For Healthcare Professionals only

(Imipenem and Cilastatin)

Sterile powder for Injection +
+

QUALITATIVE AND QUANTITATIVE COMPOSITION in neutropenic patients with a fever) should be treated with 1000mg/1000mg
Cilapen 250 administered every 6 hours.
Sterile Powder for Injection 250mg + 250mg A reduction in dose is necessary when creatinine clearance is < 90mL/min. The
Each vial contains: maximum total daily dose should not exceed 4000mg/4000mg per day.
Imipenem USP ..... 250mg as Imipenem Monohydrate
Cilastatin .... 250mg as Cilastatin Sodium USP Renal impairment:
(Product Specs.: USP) To determine the reduced dose for adults with impaired renal function: The total daily
dose (i.e., 2000/2000mg, 3000/3000mg or 4000/4000mg) that would usually be
Contains Sodium bicarbonate applicable to patients with normal renal function should be selected.
Creatinine clearance If TOTAL DAILY DOSE If TOTAL DAILY DOSE If TOTAL DAILY DOSE is:
Cilapen 500 (mL/min) is: is: 2000mg/day is: 3000mg/day 4000mg/day
Sterile Powder for Injection 500mg + 500mg ≥90 500 1000 1000
Each vial contains: (normal) q6h q8h q6h
Imipenem USP ..... 500mg as Imipenem Monohydrate reduced dosage (mg) for patients with renal impairment:
Cilastatin .... 500mg as Cilastatin Sodium USP 400 500 750
<90 - ≥60
(Product Specs.: USP) q6h q6h q8h
300 500 500
<60 - ≥30
Contains Sodium bicarbonate q6h q8h q6h
200 500 500
<30 - ≥15
q6h q12h q12h
PHARMACEUTICAL FORM
Sterile powder for Injection Patients with a creatinine clearance of <15mL/min: should not receive unless
hemodialysis is instituted within 48 hours.
CLINICAL PARTICULARS
THERAPEUTIC INDICATIONS Patients on hemodialysis: Both imipenem and cilastatin are cleared from the circulation
CILAPEN is indicated for the treatment of the following infections in adults and children during hemodialysis. The patient should receive after hemodialysis and at 12-hour
1 year of age and above: intervals timed from the end of that hemodialysis session.
• Severe pneumonia including hospital and ventilator-associated pneumonia
• Complicated intra-abdominal infections Hepatic impairment: No dose adjustment in patients with impaired hepatic function.
• Intra and post-partum infections
• Complicated urinary tract infections Elderly population: No dose adjustment is required for the elderly patients with normal
• Complicated skin and skin structure, bone and soft-tissue infections renal function
• Neutropenic patients with fever that is suspected to be due to a bacterial infection.
• Treatment of patients with bacteremia that occurs in association with, or is suspected Pediatric population: For pediatric patient’s ≥1 year of age, the recommended dose is
to be associated with, any of the infections listed above. 15/15 or 25/25mg/kg/dose administered every 6 hours.

POSOLOGY AND METHOD OF ADMINISTRATION Method of administration:

Posology: The dose recommendations for CILAPEN represent the quantity of imipenem • CILAPEN is to be reconstituted and further diluted prior to administration.
and cilastatin to be administered. • Each dose of ≤500mg/500mg should be given by intravenous infusion over 20 to 30
The daily dose should be based on the type of infection and given in equally divided minutes.
doses based on consideration of degree of susceptibility of the pathogen(s) and the • Each dose >500mg/500mg should be infused over 40 to 60 minutes. In patients who
patient's renal function. develop nausea during the infusion, the rate of infusion may be slowed.

