Vexpinem 500

Imipenem, cilastatin sodium.

Imipenem + Cilastatin: A white to light yellow crystalline powder.
Each vial contains: Sterile Imipenem USP Eq. to Imipenem Anhydrous 500 mg, Sterile Cilastatin Sodium USP Eq. to Cilastatin Anhydrous 500 mg (A sterile mixture of Imipenem, Cilastatin sodium and Sodium Bicarbonate).
Imipenem and Cilastatin for Injection is a sterile mixture of Imipenem (a thienamycin antibiotic) and Cilastatin sodium (the inhibitor of the renal dipeptidase, dehydropeptidase 1), with sodium bicarbonate added as a buffer. Imipenem and Cilastatin is a potent broad spectrum antibacterial agent 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.
Cilastatin sodium is a white to tan-colored powder. Soluble in water and in methanol.
Its chemical name is 2-Heptenoic acid, 7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-, monosodium salt, [R-[R*,S*-(Z)]]-.
Sodium (Z)-7-[[(R)-2-amino-2-carboxyethyl]thio]-2-[(S)-2,2-dimethylcyclopropanecarboxamido]-2-heptenoate. It has molecular weight is 380.44.

Pharmacological Classification: Carbapenems β-lactam antibiotics. ATC Code: J01D H51.
Pharmacology: Pharmacodynamics: Mechanism of action: Imipenem is a potent inhibitor of bacterial cell wall synthesis and is highly reactive towards penicillin-binding protein. Imipenem is more potent in its bactericidal effect than other antibiotics studied.
Cilastatin sodium is a competitive, reversible, and specific inhibitor of dehydropeptidase-1, the renal enzyme which metabolises and inactivates Imipenem. Cilastatin sodium is devoid of intrinsic antibacterial activity itself and does not affect the antibacterial activity of Imipenem.
PK/PD relationship: Imipenem exhibits primarily time-dependent killing. In common with other beta-lactams, the main PK/PD parameter that correlates with therapeutic efficacy is the time that concentrations in serum and tissue are above the MIC for the pathogens (>MIC).
Mechanism(s) of resistance: Imipenem is effectively stable to hydrolysis by most classes of beta-lactamases, including penicillinases, cephalosporinases and extended spectrum beta-lactamases, but not metallo-beta-lactamases. Resistance is generally due to a combination of decreased permeability and low- level beta-lactamase hydrolysis.
The mechanism of action of Imipenem differs from that of other classes of antibiotics, such as quinolones, aminoglycosides, macrolides and tetracyclines. There is no target-based cross-resistance between Imipenem and these substances. However, micro-organisms may exhibit resistance to more than one class of antibacterial agents when the mechanism is, or includes, impermeability to some compounds.
Pharmacokinetics: After oral administration, imipenem is not significantly absorbed. After I.V. administration of 500 mg, maximale plasma levels of about 36 mg/ml are observed. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem/cilastatin is observed.
Distribution: Imipenem is bound to plasma proteins for about 20% and cilastatin for about 40%. The volume of distribution is approximately 10 L for both drugs.
Metabolism: Imipenem is mainly metabolised in the proximal renal tubuli by dehydropeptidase 1 into the inactive open ring metabolite, resulting in relative low urinary imipenem concentrations. Imipenem systemic metabolism accounts for about 30%. Cilastatin, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem, resulting in higher imipenem urinary concentrations.
Cilastatin is partly metabolised to N-acetyl-cilastatin in the kidneys.
Elimination: The plasma clearance of imipenem is 225 mL/min and that of cilastatin about 200 mL/min. Concomitant administration results in a decrease of the imipenem plasma clearance to about 195 mL/min, and an increase in renal clearance, urinary recovery and urinary concentrations. The plasma clearance of cilastatin is not affected. The elimation half-life is about 1 h for imipenem as well as for cilastatin. Approximately 70% of the administered imipenem dose is excreted intact in urine, and approximately 70-80% of the cilastatin dose.
Special patient groups: Elderly: In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of imipenem 500 mg and cilastatin 500 mg administered intravenously over 20 minutes are consistent with those expected in subjects with slight renal impairment for which no dosage alteration is considered necessary.
Patients with renal impairment: Imipenem plasma clearance is decreased approximately 40% in subjects with moderate renal impairment to 70% in patients with severe renal impairment. In addition, the elimination half-life is increased to approximately 2.5 hours. Haemodialysis patients have an elimination half-life of about 3.4 hours. Cilastatin clearance is decreased approximately 50% in subjects with moderate renal impairment to 80% in patients with severe renal impairment. In addition, the elimination half-life is increased to approximately 4 hours. Haemodialysis patients have an elimination half-life of about 12 hours. During haemodialysis a higher clearance is observed for imipenem and cilastatin.
Children: The volume of distribution of imipenem and cilastatin in children is slightly higher than in adults. The elimination half-life for imipenem is about 1 h, and that for cilastatin about 40 min. 50-70% of the administered imipenem/cilastatin dose is excreted in urine.

