GENERIC NAME OF THE MEDICINAL PRODUCT:

Imipenem and Cilastatin for Injection IP 250mg/250mg Taj Pharma
Imipenem and Cilastatin for Injection IP 500mg/500mg Taj Pharma
Imipenem and Cilastatin for Injection IP 1g/1g Taj Pharma

QUALITATIVE AND QUANTITATIVE COMPOSITION:

a) Each vial contains:
Imipenem IP (Sterile) equivalent to Anhydrous Imipenem 250mg
Cilastatin Sodium IP (Sterile) equivalent to Cilastatin 250mg
Sodium Bicarbonate IP (Sterile) added as Buffer
b) Each vial contains:
Imipenem IP (Sterile) equivalent to Anhydrous Imipenem 500mg
Cilastatin Sodium IP (Sterile) equivalent to Cilastatin 500mg
Sodium Bicarbonate IP (Sterile) added as Buffer
c) Each vial contains:
Imipenem IP (Sterile) equivalent to Anhydrous Imipenem 1g
Cilastatin Sodium IP (Sterile) equivalent to Cilastatin 1g
Sodium Bicarbonate IP (Sterile) added as Buffer

THERAPEUTIC INDICATIONS:

Imipenem and Cilastatin is indicated for the treatment of serious infections as listed below: Lower respiratory tract infections (including severe pneumonia); Urinary tract infections (complicated and uncomplicated); Intra-abdominal infections (including complicated infections); Gynaecological infections (including intra- and post-partum infections); Bacterial septicaemia; Bone and joint infections; Skin and skin structure infections (including complicated infections); Endocarditis; Polymicrobic infections, including those in which  pneumoniae(pneumonia, septicaemia), S. pyogenes (skin and skin structure), or non-penicillinase-producing S. aureus is one of the causative organisms. However, monobacterial infections due to these organisms are usually treated with narrower spectrum antibiotics, such as penicillin G.

DIRECTION OF USE:

Reconstitute using 10ml of sterile water for injection IP.
Reconstituted solution shlould be use immediately after preparation.

CAUTION & SCHEDULE:

WARNING: To be sold by the retail on the prescription of a registered medical practitioner only. SCHEDULE 'H1 DRUG -Warning: It is dangerous to take this preparation except in accordance with the medical advice- Not to be sold by retail without the prescription of a Registered Medical Practitioner.

STORAGE & DOSAGE:

Store Below 25°C protect from light. Do not freeze.

Imipenem and Cilastatin for Injection IP 1g/1g (Zicerot) Taj Pharma

Overview

INTRODUCTION

Zicerot 1gm/1gm Injection is a combination of two antibiotics. It is prescribed to treat various types of severe bacterial infections. It fights against the infection by killing the microorganisms to prevent further infections.

Zicerot 1gm/1gm Injection should only be administered under the supervision of a healthcare professional. Do not miss any scheduled appointment for taking this medicine. The course of the medicine should be completed even if you feel better. It is advised to consult your doctor if you have any kidney or liver disease.

The common side effects of this medicine are nausea, vomiting, diarrhea, rashes, etc. You may also experience injection site redness, swelling, and pain that goes away with time. If any of the side effects get aggravated, you must consult your doctor immediately. It is advised not to drive or operate any heavy machine without consulting your doctor. Caution should be taken if the patient is pregnant or breastfeeding.

USES OF ZICEROT POWDER FOR INJECTION

  • Severe bacterial infections

ZICEROT POWDER FOR INJECTION SIDE EFFECTS

Common
  • Nausea
  • Vomiting
  • Diarrhea
  • Rash

HOW TO USE ZICEROT POWDER FOR INJECTION

Your doctor or nurse will give you this medicine. Kindly do not self administer.

HOW ZICEROT POWDER FOR INJECTION WORKS

Zicerot 1gm/1gm Injection is a combination of two medicines: Imipenem and Cilastatin. Imipenem is an antibiotic. It works by preventing the formation of the bacterial protective covering which is essential for the survival of bacteria in the human body. Cilastatin is dehydropeptidase I inhibitor which blocks the activity of an enzyme (dehydropeptidase I) that causes breakdown of Imipenem. Hence, it helps Imipenem stay active in your body for a longer period of time.