Adults and adolescents: Reconstitution:

For patients with normal renal function (creatinine clearance of ≥90mL/min), the • Contents of each vial must be transferred to 100mL of an appropriate infusion solution
recommended dose regimens are 500mg/500mg every 6 hours OR 1000mg/1000mg 0.9% sodium chloride. In exceptional circumstances where 0.9% sodium chloride
every 8 hours OR every 6 hours cannot be used for clinical reasons 5% glucose may be used instead.
It is recommended that infections suspected or proven to be due to less susceptible
bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g., • A suggested procedure is to add approximately 10mL of the appropriate infusion
 solution to the vial. Shake well and transfer the resulting mixture to the infusion recovery of cilastatin.
solution container. Pediatric population: Interaction studies have only been performed in adults.
CAUTION: THE MIXTURE IS NOT FOR DIRECT INFUSION. Fertility, pregnancy and lactation
• Repeat with an additional 10mL of infusion solution to ensure complete transfer of vial Pregnancy: Imipenem and cilastatin should only be used during pregnancy if the
contents to the infusion solution. The resulting mixture should be agitated until clear. potential benefit outweighs the potential risk
Lactation: Imipenem and cilastatin are excreted into the mother's milk in small
• The concentration of the reconstituted solution following the above procedure is quantities. If the use of Imipenem and cilastatin is deemed necessary, the benefit of
approximately 5mg/mL for both imipenem and cilastatin. breast feeding for the child should be weighed against the possible risk for the child.
Fertility: There are no data available regarding potential effects of imipenem and
Contraindications cilastatin treatment on male or female fertility.
• Hypersensitivity to the active substances
• Hypersensitivity to any other carbapenem antibacterial agents (e.g., penicillins or Effects on ability to drive and use machines
cephalosporins). No studies on the effects on the ability to drive and use machines have been performed.
• Severe hypersensitivity (e.g., anaphylactic reaction, severe skin reaction) to any
other type of beta-lactam antibacterial agent (e.g., penicillins or cephalosporins). Undesirable effects
All adverse reactions are listed under system organ class and frequency: Very common
Special warnings and precautions for use (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000
Hypersensitivity to <1/1,000), Very rare (<1/10,000) and not known (cannot be estimated from the
Before initiating therapy with Imipenem and cilastatin, careful inquiry should be made available data).
concerning previous hypersensitivity reactions to carbapenems, penicillins,
cephalosporins, other beta-lactams and other allergens. If an allergic reaction to Within each frequency grouping, undesirable effects are presented in order of
Imipenem and cilastatin occurs, discontinue the therapy immediately. decreasing seriousness.
System Organ Class Frequency Event
Serious anaphylactic reactions require immediate emergency treatment. Infections and infestations Rare Pseudomembranous colitis, candidiasis
Hepatic: Hepatic Function should be closely monitored during treatment with imipenem Very rare Gastro-enteritis
and cilastatin due to the risk of hepatic toxicity (such as increase in transaminases, Blood and lymphatic system disorders Common Eosinophilia, thrombophlebitis
hepatic failure and fulminant hepatitis). Uncommon Pancytopenia, neutropenia, leucopenia, thrombocytopenia,
Hematology: A positive direct or indirect Coombs test may develop during treatment with thrombocytosis, hypotension and flushing.
imipenem and cilastatin. Rare Agranulocytosis
Antibacterial spectrum: Concomitant use of an anti-MRSA agent may be indicated when Very rare Hemolytic anemia, bone marrow depression
Pseudomonas aeruginosa infections are suspected or proven to be involved in the Immune system disorders Rare Anaphylactic reactions
approved indications. Psychiatric disorders Uncommon Psychic disturbances including hallucinations and confusional states
Interaction with valproic acid: The concomitant use of imipenem and cilastatin and Nervous system disorders Uncommon Seizures, myoclonic activity, dizziness, somnolence
valproic acid/sodium valproate is not recommended. Rare Encephalopathy, paresthesia, focal tremor, taste perversion
Clostridioides difficile: Antibiotic-associated colitis and pseudomembranous colitis have Very rare Aggravation of myasthenia gravis, headache
been reported with imipenem and cilastatin. Discontinuation of therapy with imipenem Not known Agitation, dyskinesia
