Imipenem with cilastatin parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Powder for concentrate for solution for infusion containing imipenem (as monohydrate) with cilastatin (as the sodium salt)
Drugs List
Therapeutic Indications
Uses
Genitourinary tract infection
Gynaecological infections
Infections in neutropenic patients
Infections intra-abdominal
Pneumonia
Septicaemia
Skin and soft tissue infections
Treatment of the following infections due to susceptible organisms:
Complicated intra-abdominal infections
Severe pneumonia (including hospital and ventilator-associated pneumonia)
Intra and post-partum infections
Complicated urinary tract infections
Complicated skin and soft tissue infections
Management of neutropenic patients with fever that is suspected to be due to a bacterial infection.
Patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections previously listed.
Dosage
Dosage recommendations are expressed in terms of amounts of imipenem to be given. An equivalent amount of cilastatin is provided with this.
Adults
500mg every 6 hours OR 1000mg every 8 hours OR 1000mg every 6 hours.
It is recommended that infections suspected or proven to be due to less susceptible bacterial species (primarily some strains of P. aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 1000mg every 6 hours. The maximum total daily dose should not exceed 4000mg.
Some manufacturers suggest the following dose if bodyweight is less than 70kg:
A reduction in dose is necessary when bodyweight is less than 70kg. Doses for these patients should be calculated using the following formula: (actual body weight (kg) X standard dose) / 70 (kg). The maximum total daily dose should not exceed 4000mg.
Children
Children 1 year and older
15mg/kg or 25mg/kg administered every 6 hours.
It is recommended that infections suspected or proven to be due to less susceptible bacterial species (primarily some strains of P. aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 25mg/kg every 6 hours.
Children less than 1 year old
The manufacturers suggests there are insufficient data to recommend dosing in children under 1 years of age.
The following unlicensed doses may be suitable:
Gram-positive and Gram-negative infections and hospital-acquired septicaemia
Children 3 months to 18 years:
15mg/kg (maximum 500mg) every 6 hours.
Children 1 to 3 months:
20mg/kg every 6 hours.
Infections caused by pseudomonas or other less sensitive organisms, life-threatening infection, or empirical treatment of infection in febrile patients with neutropenia:
Children 3 months to 18 years:
25mg/kg (maximum 1g) every 6 hours.
Cystic fibrosis
Children 1 month to 18 years:
25mg/kg (maximum 1g) every 6 hours.
Neonates
The manufacturers suggests there are insufficient data to recommend dosing in children under 1 years of age.
The following unlicensed doses may be suitable:
Gram-positive and Gram-negative infections and hospital-acquired septicaemia
Neonates 21 to 28 days: 20mg/kg every 6 hours
Neonates 7 to 21 days: 20mg/kg every 8 hours
Neonates under 7 days: 20mg/kg every 12 hours
Patients with Renal Impairment
Some manufacturers suggest when bodyweight is less than 70kg, a further proportionate reduction in dose is required. This would be calculated by dividing the patient's actual bodyweight in kg by 70kg multiplied by the respective suggested dose.
The total daily dose that would be applicable to patients with normal renal function should be selected. Then select the appropriate reduced dose according to creatinine clearance.
At the time of writing, the product information for Primaxin IV injection suggests the following doses. Some manufacturers vary from these doses and so product literature should be consulted.
Total daily dose for patients with normal renal function: 2000mg/day
Creatinine clearance 60 to less than 90ml/minute
400mg every 6 hours.
Creatinine clearance 30 to less than 60ml/minute
300mg every 6 hours.
Creatinine clearance 15 to less than 30ml/minute
200mg every 6 hours.
Total daily dose for patients with normal renal function: 3000mg/day
Creatinine clearance 60 to less than 90ml/minute
500mg every 6 hours.
Creatinine clearance 30 to less than 60ml/minute
500mg every 8 hours.