Treatment of the following severe infections due to susceptible organisms: Nosocomial pneumonia or complicated community acquired pneumonia requiring hospitalisation; Complicated intra-abdominal infections; Complicated genito-urinary infections; Complicated skin and soft tissue infections.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

For intravenous administration only.
The dosage of Imipenem/Cilastatin should be based on the type or severity of infection, consideration of degree of susceptibility of the pathogen(s), renal function and bodyweight. The total daily requirement should be given in equally divided doses.
For instructions on dilution of the medicinal product enclosed.
The dosage recommendations that follow specify the amounts of imipenem to be given. One vial of Imipenem/Cilastatin 500 mg/500 mg provides the equivalent of 500 mg imipenem and 500 mg cilastatin.
Adults: Doses cited are based on a bodyweight of ≥70 kg. The usual adult daily dosage is 1.5-2 g administered in 3-4 equally divided doses (see Table 1 as follows). In infections due to less sensitive organisms, the daily dose may be increased to a maximum dose of 50 mg/kg/day (not exceeding 4 g daily).
Usual adult intravenous dosage: Each dose of 250 mg or 500 mg should be given by intravenous infusion over 20-30 minutes. Each dose of 1000 mg should be infused over 40-60 minutes. In patients who develop nausea during infusion, the infusion rate may be slowed.
IV administration: See Table 1.

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Use in elderly patients: Age does not usually affect the tolerability and efficacy of imipenem/cilastatin.
In patients with renal insufficiency: As in patients with normal renal function, dosing is based on the severity of the infection. The dosage for patients with various degrees of renal functional impairment is shown in the following table. Doses cited are based on a bodyweight of 70 kg. Proportionate reduction in dose administered should be made for patients with lower bodyweight.
Maximum dosage in relation to renal function: See Table 2.

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Patients with a creatinine clearance of 5 mL/min should not receive imipenem/cilastatin unless haemodialysis is started within 48 hours. Imipenem/cilastatin is cleared by haemodialysis. The patient should receive imipenem/cilasatin immediately after haemodialysis and at 12-hourly intervals thereafter. Dialysis patients, especially those with background CNS disease, should be carefully monitored. Patients on haemodialysis should receive imipenem/cilastatin only when the benefit outweighs the potential risk of convulsions. There are currently inadequate data to recommend the use of imipenem/cilastatin for patients on peritoneal dialysis.
Paediatric dosage: See Table 3.

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The maximum daily dose should not exceed 2 g.
Children and adolescents over 40 kg bodyweight should be dosed as adults.
Clinical data are insufficient to recommend an optimal dose for children under 3 years of age or infants and children with impaired renal function (serum creatinine >177 µmol/l).
Imipenem/cilastatin is not recommended for treatment of meningitis. If meningitis is suspected an appropriate agent should be used.

No specific information is available on the treatment of overdose with the product. Imipenem and cilastatin are haemodialysable. However, the usefulness of this procedure in the event of overdose is unknown.

Hypersensitivity to imipenem, cilastatin or any of the excipients.
Hypersensitivity to any other beta-lactam type antibiotic (e.g. penicillin, cephalosporin).

There is some clinical and laboratory evidence of partial cross-allergenicity between imipenem/cilastatin and the other beta-lactam antibiotics, penicillins and cephalosporins. Severe reactions (including anaphylaxis) have been reported with most beta-lactam antibiotics.
Before initiating therapy with imipenem/cilastatin, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. If an allergic reaction to imipenem/cilastatin occurs, the drug should be discontinued and appropriate measures undertaken.
Pseudomembranous colitis, reported with virtually all antibiotics, can range from mild to life-threatening in severity. Imipenem/cilastatin should be prescribed with caution in patients with a history of gastro-intestinal disease, particularly colitis. Treatment-related diarrhoea should always be considered as a pointer of diagnosis. While studies indicate that a toxin of Clostridium difficile is one of the primary causes of antibiotic-associated colitis, other causes should be considered.
Paediatric use:The clinical data demonstrating the efficacy and safety of Imipenem/Cilastatin in children is rather limited. Therefore, caution should be exercised when administering this drug to children 3 years and above.
Central nervous system: Note: Imipenem/Cilastatin is not indicated against central nervous system infections.
Patients with CNS disorders and/or compromised renal function (accumulation of imipenem/cilastatin may occur) have shown CNS side effects, especially when recommended dosages based on body weight and renal function were exceeded. Hence it is recommended that the dosage schedules of imipenem/cilastatin should be strictly adhered to, and established anticonvulsant therapy continued.
If focal tremors, myoclonus or convulsions occur, the patient should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If these symptoms continue, the dosage should be reduced, or imipenem/cilastatin withdrawn completely.
Under the treatment of imipenem/cilastatin asthenia and the aggravation of myasthenia gravis may occur. Therefore, in case of any symptom indicating an exacerbation of myasthenia gravis a physician must be consulted.
Use in patients with renal insufficiency: Patients with creatinine clearances of <5 mL/min 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 convulsions.

