Chemical formula: C₂₈H₄₅N₅O₁₀S₂
Imipenem and Cilastatin interacts in the following cases:
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.
Patients with pre-existing liver disorders should have liver function monitored during treatment with imipenem/cilastatin. There is no dose adjustment necessary.
To determine the reduced dose for adults with impaired renal function:
1. The total daily dose (i.e. 2000/2000, 3000/3000 or 4000/4000 mg) that would usually be applicable to patients with normal renal function should be selected.
2. From table 1 the appropriate reduced dose regimen is selected according to the patient’s creatinine clearance. Each dose of ≤500 mg/500 mg should be given by intravenous infusion over 20 to 30 minutes. Each dose >500 mg/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:
| Creatinine clearance (mL/min) is: | If TOTAL DAILY DOSE is: 2000 mg/day | If TOTAL DAILY DOSE is: 3000 mg/day | If TOTAL DAILY DOSE is: 4000 mg/day |
|---|---|---|---|
| ≥90 (normal) | 500 q6h | 1000 q8h | 1000 q6h |
| reduced dosage (mg) for patients with renal impairment: | |||
| <90 - ≥60 | 400 q6h | 500 q6h | 750 q8h |
| <60 - ≥30 | 300 q6h | 500 q8h | 500 q6h |
| <30 - ≥15 | 200 q6h | 500 q12h | 500 q12h |
These patients should not receive imipenem/cilastatin unless haemodialysis is instituted within 48 hours.
When treating patients with creatinine clearances of <15 ml/min who are undergoing dialysis use the dose recommendation for patients with creatinine clearances of 15 to 29 ml/min (see table 1).
Both imipenem and cilastatin are cleared from the circulation during haemodialysis. The patient should receive imipenem/cilastatin after haemodialysis and at 12 hour intervals timed from the end of that haemodialysis session. Dialysis patients, especially those with background central nervous system (CNS) disease, should be carefully monitored; for patients on haemodialysis, imipenem/cilastatin is recommended only when the benefit outweighs the potential risk of seizures.
Currently there are inadequate data to recommend use of imipenem/cilastatin for patients on peritoneal dialysis.
Clinical data are insufficient to recommend dosing for paediatric patients with renal impairment (serum creatinine >2 mg/dl).
Generalized seizures have been reported in patients who received ganciclovir and imipenem/cilastatin. These medicinal products should not be used concomitantly unless the potential benefit outweighs the risks.
Concomitant administration of imipenem/cilastatin 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/cilastatin was administered with probenecid. Concomitant administration of imipenem/cilastatin and probenecid doubled the plasma level and half-life of cilastatin, but had no effect on urine recovery of cilastatin.
The concomitant use of imipenem/cilastatin and valproic acid/sodium valproate is not recommended.
CNS adverse reactions 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 dose schedules is urged especially in these patients. Anticonvulsant therapy should be continued in patients with a known seizure disorder.
Special 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.
Imipenem/cilastatin combination is not recommended for the therapy of meningitis.
There are no adequate and well-controlled studies for the use of imipenem/cilastatin in pregnant women.
Studies in pregnant monkeys have shown reproductive toxicity. The potential risk for humans is unknown.
Imipenem/cilastatin should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
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/cilastatin is deemed necessary, the benefit of breast feeding for the child should be weighed against the possible risk for the child.
There are no data available regarding potential effects of imipenem/cilastatin 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 this product that may affect some patients' ability to drive or operate machinery.
In clinical trials including 1,723 patients treated with imipenem/cilastatin intravenous the most frequently reported systemic adverse reactions that were reported at least possibly related to therapy were nausea (2.0%), diarrhoea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%). Similarly, the most frequently reported local adverse reactions were phlebitis/thrombophlebitis (3.1%), pain at the injection site (0.7%), erythema at the injection site (0.4%) and vein induration (0.2%). Increases in serum transaminases and in alkaline phosphatase are also commonly reported.
The following adverse reactions have been reported in clinical studies or during post-marketing experience.
All adverse reactions are listed under system organ class and frequency: 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 not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| System Organ Class | Frequency | Event |
|---|---|---|
| Infections and infestations | Rare | pseudomembranous colitis, candidiasis |
| Very rare | gastro-enteritis | |
| Blood and lymphatic system disorders | Common | eosinophilia |
| Uncommon | pancytopenia, neutropenia, leucopenia, thrombocytopenia, thrombocytosis | |
| Rare | agranulocytosis | |
| Very rare | haemolytic anaemia, bone marrow depression | |
| Immune system disorders | Rare | anaphylactic reactions |
| Psychiatric disorders | Uncommon | psychic disturbances including hallucinations and confusional states |
| Nervous system disorders | Uncommon | seizures, myoclonic activity, dizziness, somnolence |
| Rare | encephalopathy, paraesthesia, focal tremor, taste perversion | |
| Very rare | aggravation of myasthenia gravis, headache | |
| Not known | agitation, dyskinesia | |
| Ear and labyrinth disorders | Rare | hearing loss |
| Very rare | vertigo, tinnitus | |
| Cardiac disorders | Very rare | cyanosis, tachycardia, palpitations |
| Vascular disorders | Common | thrombophlebitis |
| Uncommon | hypotension | |
| Very rare | flushing | |
| Respiratory, thoracic and mediastinal disorders | Very rare | dyspnoea, hyperventilation, pharyngeal pain |
| Gastrointestinal disorders | Common | diarrhoea, vomiting, nausea Medicinal product-related nausea and/or vomiting appear to occur more frequently in granulocytopenic patients than in non-granulocytopenic patients treated with imipenem/cilastatin |
| Rare | staining of teeth and/or tongue | |
| Very rare | haemorrhagic colitis, abdominal pain, heartburn, glossitis, tongue papilla hypertrophy, increased salivation | |
| Hepatobiliary disorders | Rare | hepatic failure, hepatitis |
| Very rare | fulminant hepatitis | |
| Skin and subcutaneous tissue disorders | Common | rash (e.g. exanthematous) |
| Uncommon | urticaria, pruritus | |
| Rare | toxic epidermal necrolysis, angioedema, Stevens- Johnson syndrome, erythema multiforme, exfoliative dermatitis | |
| Very rare | hyperhidrosis, skin texture changes | |
| Musculoskeletal and connective tissue disorders | Very rare | polyarthralgia, thoracic spine pain |
| Renal and urinary disorders | Rare | acute renal failure, oligurial/anuria, polyuria, urine discoloration (harmless and should not be confused with haematuria) The role of imipenem/cilastatin in changes in renal function is difficult to assess, since factors pre- disposing to prerenal azotemia or to impaired renal function usually have been present. |
| Reproductive system and breast disorders | Very rare | pruritus vulvae |
| General disorders and administration site conditions | Uncommon | fever, local pain and induration at the injection site, erythema at the injection site |
| Very rare | chest discomfort, asthenia/weakness | |
| Investigations | Common | increases in serum transaminases, increases in serum alkaline phosphatase |
| Uncommon | A positive direct Coombs' test, prolonged prothrombin time, decreased haemoglobin, increases in serum bilirubin, elevations in serum creatinine, elevations in blood urea nitrogen |
In studies of 178 paediatric patients ≥3 months of age, the reported adverse reactions were consistent with those reported for adults.
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