ZICEROT POWDER FOR INJECTION RELATED WARNINGS

warnings

Alcohol

CONSULT YOUR DOCTOR
It is not known whether it is safe to consume alcohol with Zicerot 1gm/1gm Injection. Please consult your doctor.
warnings

Pregnancy

CONSULT YOUR DOCTOR
Zicerot 1gm/1gm Injection may be unsafe to use during pregnancy. Although there are limited studies in humans, animal studies have shown harmful effects on the developing baby. Your doctor will weigh the benefits and any potential risks before prescribing it to you. Please consult your doctor.
warnings

Lactation

SAFE IF PRESCRIBED
Zicerot 1gm/1gm Injection is probably safe to use during breastfeeding. Limited human data suggests that the drug does not represent any significant risk to the baby.
warnings

Driving

UNSAFE
Zicerot 1gm/1gm Injection may cause side effects which could affect your ability to drive.
There are some side effects associated with this medicine (such as seeing, hearing, or feeling something that is not there) that may affect some patients’ ability to drive.
warnings

Kidney

CAUTION
Zicerot 1gm/1gm Injection should be used with caution in patients with kidney disease. Dose adjustment of Zicerot 1gm/1gm Injection may be needed. Please consult your doctor.
warnings

Liver

CONSULT YOUR DOCTOR
There is limited information available on the use of Zicerot 1gm/1gm Injection in patients with liver disease. Please consult your doctor.

Imipenem and Cilastatin for Injection IP 1g/1g (Zicerot) Taj Pharma

  1. NAME OF THE MEDICINAL PRODUCT:

Imipenem and Cilastatin for Injection IP 250mg/250mg (Zicerot) Taj Pharma

Imipenem and Cilastatin for Injection IP 500mg/500mg (Zicerot) Taj Pharma

Imipenem and Cilastatin for Injection IP 1g/1g (Zicerot) Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION:

a) Each vial contains:
Imipenem IP (Sterile) equivalent to
Anhydrous Imipenem                                 250mg
Cilastatin Sodium IP (Sterile)
equivalent to Cilastatin                              250mg
Sodium Bicarbonate IP (Sterile) added
as Buffer

b) Each vial contains:
Imipenem IP (Sterile) equivalent to
Anhydrous Imipenem                                500mg
Cilastatin Sodium IP (Sterile)
equivalent to Cilastatin                              500mg
Sodium Bicarbonate IP (Sterile) added
as Buffer

c) Each vial contains:
Imipenem IP (Sterile) equivalent to
Anhydrous Imipenem                                 1g
Cilastatin Sodium IP (Sterile)
equivalent to Cilastatin                              1g
Sodium Bicarbonate IP (Sterile) added
as Buffer

3. PHARMACEUTICAL FORM:

Dry Powder for Injection

Description:

ZICEROT is a potent broad-spectrum beta-lactam antibiotic. ZICEROT consists of two components: (1) imipenem, the first new class of beta-lactam antibiotics, the thienamycins; and, (2) cilastatin sodium, a competitive, reversible and specific inhibitor of renal dipeptidase, dehydropeptidase-I (which blocks the metabolism of imipenem in the kidneys and substantially increases the concentration of intact imipenem in the urinary tract). Imipenem and cilastatin sodium are present in ZICEROT in a 1:1 ratio by weight.

4. CLINICAL PARTICULARS:

4.1. Therapeutic indications:

ZICEROT is indicated for the treatment of serious infections as listed below:

  • Lower respiratory tract infections (including severe pneumonia )
  • Urinary tract infections (complicated and uncomplicated)
  • Intra-abdominal infections (including complicated infections)
  • Gynaecological infections (including intra- and post-partum infections)
  • Bacterial septicaemia
  • Bone and joint infections
  • Skin and skin structure infections (including complicated infections)
  • Endocarditis
  • Polymicrobic infections, including those in which  pneumoniae(pneumonia, septicaemia), S. pyogenes (skin and skin structure), or non-penicillinase-producing S. aureus is one of the causative organisms. However, monobacterial infections due to these organisms are usually treated with narrower spectrum antibiotics, such as penicillin G.

ZICEROT may be used in the management of neutropenic patients with fever that is suspected to be due to bacterial infection.

It may also be used in the treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Because of its broad spectrum of bactericidal activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, ZICEROT is useful for the treatment of mixed infections and as presumptive therapy prior to the identification of the causative organisms.

ZICEROT is not indicated in patients with meningitis because safety and efficacy have not been established.

Imipenem-cilastatin I.V. for injection has demonstrated efficacy against many infections resistant to cephalosporins, aminoglycosides and/or penicillins.

4.2. Dosage and administration:

Dosage

Adults and Adolescents          
The total daily dosage for ZICEROT should be based on the type or severity of infection and given in equally divided doses, based on consideration of the degree of susceptibility of the pathogen(s), renal function and body weight. Adult patients with impaired renal function, as judged by creatinine clearance ≤70 mL/min/1.73 m2, require adjustment of dosage as described in the succeeding section of these guidelines.

I.V. Dosage Schedule for Adults with Normal Renal Function and Body Weight ≥70 kg
Doses are based on a patient with normal renal function and a body weight of 70 kg. These doses should be used for a patient with a creatinine clearance of ≥71 mL/min/1.73 m2 and a body weight of ≥70 kg. A reduction in dose must be made for a patient with a creatinine clearance of ≤70 mL/min/1.73 m2 and/or a body weight less than 70 kg.