Imipenem/cilastatin should only be used in severe or complicated infections suspected or due to bacteria resistant to other beta-lactams and susceptible to imipenem/cilastatin.

The evaluation of adverse reactions is based on the following definition of frequency: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1 /1000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
The following reactions are rare, very rare, and/or their frequency cannot be estimated from the available data, but they may be serious: Anaphylactic reactions: angioedema, toxic epidermal necrolysis/Stevens-Johnson syndrome, exfoliative dermatitis, acute renal failure; Pseudomembranous colitis; Seizures or convulsions.
Infections and infestations: Rare: superinfections with Candida or Stenotrophomonas maltophilia.
Immune system disorders: Rare: erythema multiforme, anaphylactic reactions, severe allergic reactions (immediately).
Nervous system disorders: Uncommon: myoclonic activity, somnolence, dizziness, vertigo, headache, psychic disturbances, including hallucinations, paraesthesia, confusional states or convulsions.
Rare: encephalopathy.
Respiratory, thoracic and mediastinal disorders: Very rare: hyperventilation, dyspnoea.
Gastrointestinal disorders: Uncommon: nausea, vomiting, diarrhoea, staining of teeth and/or tongue.
Rare: pseudomembranous colitis, taste perversion.
Not known: haemorrhagic colitis, gastro-enteritis, abdominal pain, glossitis, tongue papillar hypertrophy, heartburn, pharyngeal pain, increased salivation.
Hepato-biliary disorders: Common: mild increases in serum transaminases, bilirubin and/or serum alkaline phosphatase.
Rare: hepatitis with liver failure.
Very rare: fulminant hepatitis
Skin and subcutaneous tissue disorders: Common: rash, pruritus, urticaria.
Rare: erythema multiforme, Stevens-Johnson syndrome, angioedema, toxic epidermal necrolysis, exfoliative dermatitis.
Not known: flushing, cyanosis, hyperhidrosis, skin texture changes, pruritus vulvae.
Musculoskeletal and connective tissue disorders: Very rare: asthenia and aggravation of myasthenia gravis.
Not known: polyarthralgia and chest discomfort/pain.
Renal and urinary disorders: Rare: oliguria/anuria and polyuria.
Very rare: acute renal failure, elevated serum creatinine and blood urea, a harmless urine discoloration, not to be confused with haematuria, has been seen in children.
General disorders and administration site conditions: Common: erythema, local pain and induration, thrombophlebitis.
Rare: asthenia/weakness.
Unknown: fever including drug fever.

General seizures have been reported in patients who received ganciclovir and imipenem/cilastatin. These drugs should not be used concomitantly unless the potential benefit outweighs the risk. Also, the prodrug valganciclovir can provoke seizures in combination with imipenem/cilastatin.
Concomitant probenecid has been shown to double the plasma level and half-life of cilastatin, but with no effect on its urinary recovery. Concomitant probenecid showed only minimal increases in plasma level and half-life of imipenem, with urinary recovery of active imipenem decreased to approximately 60% of the administered dose.
After co-administration with carbapenem agents, decreased plasma concentrations of valproic acid have been observed. The lowered valproic acid concentration can lead to inadequate seizure control. Alternative antibacterial agents should be considered. If imipenem and valproic acid are concomitantly administered, serum valproic acid concentrations should be closely monitored.
Imipenem/Cilastatin may cause positive Coombs test results.

Preparation of Solution: Vials: Contents of the vials must be suspended and transferred to 100 mL of infusion solution prior to intravenous infusion.
A suggested procedure is to add approximately 10 mL from the appropriate infusion solution (see list of diluents under Compatibility and Stability as follows) to the vial. Shake well and transfer the resulting suspension to the infusion solution container. Benzyl alcohol as a preservative 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. Therefore, diluents containing benzyl alcohol should not be used when imipenem and cilastatin for injection (I.V.) is constituted for administration to pediatric patients in this age range.
Repeat with an additional 10 mL of infusion solution to ensure complete transfer of vial contents to the infusion solution. The resulting mixture should be agitated until clear. (See Table 4.)

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Compatibility and Stability: Before Reconstitution: The dry powder should be stored at a temperature below 30°C.
Reconstituted Solutions: Solutions of Imipinem and Cilastatin for injection range from colorless to yellow. Variations of color within this range do not affect the potency of the product.
Vials: Imipenem and Cilastatin for Injection, as supplied in single use vials and reconstituted with the following diluents (see Preparation of Solution previously), maintains satisfactory potency for 4 hours at room temperature or for 24 hours under refrigeration (5°C). Solutions of Imipenem and Cilastatin for Injection should not be frozen.

Store at temperatures not exceeding 30°C. Protect from light.
Shelf-Life: 24 months from the date of manufacture.

Other Beta-Lactams

J01DH51 - imipenem and cilastatin ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.

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