DESCRIPTION:
CILAPEN (imipenem and cilastatin) for Injection is a sterile formulation of imipenem, a penem antibacterial, and cilastatin, a renal dehydropeptidase inhibitor with sodium bicarbonate added as a buffer. CILAPEN is an antibacterial drug for intravenous administration.
Imipenem (N-formimidoylthienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya. Its chemical name is (5R,6S)-3-[[2-(formimidoylamino)ethyl]thio]-6[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate. It is an off-white, nonhygroscopic crystalline compound with a molecular weight of 317.37. It is sparingly soluble in water and slightly soluble in methanol. Its empirical formula is C 12 H 17 N 3 O4 S•H 2 O.
Cilastatin sodium is the sodium salt of a derivatized heptenoic acid. Its chemical name is sodium(Z)-7[[(R)¬2-amino-2-carboxyethyl]thio]-2-[(S)-2,2-dimethylcyclopropane carboxamido]-2-heptenoate. It is an off-white to yellowish-white, hygroscopic, amorphous compound with a molecular weight of 380.43. It is very soluble in water and in methanol. Its empirical formula is C 16 H 25 N 2 O5 SNa.
Solutions of CILAPEN range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

COMPOSITION:

Each Cilapen 250mg vial contains:
Imipenem U.S.P. …. 250mg as Imipenem Monohydrate
Cilastatin…. 250mg as Cilastatin Sodium U.S.P.
(Product Specs.: U.S.P.)

Each Cilapen 500mg vial contains:
Imipenem U.S.P. …. 500mg as Imipenem Monohydrate
Cilastatin…. 500mg as Cilastatin Sodium U.S.P.
(Product Specs.: U.S.P.)

CLINICAL PHARMACOLOGY:

Pharmacodynamic Properties:
Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems,
ATC code: J01D H51

Mechanism of Action:
Imipenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).
Cilastatin sodium is a competitive, reversible and specific inhibitor of dehydropeptidase-I, the renal enzyme which metabolizes and inactivates imipenem. It is devoid of intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.

Microbiology:

Gram-Positive Aerobic Bacteria

• Enterococcus faecalis
• Staphylococcus aureus
• Staphylococcus epidermidis
• Streptococcus agalactiae
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Bacillus spp.
• Listeria monocytogenes
• Nocardia spp.
• Staphylococcus saprophyticus
• Group C streptococci
• Group G streptococci
• Viridans group streptococci

Gram-Negative Aerobic Bacteria:

• 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
• Aeromonas hydrophila
• Alcaligenes spp.
• Capnocytophaga spp.
• Haemophilus ducreyi
• Neisseria gonorrhoeae
• Pasteurella spp.
• Providencia stuartii
• Gram-positive Anaerobic Bacteria:
• Bifidobacterium spp.
• Clostridium spp.
• Eubacterium spp.
• Peptococcus spp.
• Peptostreptococcus spp.
• Propionibacterium spp.

Gram-negative Anaerobic bacteria:

• Bacteroides spp., including B. fragilis
• Fusobacterium spp.
• Prevotella bivia
• Prevotella disiens
• Prevotella melaninogenica
• Veillonella spp.

Pharmacokinetic Properties

Absorption:
Intravenous infusion of CILAPEN over 20 minutes resulted in peak plasma levels of imipenem ranging from 12 to 20 μg/ml for the 250 mg/250 mg dose, from 21 to 58 μg/ml for the 500 mg/500 mg dose, and from 41 to 83 μg/ml for the 1000 mg/1000 mg dose. The mean peak plasma levels of imipenem following the 250 mg/250 mg, 500 mg/500 mg, and 1000 mg /1000 mg doses were 17, 39, and 66 μg/ml, respectively. At these doses, plasma levels of imipenem decline to below 1 μg/ml or less in four to six hours. Peak plasma levels of cilastatin, following a 20 minute intravenous infusion of CILAPEN, ranged from 21 to 26 μg/ml for the 250 mg/250 mg dose, from 21 to 55 μg/ml for the 500 mg/500 mg dose and from 56 to 88 μg/ml for the 1000 mg/1000 mg dose. The mean peak plasma levels of cilastatin following the 250 mg/250 mg, 500 mg/500 mg, and 1000 mg/1000 mg doses were 22, 42, and 72 μg/ml respectively.