Dosage regimens in column A of Table 1 are recommended for infections caused by fully susceptible organisms, which represent the majority of pathogenic species. Dosage regimens in column B of Table 1 are recommended for infections caused by organisms with moderate susceptibility to imipenem, primarily some strains of Pseudomonas aeruginosa.

Table 1: I.V. Dosage Schedule of ZICEROT for Adults with Normal Renal Function and Body Weight ≥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
Pseudomonas aeruginosa
Mild250 mg q6h
(total daily dose = 1.0 g)
500 mg q6h
(total daily dose =2.0 g)
Moderate500 mg q8h
(total daily dose = 1.5 g)
or
500 mg q6h
(total daily dose = 2.0 g)
500 mg q6h
(total daily dose = 2.0 g)
or
1 g q8h
(total daily dose = 3.0 g)
Severe, life-
threatening
only
500 mg q6h
(total daily dose = 2.0 g)
1 g q8h
(total daily dose = 3.0 g)
or
1 g q6h
(total daily dose = 4.0 g)
Uncomplicated
urinary tract
infection
250 mg q6h
(total daily dose = 1.0 g)
250 mg q6h
(total daily dose = 1.0 g)
Complicated
urinary tract
infection
500 mg q6h
(total daily dose = 2.0 g)
500 mg q6h
(total daily dose =
2.0 g)

Due to the High Antimicrobial Activity of ZICEROT, it is recommended that the maximum total daily dosage not exceed 50 mg/kg/day or 4.0 g/day, whichever is lower.

There is no evidence that higher doses provide greater efficacy. However, patients over 12 years of age with cystic fibrosis and normal renal function have been treated with ZICEROT at doses up to 90 mg/kg/day in divided doses, not exceeding 4.0 g/day.

Infections suspected or proven to be due to less susceptible bacteria species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 1000 mg/1000 mg administered every 6 hours.

Reduced I.V. Schedule for Adults with Impaired Renal Function and/or Body Weight  <70 kg
Patients with a creatinine clearance of ≤70 mL/min/1.73 m2 and/or body weight ZICEROT as indicated in tables 2 and 3 below. Creatinine clearance may be calculated from serum creatinine concentration by the following equation:

To determine the dose for adults with impaired renal function and/or reduced body weight:

  1. Choose a total daily dose from Table 1, based on infection characteristics.
    1. If the total daily dose is 1.0g, 1.5g or 2.0g, use the appropriate subsection of Table 2 and continue with step 3.
    2. If the total daily dose is 3.0g or 4.0g, use the appropriate subsection of Table 3 and continue with step 3.
  2. From Tables 2 or 3, do the following:
    1. From the column titled, and body weight (kg) is, select the body weight that is closest to the patient’s body weight (kg).
    2. Select the patient’s creatinine clearance category.
    3. Where the row and column intersect, the value given is the reduced dosage regimen.

Table 2: Reduced Dosage of ZICEROT in Adult Patients with Impaired Renal Function and/or Body Weight <70 kg

If TOTAL DAILY DOSE from Table 1 is
and
body
weight
(kg) is
1.0 g/day1.5 g/day2.0 g/day
and creatinine
clearance
(ml/min/1.73 m2) is
and creatinine
clearance
(ml/min/1.73 m2) is
and creatinine
clearance
(ml/min/1.73 m2) is
≥7141-7021-406-20≥7141-7021-406-20≥7141-7021-406-20
Reduced dosage (mg) isReduced dosage (mg) isReduced dosage(mg) is
≥70250 q6h250 q8h250 q12h250 q12h500 q8h250 q6h250 q8h250 q12h500 q6h500 q8h250 q6h250 q12h
60250 q8h125 q6h250 q12h125 q12h250 q6h250 q8h250 q8h250 q12h500 q8h250 q6h250 q8h250 q12h
50125 q6h125 q6h125 q8h125 q12h250 q6h250 q8h250 q12h250 q12h250 q6h250 q6h250 q8h250 q12h
40125 q6h125 q8h125 q12h125 q12h250 q8h125 q6h125 q8h125 q12h250 q6h250 q8h250 q12h250 q12h
30125 q8h125 q8h125 q12h125 q12h125 q6h125 q8h125 q8h125 q12h250 q8h125 q6h125 q8h125 q12h

Table 3: Reduced Dosage of ZICEROT in Adult Patients with Impaired Renal Function and/or Body Weight <70 kg

