Imipenem And Cilastatin Adco 500 mg/20 ml Solution

IMIPENEM AND CILASTATIN ADCO 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
• Lower respiratory tract infections
• Gynaecological infections
• Septicaemia
• Genito-urinary tract infections (complicated and uncomplicated)
• Bone and joint infections
• Skin and soft tissue infections
• Endocarditis

IMIPENEM AND CILASTATIN ADCO 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 IMIPENEM AND CILASTATIN ADCO.

IMIPENEM AND CILASTATIN ADCO has demonstrated efficacy against many infections caused by aerobic and anaerobic gram-positive and gram-negative bacteria resistant to other antibiotics. IMIPENEM AND CILASTATIN ADCO 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.

Posology

The dosage recommendations for IMIPENEM AND CILASTATIN ADCO represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is present in the solution. The total daily dosage and route of administration of IMIPENEM AND CILASTATIN ADCO 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 1 are based on a patient with normal renal function (creatinine clearance of > 70 ml/min/1,73 m2) and a body weight of u2265 70 kg. A reduction in dose must be made for a patient with a creatinine clearance u2264 70 ml/min/1,73 m2 (see Tables 2 and 3) and/or body weight < 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 to 2 g administered in 3 to 4 divided doses. For the treatment of moderate infection, a 1 g twice a day dosage regimen may also be used. In infections due to less susceptible organisms, the daily dosage of IMIPENEM AND CILASTATIN ADCO may be increased to a maximum of 4 g/day or 50 mg/kg/day, whichever is lower.

Table 1: Dosage schedule for adults with normal renal function and body weight u2265 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)

Moderate 500 mg 8 hourly (TOTAL DAILY DOSE = 1,5 g) or 500 mg 6 hourly (TOTAL DAILY DOSE = 2,0 g)

Severe, life threatening only 500 mg 6 hourly (TOTAL DAILY DOSE = 2,0 g) or 1 g 8 hourly (TOTAL DAILY DOSE = 3,0 g)

Uncomplicated urinary tract infection 250 mg 6 hourly (TOTAL DAILY DOSE = 1,0 g)

Complicated urinary tract infection 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 the lower. However, cystic fibrosis patients with normal renal function have been treated with IMIPENEM AND CILASTATIN ADCO at doses up to 90 mg/kg/day in divided doses, not exceeding 4 g/day.

IMIPENEM AND CILASTATIN ADCO has been 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 Tables 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 u201cTreatment: Adult dosage schedule for patients with normal renal functionu201d).

Table 2: Reduced dosage of IMIPENEM AND CILASTATIN ADCO in adults with impaired renal function and/or body weight u02c2 70 kg.

If TOTAL DAILY DOSE from Table 1 is: 1,0 g/day and creatinine clearance (ml/min/1,73 m2) is: And body weight (kg) is:

u2265 71 41 - 70 21 - 40 6 - 20

Then the reduced dosage regimen (mg) is: u2265 70 250 250 250 250

6 hourly 8 hourly 12 hourly 12 hourly

60 250 8 hourly 125 6 hourly 250 12 hourly 125 12 hourly

50 125 6 hourly 125 6 hourly 125 8 hourly 125 12 hourly

40 125 6 hourly 125 8 hourly 125 12 hourly

30 125 8 hourly 125 8 hourly 125 12 hourly

If TOTAL DAILY DOSE from Table 1 is: 1,5 g/day and creatinine clearance (ml/min/1,73 m2) is: And body weight (kg) is:

u2265 71 41 - 70 21 - 40 6 - 20

Then the reduced dosage regimen (mg) is: u2265 70 500 250 250 250

8 hourly 6 hourly 8 hourly 12 hourly

60 250 6 hourly 250 8 hourly 250 8 hourly 250 12 hourly

50 250 6 hourly 250 6 hourly 250 8 hourly 250 12 hourly

40 250 6 hourly 250 8 hourly 250 12 hourly 250 12 hourly

30 250 6 hourly 250 8 hourly 250 8 hourly 250 12 hourly

If TOTAL DAILY DOSE from Table 1 is: 2,0 g/day and creatinine clearance (ml/min/1,73 m2) is: And body weight (kg) is:

u2265 71 41 - 70 21 - 40 6 - 20

Then the reduced dosage regimen (mg) is: u2265 70 500 500 250 250

6 hourly 8 hourly 6 hourly 12 hourly

60 500 8 hourly 250 6 hourly 250 8 hourly 250 12 hourly

50 250 6 hourly 250 6 hourly 250 8 hourly 250 12 hourly

40 250 6 hourly 250 8 hourly 250 12 hourly 250 12 hourly

30 250 6 hourly 250 8 hourly 250 8 hourly 250 12 hourly

When the 500 mg dose is used in patients with creatinine clearances of 6 to 20 ml/min/1,73 m2 there may be an increased risk of seizures. Patients with creatinine clearances of u2264 5 ml/min/1,73 m2 should not receive IMIPENEM AND CILASTATIN ADCO unless haemodialysis is instituted within 48 hours.

When treating patients with creatinine clearances of u02c2 5 ml/min/1,73 m2 who are undergoing haemodialysis, use the dosage recommendation for patients with creatinine clearances of 6 to 20 ml/min/1,73 m2 (see u201cTreatment: Adult dosage schedule for patients with impaired renal functionu201d). Both imipenem and cilastatin are cleared from the circulation during haemodialysis. The patient should receive IMIPENEM AND CILASTATIN ADCO after haemodialysis and at 12 hour intervals timed from the end of that haemodialysis session. Dialysis patients, especially those with background central nervous system disease, should be carefully monitored; for patients on haemodialysis, IMIPENEM AND CILASTATIN ADCO is recommended only when the benefit outweighs the potential risk of seizures (see section 4.8).

Currently there are inadequate data to recommend use of IMIPENEM AND CILASTATIN ADCO for patients on peritoneal dialysis. Renal status of elderly patients may not be accurately portrayed by measurement of blood urea nitrogen or creatinine alone. Determination of creatinine clearance is suggested to provide guidance for dosing in such patients.

Prophylaxis: Adult dosage schedule

To reduce the risk of wound sepsis in adults after colorectal surgery: 1 000 mg IMIPENEM AND CILASTATIN ADCO intravenously on induction of anaesthesia and 1 000 mg three hours later; with two additional 500 mg doses at 8 and 16 hours after induction.

There are insufficient data on which to base a dosage recommendation for prophylaxis in patients with a creatinine clearance of u2264 70 ml/min/1,73 m2.

Treatment: Paediatric population (3 months and older)

Experience with IMIPENEM AND CILASTATIN ADCO in children is limited. For children and infants, the following dosage schedule is recommended:

• Children with body weight u2265 40 kg should receive adult doses.
• Children and infants with a body weight u02c2 40 kg should receive 15 mg/kg every 6 hours. The total daily dose should not exceed 2 g.

Clinical data are insufficient to recommend dosing for children u02c2 3 months of age, or paediatric patients with impaired renal function (serum creatinine > 0,02 g/l).

Method of administration

Each dose of u2264 500 mg of IMIPENEM AND CILASTATIN ADCO should be given by intravenous infusion over 20 to 30 minutes. Each dose > 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. For instructions on reconstitution of the medicine before administration, see section 6.6.

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1
• Hypersensitivity to any other carbapenem antibacterial medicine
• Meningitis
• Pregnancy and lactation.

Prescribers must adhere to the principles of antibiotic stewardship. IMIPENEM AND CILASTATIN ADCO is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used (see section 4.3). IMIPENEM AND CILASTATIN ADCO may be used in children with sepsis as long as they are not suspected of having meningitis.

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in patients taking beta-lactam antibiotics. When SCAR is suspected beta-lactam antibiotics should be discontinued.