Creatinine clearance 15 to less than 30ml/minute
500mg every 12 hours.
Total daily dose for patients with normal renal function: 4000mg/day
Creatinine clearance 60 to less than 90ml/minute
750mg every 8 hours.
Creatinine clearance 30 to less than 60ml/minute
500mg every 6 hours.
Creatinine clearance 15 to less than 30ml/minute
500mg every 12 hours.
Creatinine clearance less than 15ml/minute
Patients should not receive imipenem with cilastatin unless haemodialysis is started within 48 hours.
Haemodialysis
Imipenem with cilastatin is removed by haemodialysis.
Patients with creatinine clearance of less than 15ml/minute can be treated with the recommended doses for patients with a creatinine clearance of 15 to less than 30ml/minute that are listed above. The dose should be given immediately after haemodialysis and at 12-hourly intervals thereafter. Dialysis patients, especially those with background CNS disease, should be carefully monitored. Patients on haemodialysis should receive imipenem with cilastatin only when the benefit outweighs the potential risk of convulsions.
There are currently inadequate data to recommend the use of imipenem with cilastatin for patients on peritoneal dialysis.
Children with renal impairment
Clinical data are insufficient to recommend an optimal dose for children with impaired renal function.
Administration
For intravenous infusion only.
Each dose of 500mg or less should be given by intravenous infusion over 20 to 30 minutes.
Each dose of more than 500mg should be infused over 40 to 60 minutes. In patients who develop nausea during infusion, the infusion rate may be slowed.
Contraindications
None known
Precautions and Warnings
Children under 1 year
History of serious hypersensitivity reactions
Restricted sodium intake
Weight below 70kg
Breastfeeding
Central nervous system disorder
Epileptic disorder
Haemodialysis
Hepatic disorder
Pregnancy
Renal impairment - creatinine clearance below 90ml/minute
Reduce dose in patients with creatinine clearance below 90ml/min
Sodium content of formulation may be significant
Advise ability to drive/operate machinery may be affected by side effects
Before initiating therapy enquire about previous hypersensitivity reactions
Consult national/regional policy on the use of anti-infectives
Emergency equipment must be available
For intravenous use only
Monitor hepatic function
Consider pseudomembranous colitis if patient presents with diarrhoea
If tremors, myoclonus or convulsion occur, consider anticonvulsant therapy
Test interference: May cause false positive Coombs test
Discontinue at once if pseudomembranous colitis occurs
Discontinue if drug-related rash or other hypersensitivity reactions occur
Reduce dose or discontinue if neurological symptoms develop and persist
Imipenem with cilastatin is bactericidal against a wide spectrum of Gram-positive, Gram-negative, aerobic and anaerobic pathogens. It is useful for treating single and polymicrobic infections and initiating therapy prior to identification of the causative organisms.
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, imipenem with cilastatin is usually effective against Bacteroides fragilis sp., the most commonly encountered anaerobic pathogen, which is usually resistant to the aminoglycosides, cephalosporins and penicillins.
The antibacterial spectrum of imipenem with cilastatin should be taken into account, especially in life-threatening conditions, before embarking on any empiric treatment. Due to the limited susceptibility of specific pathogens associated with e.g. bacterial skin and soft-tissue infections, to imipenem with cilastatin, caution should be exercised. The use of imipenem with cilastatin is not suitable for treatment of these types of infections unless the pathogen is already documented and known to be susceptible to treatment. Concomitant use of an appropriate anti-MRSA agent 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.
Awareness should be made to neurological symptoms or convulsions in children with known risk factors for seizures, or on concomitant treatment with medicinal products lowering the seizures threshold.
Pregnancy and Lactation
Pregnancy
Use imipenem with cilastatin with caution in pregnancy.
Schaefer (2007) suggests beta-lactam antibiotics can be used during pregnancy where strongly indicated. The manufacturers suggest imipenem with cilastatin is not recommended for use during pregnancy unless the potential benefit justifies the possible risk to foetus.