If TOTAL DAILY DOSE from Table 1 is
and
body
weight
(kg) is
3.0 g/day4.0 g/day
and creatinine
clearance
(ml/min/1.73 m2) is
and creatinine
clearance
(ml/min/1.73 m2) is
≥7141-7021-406-20≥7141-7021-406-20
Reduced dosage (mg) isReduced dosage (mg) is
≥701,000 q8h500 q6h500 q8h500 q12h1,000 q6h750 q8h500 q6h500 q12h
60750 q8h500 q8h500 q8h500 q12h1000 q8h750 q8h500 q8h500 q12h
50500 q6h500 q8h250 q6h250 q12h750 q8h500 q6h500 q8h500 q12h
40500 q8h250 q6h250 q8h250 q12h500 q6h500 q8h250 q6h250 q12h
30250 q6h250 q8h250 q8h250 q12h500 q8h250 q6h250 q8h250 q12h

Patients with creatinine clearances of 6-20 mL/min/1.73 m2 should be treated with ZICEROT 125 mg or 250 mg every 12 hours for most pathogens. There may be an increased risk of seizures when doses of 500 mg every 12 hours are administered to these patients.

Patients with creatinine clearance ≤5 mL/min/1.73 m2 should not receive ZICEROT unless haemodialysis is instituted within 48 hours. There is inadequate information to recommend the usage of ZICEROT for patients undergoing peritoneal dialysis.

Haemodialysis
When treating patients with creatinine clearances of ≤5 mL/min/1.73 m2 who are undergoing haemodialysis, use the dosage recommendations for patients with creatinine clearances of 6-20 mL/min/1.73 m2. Both imipenem and cilastatin are cleared from the circulation during haemodialysis. The patient should receive ZICEROT after haemodialysis and at 12-hour intervals timed from the end of that haemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on haemodialysis, ZICEROT is recommended only when the benefit outweighs the potential risk of seizures.

Hepatic Impairment
No dose adjustment is recommended in patients with impaired hepatic function.

Paediatric
For paediatric patients ≥3 months of age, the recommended dose for non-CNS infections is 15-25 mg/kg/dose administered every 6 hours. Based on studies in adults, the maximum daily dose for treatment of infections with fully susceptible organisms is 2.0g per day; for infections with moderately susceptible organisms (primarily some strains of Pseudomonas aeruginosa), it is 4.0 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis.

Paediatric patients ≥1 year of age with very severe infections (e.g., in neutropenic patients with a fever) should be treated with 25 mg/kg administered every 6 hours.

For paediatric patients who are ≤3 months of age (weighing ≥1,500g), the following dosage schedule is recommended for non-CNS infections:

<1 week of age: 25 mg/kg every 12 hours
1 to 4 weeks of age: 25 mg/kg every 8 hours
4 weeks to 3 months of age: 25 mg/kg every 6 hours

Renal Impairment
Clinical data are insufficient to recommend dosing for paediatric patients with renal impairment (serum creatinine >2 mg/dl).

ZICEROT is not recommended in

  1. paediatric patients with CNS infections because of the risk of seizures; and,
  2. paediatric patients

Method of Preparation

The following table is provided for convenience in reconstituting ZICEROT for infusion.

Table 4: Reconstituting ZICEROT for Infusion

Dose of ZICEROT
(mg of Imipenem)
Volume of Diluent Added
(ml)
Approximate
Concentration of
Imipenem (mg/ml)
250505
5001005
10002504

Reconstitution of Vial
Procedure for ZICEROT250mg
The contents of the vials must be suspended and transferred to 50mL of an appropriate infusion solution. A suggested procedure is to add approximately 10 mL from the appropriate infusion solution (see Compatibility and Stability) to the vial. Shake well and transfer the resulting suspension to the infusion solution container. Repeat with an additional 10 mL of infusion solution to ensure the complete transfer of the vial contents to the infusion solution. The resulting mixture should be agitated until clear.

Procedure for ZICEROT 500mg
The contents of the vials must be suspended and transferred to 100 mL of an appropriate infusion solution. A suggested procedure is to add approximately 10 mL from the appropriate infusion solution (see Compatibility and Stability) to the vial. Shake well and transfer the resulting suspension to the infusion solution container. Repeat with an additional 10 mL of infusion solution to ensure the complete transfer of the vial contents to the infusion solution. The resulting mixture should be agitated until clear.

Procedure for ZICEROT 1g
The contents of the vial must be suspended and transferred to 250 mL of an appropriate compatible infusion solution. A suggested procedure is to add approximately 20 mL from the appropriate compatible infusion solution (see Compatibility and Stability) to the vial. Shake well and transfer the resulting suspension to the compatible infusion solution container. Repeat with an additional 20 mL of compatible infusion solution to ensure complete the transfer of the vial contents to the compatible infusion solution. The resulting mixture should be agitated until clear.

Benzyl alcohol as a preservative has been associated with toxicity in neonates. While toxicity has not been demonstrated in paediatric patients >3 months of age, small paediatric patients in this age range may also be at risk for benzyl alcohol toxicity. Therefore, diluents containing benzyl alcohol should not be used when ZICEROT is constituted for administration to paediatric patients in this age range.

