervous system Central nervous system side effects such as myoclonic activity, confusional states, or seizures have been reported with CILAPEN 500, especially when recommended dosage based on renal function and body mass were exceeded. These symptoms have been reported most commonly in patients with CNS disorders (e.g. brain lesions or history of seizures) and/or compromised renal function in whom accumulation of the administered entities could occur. Hence, close adherence to recommended dosage schedule is urged, especially in these patients (see section 4.2). Anticonvulsant therapy should be continued in patients with a known seizure disorder.

If focal tremor, myoclonus or seizures occur, patients should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If CNS symptoms continue, the dosage of CILAPEN 500 should be decreased or discontinued. Patients with creatinine clearances of less than or equal to 5 ml/min/1,73 m2 should not receive CILAPEN 500 unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, CILAPEN 500 is recommended only when the benefit outweighs the potential risk of seizures.

Interaction with valproic acid The concomitant use of CILAPEN 500 and valproic acid/sodium valproate is not recommended (see section 4.5).

Sodium CILAPEN 500 contains 36,14 mg sodium per bottle, equivalent to 1,807 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

In in-vitro experiments, imipenem/cilastatin sodium has been reported to induce beta-lactamases capable of hydrolyzing other beta-lactam antibiotics. Although the clinical significance of this is unknown, caution should be exercised in combining CILAPEN 500 with other beta-lactam antibiotics. Generalized seizures have been reported in patients who received ganciclovir and CILAPEN 500. Decreases in valproic acid levels that may fall below the therapeutic range have been reported when valproic acid was co-administered with carbapenem agents. The lowered valproic acid levels can lead to inadequate seizure control; therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended and alternative antibacterial or anti-convulsant therapies should be considered (see section 4.4). Simultaneous administration of antibiotics with warfarin may augment its anti-coagulant effects. There have been many reports of increases in the anti-coagulant effects of orally administered anti-coagulant agents, including warfarin in patients who are concomitantly receiving antibacterial agents. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the antibiotic to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of antibiotics with an oral anti-coagulant agent. Concomitant administration of imipenem/cilastatin and probenecid results in minimal increases in the plasma levels and plasma half-life of imipenem. The urinary recovery of active (non-metabolised) imipenem decreases to approximately 60 % of the dose when imipenem/cilastatin is administered with probenecid. Concomitant administration of imipenem/cilastatin and probenecid doubles the plasma level and half-life of cilastatin, but has no effect on urine recovery of cilastatin.

Pregnancy There are no adequate and reported well-controlled studies in pregnant women. CILAPEN 500 should therefore not be used during pregnancy.

Breastfeeding Imipenem has been detected in human milk. If the use of CILAPEN 500 is deemed essential, the patient should stop breast feeding.

Fertility There are no data available regarding potential effects of imipenem/cilastatin treatment on male or female fertility.

Side effects such as hallucination, dizziness, somnolence, and vertigo are associated with CILAPEN 500 that may affect a patients' ability to drive or operate machinery (see section 4.8).

System Organ Class Frequency Event

• Infections and infestations Less frequent pseudomembranous colitis, candidiasis, gastro-enteritis
• Blood and the lymphatic system disorders Frequent eosinophilia Less frequent pancytopenia, neutropenia, leucopoenia, thrombocytopenia, thrombocytosis, agranulocytosis, haemolytic anaemia, bone marrow depression
• Immune system disorders Less frequent anaphylactic reactions
• Psychiatric disorders Less frequent psychic disturbances including hallucinations and confusional states
• Nervous system disorders Less frequent seizures, myoclonic activity, dizziness, somnolence, encephalopathy, paraesthesia, focal tremor, taste perversion, aggravation of myasthenia gravis, headache Frequency unknown agitation, dyskinesia
• Ear and labyrinth disorders Less frequent hearing loss, vertigo, tinnitus
• Cardiac disorders Less frequent cyanosis, tachycardia, palpitations, Kounis syndrome
• Vascular disorders Frequent thrombophlebitis Less frequent hypotension, flushing
• Respiratory, thoracic and mediastinal disorders Less frequent dyspnoea, hyperventilation, pharyngeal pain
• Gastrointestinal disorders Frequent diarrhoea, vomiting, nausea Less frequent staining of teeth and/or tongue, haemorrhagic colitis, abdominal pain, heartburn, glossitis, tongue papilla hypertrophy, increased salivation
• Hepatobiliary disorders Less frequent hepatic failure, hepatitis, fulminant hepatitis
• Skin and subcutaneous tissue disorders Frequent rash (e.g. exanthematous) Less frequent urticaria, pruritus, toxic epidermal necrolysis, angioedema, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, hyperhidrosis, skin texture changes Frequency unknown Linear IgA disease
• Musculoskeletal and connective tissue disorders Less frequent polyarthralgia, thoracic spine pain disorders
• Renal and urinary disorders Less frequent acute renal failure, oligurial/anuria, polyuria, urine discoloration (harmless and should not be confused with haematuria) The role of CILAPEN 500 in changes in renal function is difficult to assess, since factors predisposing to pre-renal uraemia or to impaired renal function usually have been present.
• Reproductive system and breast disorders Less frequent pruritus vulvae
• General disorders and administration site conditions Less frequent fever, local pain and induration at the injection site, erythema at the injection site, chest discomfort, asthenia/weakness
• Investigations Frequent increases in serum transaminases, increases in serum alkaline phosphatase Less frequent A positive direct Coombs' test, prolonged prothrombin time, decreased haemoglobin, increases in serum bilirubin, elevations in serum creatinine, elevations in blood urea nitrogen

Reporting of suspected adverse reactions 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 u20186.04 Adverse Drug Reaction Reporting formu2019, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/index/8

There are no data available on overdosage. Treatment is symptomatic and supportive. Imipenem/cilastatin sodium is haemodialysable. However, usefulness of this procedure in the overdosage setting is unknown.