General

The selection of IMIPENEM AND CILASTATIN ADCO to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial medicine based on factors such as severity of the infection, the prevalence of resistance to other suitable antibacterial medicine and the risk of selecting for carbapenem-resistant bacteria.

Hypersensitivity

There is some clinical and laboratory evidence of partial cross-allergenicity between IMIPENEM AND CILASTATIN ADCO and the other beta-lactam antibiotics, penicillins and cephalosporins. Severe reactions (including anaphylaxis) have been reported with most beta-lactam antibiotics. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before therapy with IMIPENEM AND CILASTATIN ADCO, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. If an allergic reaction to IMIPENEM AND CILASTATIN ADCO occurs, the medicine should be discontinued and appropriate measures undertaken. Serious anaphylactic reactions require immediate emergency treatment. 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 IMIPENEM AND CILASTATIN ADCO 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 IMIPENEM AND CILASTATIN ADCO. There is no dose adjustment necessary (see section 4.2).

Haematology

A positive direct or indirect Coombs test may develop during treatment with IMIPENEM AND CILASTATIN ADCO.

Antibacterial spectrum

The antibacterial spectrum of IMIPENEM AND CILASTATIN ADCO should be taken into account especially in life-threatening conditions before embarking on any empiric treatment. Furthermore, due to the limited susceptibility of specific pathogens associated with e.g. bacterial skin and soft-tissue infections, to IMIPENEM AND CILASTATIN ADCO, caution should be exercised. The use of IMIPENEM AND CILASTATIN ADCO is not suitable for treatment of these types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment. Concomitant use of an appropriate anti-MRSA medicine may be indicated when MRSA infections are suspected or proven to be involved in the approved indications. Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infections are suspected or proven to be involved in the approved indications (See section 4.1).

In vitro experiments, IMIPENEM AND CILASTATIN ADCO has been reported to induce beta-lactamases capable of hydrolysing other beta-lactam antibiotics. Although the clinical significance of this is unknown, caution should be exercised in combining IMIPENEM AND CILASTATIN ADCO with other beta-lactam antibiotics.

Generalised seizures have been reported in patients who received ganciclovir and IMIPENEM AND CILASTATIN ADCO. These medicines should not be used concomitantly.

Co-administration of carbapenems, including imipenem, to patients receiving valproic acid or divalproex sodium results in a reduction of valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. Concomitant use of imipenem and valproic acid/sodium valproate is not recommended and alternative antibacterial or anticonvulsant therapies should be considered (see section 4.4).

Oral anticoagulants

Simultaneous administration of antibiotics with warfarin may augment its anticoagulant effects. There have been many reports of increases in the anticoagulant effects of orally administered anticoagulant medicines, including warfarin in patients who are concomitantly receiving antibacterial medicines. 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 anticoagulant agent.

Concomitant administration of IMIPENEM AND CILASTATIN ADCO and probenecid resulted in minimal increases in the plasma levels and plasma half-life of imipenem. The urinary recovery of active (non-metabolised) imipenem decreased to approximately 60 % of the dose when IMIPENEM AND CILASTATIN ADCO was administered with probenecid. Concomitant administration of IMIPENEM AND CILASTATIN ADCO and probenecid doubled the plasma level and half-life of cilastatin but had no effect on urine recovery of cilastatin.

Paediatric population

It is not known if the extent of interactions is similar in the paediatric age group to that in adults.

Pregnancy

Safety in pregnancy and lactation has not been established. There are no adequate and well-controlled studies in pregnant women. IMIPENEM AND CILASTATIN ADCO should therefore not be used during pregnancy.

Breastfeeding

Safety in pregnancy and lactation has not been established. Imipenem and cilastatin are excreted into the mother's milk in small quantities. Little absorption of either compound occurs following oral administration. Therefore, it is unlikely that the suckling infant will be exposed to significant quantities. If the use of IMIPENEM AND CILASTATIN ADCO is deemed necessary, the patient should stop breast-feeding.