CAUTION: THE SUSPENSION IS NOT FOR DIRECT INFUSION.

Method of Administration

Adults and Adolescents
The dosage recommendations for ZICEROT represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. Each 250mg or 500mg dose should be given by I.V. administration over 20-30 minutes. 1,000 mg dose should be infused over 40-60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Paediatric
Doses less than or equal to 500mg should be given by I.V. infusion over 15-30 minutes.
Doses greater than 500mg should be given by I.V. infusion over 40-60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Compatibility and Stability

Before Reconstitution
The dry powder should be stored at a temperature below 25ºC (77ºF).

Reconstituted Solutions
Solutions of ZICEROT range from colourless to yellow. Variations of colour within this range do not affect the potency of the product. However, ZICEROT may be administered concomitantly with other antibiotics, such as aminoglycosides.

ZICEROT 250mg and ZICEROT 500mg, reconstituted with 0.9% Sodium Chloride Injection, maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (2º to 8ºC).

ZICEROT 1g , reconstituted with 0.9% Sodium Chloride Injection or 5% dextrose solution, maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (2º to 8ºC).

Solutions of ZICEROT should not be frozen.

Imipenem-cilastatin I.V. for injection may also be reconstituted with the diluents mentioned below:
5% or 10% Dextrose Injection
5% Dextrose Injection with 0.225% or 0.45% saline solution
In exceptional circumstances, 5% glucose may also be used.

Imipenem-cilastatin I.V. for injection should not be mixed with, or physically added to, other antibiotics.

4.3. Contraindications:

Imipenem/Cilastatin is contraindicated in patients who have shown a hypersensitivity to any component of this product or to any other carbapenem antibacterial agent and other beta-lactam agents. It is contraindicated in case of severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins or cephalosporins).

4.4. Warnings and Precautions:
General

Serious and, occasionally, fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more apt to occur in persons with a history of sensitivity to multiple allergens. There have been reports of patients with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta-lactam. Before initiating therapy with imipenem/cilastatin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction occurs, imipenem/cilastatin should be discontinued.

Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, I.V. steroids, and airway management, including intubation, may also be administered as indicated.

Antibiotic-associated colitis, Clostridium difficile-associated diarrhoea (CDAD) and pseudomembranous colitis have been reported with imipenem/cilastatin and with nearly all other anti-bacterial agents and may range from mild to life-threatening in severity.

Discontinuation of therapy with imipenem/cilastatin and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
In case of CDAD, appropriate fluid and electrolyte management, protein supplementation, and surgical evaluation should be instituted as clinically indicated.

It is not recommended for the therapy of meningitis.

CNS-adverse experiences such as confusional states, myoclonic activity and seizures have been reported during treatment with imipenem-cilastatin I.V. for injection, especially when the recommended dosages were exceeded. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function. However, there have been reports of CNS-adverse experiences in patients who had no recognized or documented underlying CNS disorder or compromised renal function.

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.

When the recommended doses were exceeded, adult patients with creatinine clearances of ≤20 mL/min/1.73 m2, whether or not undergoing haemodialysis, had a higher risk of seizure activity than those without impairment of renal function. Therefore, close adherence to the dosing guidelines for these patients is recommended.

Patients with creatinine clearances of ≤5 mL/min/1.73 m2 should not receive imipenem/cilastatin unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, imipenem/cilastatin is recommended only when the benefit outweighs the potential risk of seizures. Close adherence to the recommended dosage and dosage schedules is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of imipenem/cilastatin re-examined to determine whether it should be decreased or the antibiotic discontinued.

Hepatic function should be closely monitored during treatment with imipenem/cilastatin 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/cilastatin. There is no dose adjustment necessary.

A positive direct or indirect Coombs test may develop during treatment with imipenem/cilastatin.

As with other antibiotics, prolonged use of imipenem/cilastatin may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Prescribing imipenem/cilastatin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

While imipenem/cilastatin possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

4.5. Drug Interactions:

Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin I.V. for injection. These drugs should not be used concomitantly unless the potential benefits outweigh the risks. Since concomitant administration of imipenem-cilastatin I.V. for injection and probenecid results in only minimal increases in plasma levels of imipenem and plasma half-life, it is not recommended that probenecid be given with imipenem/cilastatin.

Case reports in the literature have shown that co-administration of carbapenems, including imipenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. In some cases, breakthrough seizures have occurred. The concomitant use of imipenem and valproic acid/divalproex sodium is generally not recommended.

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 underlying infection, age and general status of the patient so that the contribution of the antibiotic to the increase in the international normalized ratio (INR) 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 resulted in minimal increase in the plasma levels and plasma half-life of imipenem. The urinary recovery of active (non-metabolized) 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.

4.6. Pregnancy, lactation and others:

Renal Impairment
Please refer DOSAGE AND ADMINISTRATION.