and cilastatin and the administration of specific treatment for Clostridioides difficile Ear and labyrinth disorders Rare Hearing loss
should be considered. Medicinal products that inhibit peristalsis should not be given. Very rare Vertigo, tinnitus
Meningitis: Imipenem and cilastatin is not recommended for the therapy of meningitis. Cardiac disorders Very rare Cyanosis, tachycardia, palpitations
Renal impairment: Imipenem and cilastatin accumulates in patients with reduced kidney Vascular disorders Common Thrombophlebitis
function. CNS adverse reactions may occur if the dose is not adjusted to the renal Uncommon Hypotension
function. Very rare Flushing
Central nervous system: Adverse reactions such as myoclonic activity, confusional Respiratory, thoracic and mediastinal disorders Very rare Dyspnea, hyperventilation, pharyngeal pain
states, or seizures have been reported in patients with CNS disorders (e.g., brain Gastrointestinal disorders Common Diarrhea, vomiting, nausea
lesions or history of seizures) and/or compromised renal function in whom accumulation Rare Staining of teeth and/or tongue
of the administered entities could occur. Hence close adherence to recommended dose Very rare Hemorrhagic colitis, abdominal pain, heartburn, glossitis, tongue
papilla hypertrophy, increased salivation
schedules is urged especially in these patients.
Hepatobiliary disorders Rare Hepatic failure, hepatitis
Patients with creatinine clearances of <15mL/min should not receive Imipenem and
Very rare Fulminant hepatitis
cilastatin unless hemodialysis is instituted within 48 hours. For patients on hemodialysis,
Skin and subcutaneous tissue disorders Common Rash (e.g.,exanthematous)
Imipenem and cilastatin is recommended only when the benefit outweighs the potential
Uncommon Urticaria, pruritus
risk of seizures.
Rare Toxic epidermal necrolysis, angioedema, Stevens-Johnson
Sodium:
syndrome, erythema multiforme, exfoliative dermatitis
Imipenem and Cilastatin 250mg+250mg contains 0.8mmol (18.8mg) sodium per dose.
Very rare Hyperhidrosis, skin texture changes
Imipenem and Cilastatin 500mg+500mg contains 1.6mmol (37.5mg) sodium per dose.
Musculoskeletal and connective tissue disorders Very rare Polyarthralgia, thoracic spine pain
This should be taken into consideration by patients on a controlled sodium diet.
Pediatric population (≥3 months of age); The reported adverse reactions were
Interaction with other medicinal products and other forms of interaction consistent with those reported for adults.
Ganciclovir: Generalized seizures have been reported in patients who received
ganciclovir and Imipenem and cilastatin. It should not be used concomitantly unless the Overdose
potential benefit outweighs the risks. No specific information is available on treatment of overdose with Imipenem and
Valproic acid: Decreases in valproic acid levels have been reported when cilastatin. It is hemodialyzable. However, usefulness of this procedure in the overdose
co-administered with carbapenem agents. Concomitant use of imipenem and valproic setting is unknown.
acid/sodium valproate is not recommended
Oral anti-coagulants: Simultaneous administration of antibiotics with warfarin may PHARMACOLOGICAL PROPERTIES
augment its anti-coagulant effects. PHARMACODYNAMIC PROPERTIES
Concomitant administration of imipenem and cilastatin and probenecid: Resulted in Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems.
minimal increases in the plasma levels and plasma half-life of imipenem and doubled ATC code: J01D H51
the plasma level and half-life of cilastatin, the urinary recovery of active (non-metabo-
lized) imipenem decreased to approximately 60% of the dose but had no effect on urine
Mechanism of action accumulation of imipenem in plasma or urine has been observed with regimens of
CILAPEN consists of two components: Imipenem and cilastatin sodium in a 1:1 ratio by imipenem, administered as frequently as every six hours, in patients with normal renal
weight function.
Imipenem, also referred to as N-formimidoyl-thienamycin, is a semi-synthetic derivative
of thienamycin, the parent compound produced by the filamentous bacterium Cilastatin
Streptomyces cattleya. Absorption: Peak plasma levels of cilastatin, following a 20-minute intravenous infusion
Imipenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in of (Imipenem and Cilastatin), ranged from 21 to 26μg/mL for the 250mg/250mg dose,
Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins from 21 to 55μg/mL for the 500mg/500mg dose and from 56 to 88μg/mL for the
(PBPs). 1000mg/1000mg dose. The mean peak plasma levels of cilastatin following the