Fertility

There are no data available regarding potential effects of IMIPENEM AND CILASTATIN ADCO treatment on male or female fertility.

No studies on the effects on the ability to drive and use machines have been performed. However, there are some side effects (such as hallucination, dizziness, somnolence and vertigo) associated with IMIPENEM AND CILASTATIN ADCO that may affect some patients' ability to drive or operate machinery (see section 4.8). IMIPENEM AND CILASTATIN ADCO may affect mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision.

a. Summary of the safety profile

The most frequently reported systemic adverse reactions were nausea, diarrhoea, vomiting, rash, fever, hypotension, seizures (see section 4.4), dizziness, pruritus, urticaria, and somnolence. Similarly, the most frequently reported local adverse reactions were phlebitis/thrombophlebitis, pain at the injection site, erythema at the injection site and vein induration. Increases in serum transaminases and in alkaline phosphatase are also commonly reported.

b. Tabulated summary of adverse reactions

The following adverse reactions have been reported in clinical studies or during post-marketing experience.

System organ classification

Frequency

Side effects

Infections and infestations

Less frequent

Candidiasis, pseudomembranous colitis, gastro-enteritis

Blood and lymphatic system disorders

Frequent

Eosinophilia

Less frequent

Leukopenia, thrombocytopenia, thrombocytosis, pancytopenia, neutropenia, agranulocytosis, haemolytic anaemia, bone marrow depression

Immune system disorders

Less frequent

Anaphylactic reactions

Psychiatric disorders

Less frequent

Psychic disturbances including hallucinations and confusional states

Frequency unknown

Agitation

Nervous system disorders

Less frequent

Myoclonic activity, seizures, dizziness, somnolence, encephalopathy, taste perversion, paraesthesia, focal tremor, aggravation of myasthenia gravis, headache

Frequency unknown

Dyskinesia

Ear and labyrinth disorders

Less frequent

Hearing loss, vertigo, tinnitus

Cardiac disorders

Less frequent

Cyanosis, tachycardia, palpitations

Frequency not known

Kounis syndrome

Vascular disorders

Frequent

Thrombophlebitis

Less frequent

Hypotension, flushing

Respiratory, thoracic and mediastinal disorders

Less frequent

Dyspnoea, hyperventilation, pharyngeal pain

Gastrointestinal disorders

Frequent

Nausea, vomiting, diarrhoea

Medicinal product-related nausea and/or vomiting appear to occur more frequently in granulocytopenic patients than in non-granulocytopenic patients treated with IMIPENEM AND CILASTATIN ADCO

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

Erythema, pruritus, urticarial, angioedema, erythema multiforme, hyperhidrosis, skin texture changes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, petechiae, purpura, diaphoresis, flushing, acute generalised exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic syndrome (DRESS)

Frequency not known

Linear IgA disease

Musculoskeletal and connective tissue disorders

Less frequent

Polyarthralgia, thoracic spine pain

Renal and urinary disorders

Less frequent

Reddish urine discolouration (harmless and should not be confused with haematuria), oliguria/anuria, polyuria, acute renal failure. The role of IMIPENEM AND CILASTATIN ADCO in changes in renal function is difficult to assess, since factors predisposing to pre-renal azotaemia 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

Local pain and induration at the injection site, erythema at the injection site, fever, 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

Paediatric population (u2265 3 months of age)

In studies of 178 paediatric patients u2265 3 months of age, the reported adverse reactions were consistent with those reported for adults.

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 requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

For reporting of side effects directly to the Holder of Certificate of Registration, contact +27 11 635 0134 or email [email protected].

There are no data available on overdosage. Symptoms of overdose that can occur are consistent with the adverse reaction profile; these may include seizures, confusion, tremors, nausea, vomiting, hypotension and bradycardia. Treatment is symptomatic and supportive. Imipenem/cilastatin sodium is haemodialysable. However, usefulness of this procedure in the overdosage setting is unknown.