Hepatic Impairment
Please refer DOSAGE AND ADMINISTRATION.

Pregnancy
Pregnancy Category C
Imipenem/cilastatin should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and the foetus.

Lactation
Imipenem and cilastatin are excreted into the mother’s milk in small quantities. If the use of this drug is deemed necessary, the benefit of breast feeding for the child should be weighed against the possible risk for the child.

Paediatric Use
Please refer DOSAGE AND ADMINISTRATION.

Geriatric Use
No dosage adjustment is required based on age. Dosage adjustment in the case of renal impairment is necessary.

4.7. Undesirable effects:
Adults

Imipenem/cilastatin is generally well tolerated.

Local Adverse Reactions
Adverse local clinical reactions that were reported as possibly, probably or definitely related to therapy with imipenem-cilastatin I.V. for injection were as follows:
Phlebitis/thrombophlebitis – 3.1%
Pain at the injection site – 0.7%
Erythema at the injection site – 0.4%
Vein induration – 0.2%
Infused vein infection – 0.1%

Systemic Adverse Reactions
The most frequently reported systemic adverse clinical reactions that were reported as possibly, probably or definitely related to imipenem-cilastatin I.V. for injection 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%), and somnolence (0.2%). Rarely, incidences of anaphylactic reactions have also been reported.

Other Adverse Reactions
The other adverse events reported as possibly, probably or definitely drug-related occurring in less than 0.2% patients included the following:

Gastrointestinal
Pseudomembranous colitis, haemorrhagic colitis, hepatitis (including fulminant hepatitis), hepatic failure, jaundice, gastroenteritis, abdominal pain, glossitis, tongue papillar hypertrophy, staining of teeth and/or tongue, heartburn, pharyngeal pain and increased salivation.

Blood and Lymphatic System
Pancytopenia, eosinophilia, bone marrow depression, thrombocytopenia, neutropenia, leucopenia, thrombocytosis and haemolytic anaemia.

Central Nervous System
Encephalopathy, tremor, confusion, myoclonus, paresthesia, vertigo, headache and psychic disturbances, including hallucinations. Very rarely, aggravation of myasthenia gravis has also been reported.

Special Senses
Hearing loss, tinnitus and taste perversion.

Respiratory Tract
Chest discomfort, dyspnoea, hyperventilation and thoracic spine pain.

Cardiovascular
Palpitations and tachycardia.

Skin-related
Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, anginoneurotic oedema, flushing, cyanosis, hyperacidosis, skin texture changes, candidiasis and pruritus vulvae.

Renal
Acute renal failure, oliguria/anuria, polyuria and urine discolouration.

The role of imipenem-cilastatin I.V. for injection 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.

Others
Polyarthralgia, flushing, asthenia/weakness and drug fever.

Adverse Laboratory Changes
The adverse laboratory changes without regard to drug relationship that were reported during clinical trials or postmarketing surveillance included the following:

Hepatic
Increased serum transaminases, alkaline phosphatase, bilirubin and LDH.

Haematological
Increased eosinophils, lymphocytes, positive Coombs test, WBC, platelets, monocytes and basophils, decreased haemoglobin and haematocrit, and agranulocytosis. There are also reports of abnormal prothrombin time.

Electrolytes
Decreased serum sodium, increased potassium and increased chloride.

Renal
Increased BUN and creatinine.

Urinalysis
Presence of urine protein, urine red blood cells, urine WBCs, urine casts, urine bilirubin and urine urobilinogen.

Paediatrics
In studies of 178 paediatric patients, ≥3 months of age, the following adverse events were noted:

Table 5: Most common clinical adverse experiences without regard to drug relationship (Patient Incidence >1%)

Adverse ExperienceNo. of Patients
(%)
Digestive System
Diarrhoea7*(3.9)
Gastroenteritis2(1.1)
Vomiting2*(1.1)
Skin
Rash4(2.2)
Irritation, I.V. site2(1.1)
Urogenital System
Urine discolouration2(1.1)
Cardiovascular System
Phlebitis4(2.2)
*One patient had both vomiting and
diarrhoea and is counted in each category.