Distribution:
The binding of imipenem to human serum proteins is approximately 20%. The binding of cilastatin to human serum proteins is approximately 40%.

Metabolism:
When administered alone, imipenem is metabolised in the kidneys by dehydropeptidase-I. Individual urinary recoveries ranged from 5 to 40%, with an average recovery of 15-20%. Cilastatin is a specific inhibitor of dehydropeptidase-I enzyme and effectively inhibits metabolism of imipenem so that concomitant administration of imipenem and cilastatin allows therapeutic antibacterial levels of imipenem to be attained in both urine and plasma.

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 500 mg/500 mg dose of CILAPEN. The remainder of the administered dose was recovered in the urine as antibacterially inactive metabolites, and faecal elimination of imipenem was essentially nil.
No accumulation of imipenem in plasma or urine has been observed with regimens of CILAPEN, administered as frequently as every six hours, in patients with normal renal function.
The plasma half-life of cilastatin is approximately one hour. Approximately 70-80% of the dose of cilastatin was recovered unchanged in the urine as cilastatin within 10 hours of administration of CILAPEN. No further cilastatin appeared in the urine thereafter. Approximately 10% was found as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of cilastatin. Activity of dehydropeptidase-I in the kidney returned to normal levels shortly after the elimination of cilastatin from the blood stream.

SPECIFIC POPULATIONS

Renal Insufficiency
Following a single 250 mg/250 mg intravenous dose of CILAPEN, the area under the curve (AUCs) for imipenem increased 1.1-fold, 1.9-fold, and 2.7-fold with mild (Creatinine Clearance (CrCL) 50-80 ml/min/1.73 m2), moderate (CrCL 30-<50 ml/min/1.73 m2), and severe (CrCL <30 ml/min/1.73 m2) renal impairment and AUCs for cilastatin increased 1.6-fold, 2.0-fold, and 6.2-fold with mild, moderate, and severe renal impairment. Following a single 250 mg/250 mg intravenous dose of CILAPEN given 24 hours after haemodialysis, AUCs for imipenem and cilastatin were 3.7-fold and 16.4-fold higher asa compared to normal renal function. Urinary recovery, renal clearance and plasma clearance of imipenem and cilastatin decrease with decreasing renal function following intravenous administration of CILAPEN. Dose adjustment is necessary for patients with impaired renal function.
Hepatic Insufficiency The pharmacokinetics of imipenem in patients with hepatic insufficiency have not been established. Due to the limited extent of hepatic metabolism of imipenem, its pharmacokinetics are not expected to be affected by hepatic impairment. Therefore, no dose adjustment is recommended in patients with hepatic impairment.

Pediatrics
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 15/15 mg/kg per body weight of imipenem/cilastatin to paediatric patients was approximately 30% higher than the exposure in adults receiving a 500 mg/500 mg dose. At the higher dose, the exposure following administration of 25/25 mg/kg imipenem/cilastatin to children was 9% higher as compared to the exposure in adults receiving a 1000 mg/1000 mg dose.

Elderly
The pharmacokinetics of a single dose of CILAPEN 500 mg/500 mg administered intravenously over 20 minutes were consistent. The mean plasma half-lives of imipenem and cilastatin were 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/cilastatin was observed.

THERAPEUTIC INDICATIONS:
CILAPEN is indicated for the treatment of the following infections in adults and children 1 year of age and above:

• 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

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

DOSAGE AND ADMINISTRATION:
The dose recommendations for CILAPEN represent the quantity of imipenem/cilastatin to be administered. The daily dose of CILAPEN should be based on the type of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s) and the patient’s renal function.