Cilastatin sodium is a competitive, reversible and specific inhibitor of dehydropepti- 250mg/250mg, 500mg/500mg, and 1000mg/1000mg doses were 22, 42, and 72µg/mL
dase-I, the renal enzyme which metabolizes and inactivates imipenem. respectively.
Distribution: The binding of cilastatin to human serum proteins is approximately 40%.
Microbiology: Biotransformation and elimination: The plasma half-life of cilastatin is approximately one
Commonly susceptible species: hour. Approximately 70-80% of the dose of cilastatin was recovered unchanged in the
Gram-positive aerobes: Enterococcus faecalis, Staphylococcus aureus urine as cilastatin within 10 hours of administration of imipenem.
(Methicillin-susceptible) Staphylococcus coagulase negative (Methicillin-susceptible),
Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes and Pharmacokinetics in special populations
Streptococcus viridans group. Renal insufficiency: Dose adjustment is necessary for patients with impaired renal
Gram-negative aerobes: Citrobacter freundii, Enterobacter cloacae, Escherichia coli, function.
Haemophilus influenza, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella Hepatic insufficiency: No dose adjustment is recommended in patients with hepatic
aerogenes (formerly Enterobacter aerogens), Moraxella catarrhalis and Serratia impairment.
marcescens Pediatric population: The average clearance (CL) and volume of distribution (Vdss) for
Gram-positive anaerobes: Clostridium perfringens and Peptostreptococcus spp. imipenem were approximately 45% higher in pediatric patients (3 months to 14 years)
Gram-negative anaerobes: Bacteroides fragilis group, Fusobacterium spp, as compared to adults. The AUC for imipenem following administration of 15/15mg/kg
Porphyromonas asaccharolytica, Prevotella spp. and Veillonella spp. per body weight of imipenem and cilastatin to pediatric patients was approximately 30%
higher than the exposure in adults receiving a 500mg/500mg dose. At the higher dose,
Breakpoints the exposure following administration of 25/25mg/kg imipenem and cilastatin to children
Minimum Inhibitory Concentrations (mg/L) was 9% higher as compared to the exposure in adults receiving a 1000mg/1000mg
Organism Group
Susceptible ≤ Resistant > dose.
Enterobacterales, Acinetobacter spp. 2 4 Elderly: In healthy elderly volunteers (65 to 75 years of age with normal renal function
Enterobacterales (Morganella morganii, Proteus spp. and Providencia spp.)
0.001 4 for their age), the pharmacokinetics of a single dose of imipenem and cilastatin
Pseudomonas spp. and Enterococcus spp.
500mg/500mg administered intravenously over 20 minutes were consistent with those
Staphylococcus spp. Inferred from cefoxitin susceptibility
expected in subjects with slight renal impairment for which no dose alteration is
Streptococcus A, B, C, G Inferred from the benzylpenicillin susceptibility
Streptococcus pneumoniae, Viridans group streptococci Haemophilus
considered necessary. The mean plasma half-lives of imipenem and cilastatin were 91
2 2 ± 7.0 minutes and 69 ± 15 minutes, respectively.
influenza and Moraxalla catarrhalis
Gram-positive anaerobes except Clostridioides difficile, Burkholderia
pseudomallei, Gram-negative anaerobes and non-species related 2 4
breakpoints
PHARMACEUTICAL PARTICULARS
Incompatibilities
PHARMACOKINETIC PROPERTIES This medicinal product is chemically incompatible with lactate and should not be
Imipenem reconstituted in diluents containing lactate. However, it can be administered into an I.V.
Absorption system through which a lactate solution is being infused.
Intravenous infusion of imipenem and cilastatin over 20 minutes resulted in peak plasma
levels of imipenem ranging from 12 to 20μg/mL for the 250mg/250mg dose, from 21 to Special precautions for disposal and other handling:
58μg/mL for the 500mg/500mg dose, and from 41 to 83μg/mL for the 1000mg/1000mg After reconstitution: Diluted solutions should be used immediately. The time interval
dose. The mean peak plasma levels of imipenem following the 250mg/250mg, between the beginning of reconstitution and the end of intravenous infusion should not
500mg/500mg, and 1000mg /1000mg doses were 17, 39, and 66μg/mL, respectively. At exceed two hours.
these doses, plasma levels of imipenem decline to below 1μg/mL or less in four to six
hours. Each vial is for single use only.
Variations of colour, from colourless to yellow, do not affect the potency of the product.
Distribution Any unused medicinal product or waste material should be disposed off in accordance
The binding of imipenem to human serum proteins is approximately 20%. with local requirements.