In studies of 135 patients (newborn to 3 months of age), the following adverse events were noted:

Table 6: The most common clinical adverse experiences without regard to drug relationship (Patient Incidence >1%)

Adverse
Experience
No. of
Patients (%)
Digestive System
Diarrhoea
Oral candidiasis
4 (3.0%)

2 (1.5%)

Skin
Rash2 (1.5%)
Urogenital System
Oliguria/anuria3 (2.2%)
Cardiovascular System
Tachycardia2 (1.5%)
Nervous System
Convulsions8 (5.9%)

Table 7: Patients (≥3 months of age) with normal pre-therapy but abnormal during therapy laboratory values

Laboratory
Parameter
AbnormalityNo. of Patients with
Abnormalities/No. of
Patients with Lab Done
(%)
Haemoglobin19/129 (14.7)
6 months-12 years
Haematocrit23/129 (17.8)
6 months-12 years
Neutrophils≤1,000/mm3 (absolute)4/123 (3.3)
Eosinophils≥7%15/117 (12.8)
Platelet count≥500 ths/mm316/119 (13.4)
Urine protein≥18/97 (8.2)
Serum creatinine>1.2 mg/dL0/105 (0)
BUN>22 mg/dL0/108 (0)
AST (SGOT)>36 IU/L14/78 (17.9)
ALT (SGPT)>30 IU/L10/93 (10.8)

Table 8: Patients (<3 months of age) with normal pre-therapy but abnormal during therapy laboratory values

Laboratory ParameterNo. of Patients with Abnormalities* (%)
Eosinophil count↑11 (9.0%)
Haematocrit↓3 (2.0%)
Haematocrit↑1 (1.0%)
Platelet count↑5 (4.0%)
Platelet count↓2 (2.0%)
Serum creatinine↑5 (5.0%)
Bilirubin↑3 (3.0%)
Bilirubin↓1 (1.0%)
1 (1.0%)5 (6.0%)
ALT (SGPT)↑3 (3.0%)
Serum alkaline phosphate↑2 (3.0%)

* The denominator used for percentages was the number of patients for whom the test was performed during treatment or post-treatment and, therefore, varies by test.

Examination of published literature and spontaneous adverse event reports suggested a similar spectrum of adverse events in adult and paediatric patients.

4.8. Overdosage:

Symptoms of overdose that can occur are consistent with the adverse reaction profile; these may include seizures, confusion, tremors, nausea, vomiting, hypotension, bradycardia. In case of overdosage, discontinue imipenem/cilastatin, treat symptomatically and institute supportive measures as required. Imipenem-cilastatin I.V. for injection is haemodialysable. However, the usefulness of this procedure in the overdosage setting is questionable.

5. PHARMACOLOGICAL PROPERTIES:

5.1. Pharmacodynamic properties:

The bactericidal activity of imipenem results from the inhibition of cell wall synthesis. Its greatest affinity is for penicillin-binding proteins (PBPs) 1A, 1B, 2, 4, 5 and 6 of Escherichia coli, and 1A, 1B, 2, 4 and 5 of Pseudomonas aeruginosa. The lethal effect is related to the binding to PBP 2 and PBP 1B. Imipenem has a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria. It is a potent inhibitor of beta-lactamases from certain gram-negative bacteria that are inherently resistant to most beta-lactam antibiotics, e.g., Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp.

Cilastatin sodium is devoid of intrinsic antibacterial activity itself and does not affect the antibacterial activity of imipenem.

Imipenem has In vitro activity against a wide range of gram-positive and gram-negative organisms. Imipenem has been shown to be active against most strains of the following microorganisms, both In vitro and in clinical infections treated with the I.V. formulation of imipenem-cilastatin sodium:

Gram-positive aerobes
Enterococcus faecalis (formerly S. faecalis)
Staphylococcus aureus, including penicillinase-producing strains
Staphylococcus epidermidis, including penicillinase-producing strains
Streptococcus agalactiae (Group B streptococci)
Streptococcus pneumoniae
Streptococcus pyogenes

(NOTE: Imipenem is inactive In vitro against Enterococcus faecium . Methicillin-resistant staphylococci should be reported as resistant to imipenem.)

Gram-negative aerobes
Acinetobacter spp.
Citrobacter spp.
Enterobacter spp.
Escherichia coli
Gardnerella vaginalis
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella spp.
Morganella morganii
Proteus vulgaris
Providencia rettgeri
Pseudomonas aeruginosa

Serratia spp., including S. marcescens
(NOTE: Imipenem is inactive In vitro against Stenotrophomonas maltophilia and some strains of Burkholderia cepacia.)

Gram-positive anaerobes
Bifidobacterium spp.
Clostridium spp.
Eubacterium spp.
Peptococcus spp.
Peptostreptococcus spp.
Propionibacterium spp.

Gram-negative anaerobes
Bacteroides spp., including B. fragilis
Fusobacterium spp.

The following In vitro data are available, but their clinical significance is unknown.

Imipenem exhibits In vitro minimum inhibitory concentrations (MICs) of 4 μg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of imipenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:

Gram-positive aerobes
Bacillus spp.
Listeria monocytogenes
Nocardia spp.
Staphylococcus saprophyticus
Group C streptococci
Group G streptococci
Viridans group streptococci

Gram-negative aerobes
Aeromonas hydrophila
Alcaligenes spp.
Capnocytophaga spp.
Haemophilus ducreyi
Neisseria gonorrhoeae, including penicillinase-producing strains
Pasteurella spp.
Providencia stuartii

Gram-negative anaerobes
Prevotella bivia
Prevotella disiens
Prevotella melaninogenica
Veillonella
 spp.