Adults and adolescents
For patients with normal renal function (creatinine clearance of ≥90 ml/min), the recommended dose regimens are: 500 mg/500 mg every 6 hours OR 1000 mg/1000 mg every 8 hours OR every 6 hours.
It is recommended that infections suspected or proven to be due to less susceptible bacterial speciesand very severe infections should be treated with 1000 mg/1000 mg administered every 6 hours.
A reduction in dose is necessary when creatinine clearance is < 90 ml/min. The maximum total daily dose should not exceed 4000 mg/4000 mg per day.

Patients with Renal Impairment:

The appropriate reduced dose regimen is selected according to the patient’s creatinine clearance.

Patients with a creatinine clearance of <15 ml/min These patients should not receive CILAPEN unless haemodialysis is instituted within 48 hours.

Patients on haemodialysis
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. Both imipenem and cilastatin are cleared from the circulation during haemodialysis. The patient should receive CILAPEN 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, CILAPEN 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.

Elderly population
No dose adjustment is required for the elderly patients with normal renal function.

Paediatric population ≥1 year of age
For paediatric patients ≥1 year of age, the recommended dose is 15/15 or 25/25 mg/kg/dose administered every 6 hours.
It is recommended that infections suspected or proven to be due to less susceptible bacterial species, and very severe infections, should be treated with 25/25 mg/kg administered every 6 hours.

Paediatric population <1 year of age
Clinical data are insufficient to recommend dosing for children less than 1 year of age.

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

Method of Administration:
CILAPEN is to be reconstituted and further diluted prior to administration. 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.

Reconstitution:

• Do not use diluents containing benzyl alcohol to reconstitute CILAPEN for administration to neonates because it has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than three months of age, small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity.

• Contents of the vials must be reconstituted by adding approximately 10 mL of the appropriate diluent to the vial. List of appropriate diluents are as follows:

• 9% Sodium Chloride Injection
• 5% Dextrose Injection
• 5% Dextrose and 0.9% Sodium Chloride Injection
• 5% Dextrose Injection with 0.225% or 0.45% saline solution
• Reconstituted Solutions of CILAPEN range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

• The reconstituted suspension must not be administered by direct Intravenous Infusion.
• After reconstitution, shake vial well and transfer the resulting suspension to 100 mL of an appropriate infusion solution before administering by intravenous infusion.
• Repeat transfer of the resulting suspension with an additional 10 mL of infusion solution to ensure complete transfer of vial contents to the infusion solution. Agitate the resulting mixture until clear.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

CONTRAINDICATIONS:
Hypersensitivity to the active substances or to any of the excipients or to any other carbapenem antibacterial agent. Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent.

WARNINGS AND PRECAUTIONS:

Hypersensitivity
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before initiating therapy with CILAPEN, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction to CILAPEN occurs, discontinue the therapy immediately. Serious anaphylactic reactions require immediate emergency treatment.

Hepatic
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

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

Antibacterial spectrum
The antibacterial spectrum of imipenem/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/cilastatin, caution should be exercised. The use of imipenem/cilastatin is not suitable for treatment of these types of infections.

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.

Clostridioides difficile
Antibiotic-associated colitis 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. It is important to consider this diagnosis in patients who develop diarrhoea during or after the use of imipenem/cilastatin.
Discontinuation of therapy with imipenem/cilastatin and the administration of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Meningitis
CILAPEN is not recommended for the therapy of meningitis.

Renal impairment
Imipenem-cilastatin accumulates in patients with reduced kidney function. CNS adverse reactions may occur if the dose is not adjusted to the renal function.

Central nervous system
CNS adverse reactions such as myoclonic activity, confusional states, or seizures have been reported, especially when recommended doses based on renal function and body weight were exceeded. These experiences 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.
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.
If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If CNS symptoms continue, the dose of CILAPEN should be decreased or discontinued.
Patients with creatinine clearances of <15 ml/min should not receive CILAPEN unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, CILAPEN is recommended only when the benefit outweighs the potential risk of seizures.