Biotransformation Shelf life:

When administered alone, imipenem is metabolized in the kidneys by dehydropepti- 2 years.
dase-I. Individual urinary recoveries ranged from 5 to 40%, with an average recovery of
15-20% in several studies. Storage
Cilastatin is a specific inhibitor of dehydropeptidase-I enzyme and effectively inhibits Protect from heat, sunlight & moisture, store below 25°C.
metabolism of imipenem so that concomitant administration of imipenem and cilastatin Do not freeze the reconstituted solution.
allows therapeutic antibacterial levels of imipenem to be attained in both urine and Keep out of the reach of children
plasma. The expiration date refers to the product correctly stored at the required conditions
To be sold on the prescription of a registered medical practitioner only.
Elimination
The plasma half-life of imipenem was one hour. Approximately 70% of the administered
antibiotic was recovered intact in the urine within ten hours, and no further urinary
excretion of imipenem was detectable. Urine concentrations of imipenem exceeded 10
μg/mL for up to eight hours after a 500mg/500mg dose of imipenem and cilastatin. The
remainder of the administered dose was recovered in the urine as antibacterially
inactive metabolites, and fecal elimination of imipenem was essentially nil. No
REGISTRATION HOLDER / MARKETING AUTHORIZATION HOLDER DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Head Office: 09-02-2008 / 08-02-2023
Bosch Pharmaceuticals (Pvt.) Ltd.,
8, Modern Society, Tipu Sultan Road, Karachi-Pakistan DATE OF REVISION OF TEXT
01-04-2024
Manufacturer:
Bosch Pharmaceuticals (Pvt.) Ltd.,
Plot No. 221-223, Sector 23, Korangi Industrial area, Karachi-Pakistan

MARKETING AUTHORISATION NUMBER(S)

Cilapen 250
Sterile powder for Injection
250mg+250mg: 048490

Cilapen 500
Sterile powder for injection
500mg+500mg: 048491

Nature and Content of Container / Presentation:

Cilapen 250
Sterile powder for Injection
250mg+250mg:
Pack of 1 vial plus 1 ampoule of 10mL Soride 0.9% (NaCl) as solvent

Cilapen 500
Sterile powder for injection
500mg+500mg:
Pack of 1 vial plus 1 ampoule of 10mL Soride 0.9% (NaCl) as solvent

Manufactured by:
Bosch Pharmaceuticals (Pvt.) Ltd.
221-223, Sector 23, Korangi Industrial Area,
Karachi - Pakistan