In vitro tests show that imipenem acts synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.

5.2. Pharmacokinetic properties:

Adults
An infusion of imipenem-cilastatin I.V. for injection over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 14 to 24 μg/mL for the 250mg dose, from 21 to 58 μg/mL for the 500 mg dose, and from 41 to 83μg/mL for the 1000 mg dose. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 μg/mL or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute infusion of imipenem-cilastatin I.V. for injection range from 15 to 25 μg/mL for the 250mg dose, from 31 to 49μg/mL for the 500mg dose, and from 56 to 88μg/mL for the 1000mg dose.

When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Individual urinary recoveries ranged from 5% to 40%, with an average recovery of 15-20% in several studies.

The plasma half-life of each component is approximately 1 hour. The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%. Approximately 70% of the administered imipenem is recovered in the urine within 10 hours, after which no further urinary excretion is detectable. Urine concentrations of imipenem in excess of 10 μg/mL can be maintained for up to 8 hours with imipenem-cilastatin I.V. for injection at the 500 mg dose. Approximately 70% of the cilastatin sodium dose is recovered in the urine within 10 hours of administration of imipenem-cilastatin I.V. for injection.

No accumulation of imipenem or cilastatin in plasma or urine has been observed with regimens administered as frequently as every 6 hours in patients with normal renal function.

In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single I.V. dose of imipenem 500mg and cilastatin 500mg administered over 20 minutes are consistent with those expected in subjects with slight renal impairment for which no dosage alteration is considered necessary. The mean plasma half-lives of imipenem and cilastatin are 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem or cilastatin is observed.

Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase-I, resulting in relatively low levels in the urine. Cilastatin sodium, an inhibitor of this enzyme, effectively prevents the renal metabolism of imipenem so that when imipenem and cilastatin sodium are given concomitantly, fully adequate antibacterial levels of imipenem are achieved in the urine.

Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable.

Paediatrics
Based on published studies of 178 paediatric patients ≥3 months of age (with non-central nervous system infections), the recommended dose of imipenem and cilastatin sodium I.V. for injection is 15-25 mg/kg/dose administered every 6 hours. Doses of 25 mg/kg/dose in patients, 3 months to <3 years of age, and 15mg/kg/dose in patients, 3–12 years of age, were associated with mean trough plasma concentrations of imipenem of 1.1 ± 0.4 mcg/mL and 0.6 ± 0.2 mcg/mL following multiple 60-minute infusions, respectively; trough urinary concentrations of imipenem were in excess of 10 mcg/mL for both doses.

These doses have provided adequate plasma and urine concentrations for the treatment of non-CNS infections.

In a published dose-ranging study of smaller premature infants (670-1,890g) in the first week of life, a dose of 20mg/kg q12h by infusion over 15-30 minutes was associated with mean peak and trough plasma imipenem concentrations of 43mcg/mL and 1.7 mcg/mL after multiple doses, respectively. However, moderate accumulation of cilastatin sodium in neonates may occur following multiple doses of imipenem-cilastatin sodium I.V. for injection. The safety of this accumulation is unknown.

The average clearance (CL) and volume of distribution (Vdss) for imipenem were approximately 45% higher in paediatric patients (3 months to 14 years) as compared to adults. The AUC for imipenem following administration of 15mg/15mg/kg per body weight of imipenem-cilastatin sodium I.V. for injection to paediatric patients was approximately 30% higher than the exposure in adults receiving a 500mg/500mg dose. At the higher dose, the exposure following administration of 25mg/25mg/kg imipenem-cilastatin sodium I.V. for injection to children was 9% higher as compared to the exposure in adults receiving a 1,000mg/1,000mg dose.

6. PHARMACEUTICAL PARTICULARS:

6.1. Incomaptibilities:

ZICEROT should not be mixed with or physically added to other antibiotics. However,
ZICEROT may be administered concomitantly with other antibiotics, such as aminoglycosides.

This medicinal product is chemically incompatible with lactate and should not be reconstituted in diluents containing lactate. However, it can be administered into an I.V. system through which a lactate solution is being infused.

6.2. Shelf life:
2 years

6.3. Storage and handling instructions:
The dry powder should be stored below 25ºC (77ºF). Do not expose to temperatures above 50ºC.

6.4. Packaging information:
ZICEROT 250mg: Vial of 20mL
ZICEROT 500mg: Vial of 30mL
ZICEROT 1g: Vial of 30mL

6.5. Special precautions for disposal and other handling:
N/A

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
Survey No. 622/2/1/4, Dedhrota, Himatnagar – Vijapur Highway,
Dist. – Sabarkantha – 383220, Gujarat, INDIA.