DRUG INTERACTIONS:
Generalized seizures have been reported in patients who received ganciclovir and CILAPEN. These medicinal products should not be used concomitantly unless the potential benefit outweighs the risks.
Decreases in valproic acid levels that may fall below the therapeutic range have been reported when valproic acid was co-administered with carbapenem agents. The lowered valproic acid levels can lead to inadequate seizure control; therefore, concomitant use of imipenem and valproic acid/sodium valproate is not recommended and alternative antibacterial or anti-convulsant therapies should be considered.
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 normalized 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.
Concomitant administration of CILAPEN 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 CILAPEN was administered with probenecid.
Concomitant administration of CILAPEN and probenecid doubled the plasma level and half-life of cilastatin, but had no effect on urine recovery of cilastatin.

ADVERSE EFFECTS:

Common:
Eosinophilia, thrombophlebitis, diarrhoea, vomiting, nausea, rash (e.g. exanthematous), increases in serum transaminases, increases in serum alkaline phosphatase.

Uncommon:
Pancytopenia, neutropenia, leucopenia, thrombocytopenia, thrombocytosis, psychic disturbances including hallucinations and confusional states, seizures, myoclonic activity, dizziness, somnolence, hypotension, urticaria, pruritus, fever, local pain and induration at the injection site, erythema at the injection site, A positive direct Coombs’ test, prolonged prothrombin time, decreased haemoglobin, increases in serum bilirubin, elevations in serum creatinine, elevations in blood urea nitrogen.

Rare:
pseudomembranous colitis, candidiasis, agranulocytosis, anaphylactic reactions, encephalopathy, paraesthesia, focal tremor, taste perversion, hearing loss, staining of teeth and/or tongue, hepatic failure, hepatitis, toxic epidermal necrolysis, angioedema, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, acute renal failure, oligurial/anuria, polyuria, urine discoloration

Very Rare:
gastro-enteritis, haemolytic anaemia, bone marrow depression, aggravation of myasthenia gravis, headache, vertigo, tinnitus, cyanosis, tachycardia, palpitations, flushing, dyspnoea, hyperventilation, pharyngeal pain, haemorrhagic colitis, abdominal pain, heartburn, glossitis, tongue papilla hypertrophy, increased salivation, fulminant hepatitis, hyperhidrosis, skin texture changes, polyarthralgia, thoracic spine pain, pruritus vulvae, chest discomfort, asthenia/weakness.

Not Known:
agitation, dyskinesia.

USE IN PREGNANCY AND LACTATION:

Pregnancy:
There are no adequate and well-controlled studies for the use of imipenem/cilastatin in pregnant women. CILAPEN should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Lactation:
There are insufficient data on the presence of imipenem/cilastatin in human milk, and no data on the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CILAPEN and any potential adverse effects on the breastfed child from CILAPEN or from the underlying maternal condition.

OVERDOSE:
In the case of overdosage, discontinue CILAPEN, treat symptomatically, and institute supportive measures as required. CILAPEN is hemodialyzable.

INCOMPATIBILITIES:
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.

SHELF LIFE: 2 years
After reconstitution, it maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (5°C).

STORAGE AND INSTRUCTIONS:

• Protect from heat, sunlight & moisture,
• store below 25°C.
• The expiration date refer to the product correctly stored at the required condition.
• Keep out of the reach of children.
• Do not freeze the reconstituted solution.
• Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
• To be sold on prescription of a registered medical practitioner only.

PRESENTATION:
Cilapen 250mg Injection: Pack of 1 vial plus 1 ampoule of 10ml sterile water for injection as solvent.
Cilapen 500mg Injection: Pack of 1 vial plus 1 ampoule of 10ml sterile water for injection as solvent.