Imipenem and cilastatin cross the placenta to the foetus. There are no adequate and well controlled studies, at the time of writing, for the use of imipenem with cilastatin in human pregnancy.
Animal studies in pregnant cynomolgus monkeys have shown evidence of maternal and foetal toxicity with bolus injections at doses equivalent to twice the human dose. However, reproductive studies in pregnant rabbits and rats with imipenem at doses up to 2 and 30 times, respectively, and with cilastatin sodium at 10 and 33 times, respectively, the maximum recommended human dose showed no evidence of adverse foetal effects.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Use imipenem with cilastatin with caution during breastfeeding.
The manufacturers suggest if treatment with imipenem with cilastatin is required, the benefit should outweigh the possible risk to the breastfeeding child.
Imipenem and cilastatin have been detected in human milk in small quantities. Limited information indicates that single maternal doses of imipenem up to 500 mg produce low levels in milk that are not expected to cause adverse effects in infants. Little absorption of imipenem or cilastatin occurs following oral administration, therefore it is unlikely the breastfeeding child will be exposed to significant quantities.
Imipenem is destroyed by gastric acidity. Disruption of the infant's gastrointestinal flora, resulting in diarrhoea or thrush has occasionally been reported with beta-lactams.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Counselling
Advise the patient that if vomiting occurs, she should follow the guidance for the oral contraceptive in respect of additional doses or contraceptive precautions.
Side Effects
Abdominal pain
Acute renal failure
Agranulocytosis
Anaphylaxis
Angioedema
Antibiotic-associated colitis
Anuria
Arthralgia
Asthenia
Blood urea increased
Bone marrow depression
Candidiasis
Chest discomfort
Confusion
Convulsions
Cyanosis
Decrease in haemoglobin
Diarrhoea
Discolouration of teeth and tongue
Discolouration of urine
Dizziness
Drug fever
Dyspnoea
Encephalopathy
Eosinophilia
Erythema at injection site
Erythema multiforme
Exacerbation of myasthenia gravis
Exfoliative dermatitis
Fever
Flushing
Fulminant hepatitis
Gastro-enteritis
Glossitis
Haemolytic anaemia
Haemorrhagic colitis
Hallucinations
Headache
Hearing loss
Heartburn
Hepatic failure
Hepatitis
Hyperhidrosis
Hypersensitivity reactions
Hyperventilation
Hypotension
Increase in alkaline phosphatase
Increase of liver transaminases
Induration (injection site)
Leucopenia
Local pain (injection site)
Myoclonus
Nausea
Neutropenia
Oliguria
Palpitations
Pancytopenia
Paraesthesia
Pharyngeal pain
Polyuria
Positive Coombs test
Prothrombin time increased
Pruritus
Pruritus vulvae
Pseudomembranous colitis
Psychiatric disorders
Rash
Salivation changes
Serum bilirubin increased
Serum creatinine increased
Skin texture changes
Somnolence
Stevens-Johnson syndrome
Tachycardia
Taste disturbances
Thoracic spine pain
Thrombocytopenia
Thrombocytosis
Thrombophlebitis (injection site)
Tinnitus
Tongue papillae hypertrophy
Toxic epidermal necrolysis
Urticaria
Vertigo
Vomiting
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: February 2015
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.
Summary of Product Characteristics: Imipenem/cilastatin 500 mg/500 mg powder for solution for injection. Actavis UK Ltd. Revised October 2014.
Summary of Product Characteristics: Imipenem/cilastatin 500 mg/500 mg powder for solution for infusion. Hospira UK Ltd. Revised February 2013.
Summary of Product Characteristics: Primaxin IV 500 mg Injection. Merck Sharp & Dohme Ltd. Revised December 2015.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 22 September 2017
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Imipenem and Cilastatin. Last revised: 7 September, 2013
Last accessed: 18 February, 2015
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