| PRIMAXIN® |
|Imipenem - Cilastatin Sodium |
|Action And Clinical Pharmacology: Imipenem exerts a bactericidal action by inhibiting cell wall synthesis in aerobic and anaerobic gram-positive and gram-negative bacteria.
Primaxin consists of 2 components: imipenem, a derivative of thienamycin, a carbapenem antibiotic; and cilastatin sodium, a specific inhibitor of dehydropeptidase-I a renal enzyme which metabolizes and inactivates imipenem. Cilastatin blocks the metabolism of imipenem in the kidney, so that concomitant administration of imipenem and cilastatin allows antibacterial levels of imipenem to be attained in the urine.
Inhibition of cell-wall synthesis is achieved in gram-negative bacteria by the binding of imipenem to penicillin binding proteins (PBPs). In the case of E. coli and selected strains of P. aeruginosa, imipenem has been shown to have highest affinity for PBP-2, PBP-1a and PBP-1b, with lower activity against PBP-3. The preferential binding of imipenem on PBP-2 and PBP-1b leads to direct conversion of the individual cell to a spheroplast resulting in rapid lysis and cell death without filament formation. When imipenem is removed prior to complete killing of gram-negative species, the remaining viable cells show a measurable lag, termed a "post-antibiotic effect" (PAE), prior to resumption of new growth.
Pharmacokinetics: Primaxin was administered via i.v. infusion over 20 minutes at a single dose of 250/250 mg to 4 male subjects (mean age: 31.5±0.6 years), at a single dose of 500/500 mg to 20 male subjects (mean age: 26.8±4.1 years), and at a single dose of 1000/1000 mg to 8 male subjects (mean age: 24.8±3.7 years). Peak plasma levels of imipenem and of cilastatin were measured at the end of a 20-minute infusion, and are presented in Table I. Plasma levels of imipenem antimicrobial activity are proportional to the dose and decline to below 1 µg/mL or less in 4 to 6 hours.
Primaxin was administered via the i.v. route over a 30-minute period, every 6 hours, for a period of 10 days, at a dose of 1 000/1 000 mg, to a group of 6 male volunteers (mean age 28.2±5).
The pharmacokinetic parameters for imipenem and cilastatin, when Primaxin was administered at a dose of 1 000/1 000 mg, are summarized in Table II.
Excretion and Metabolism: Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase-I and therefore achieves relatively low levels in urine.
Cilastatin is a specific inhibitor of this enzyme and it prevents renal metabolism of imipenem. When imipenem and cilastatin are given concomitantly, approximately 70% of the administered imipenem and cilastatin are recovered unchanged in the urine within 10 hours of administration, 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 Primaxin, at the 500 mg dose.
The remainder of the administered dose of imipenem is recovered in the urine as antibacterially inactive metabolites, and fecal elimination of imipenem is essentially nil.
Approximately 10% of the cilastatin administered is found as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of the parent drug. Activity of dehydropeptidase-I in the kidney returns to normal levels within approximately 8 to 12 hours after the elimination of cilastatin from the bloodstream.
No accumulation of imipenem and cilastatin in plasma is observed with regimens of Primaxin administered at therapeutic doses, in patients with normal renal function.
Serum Protein Binding: At serum concentration of 25 mg/L the human serum protein binding of imipenem is 20%. Cilastatin binding to protein was found to be approximately 35% in the human serum.
Impaired Renal Function: Primaxin was administered to 6 healthy male volunteers and 25 patients with different degrees of renal impairment at a dose of 250/250 mg, in single i.v. infusions over 5 minutes. The pharmacokinetic parameters for imipenem and cilastatin are summarized
Indications And Clinical Uses: In the treatment of serious infections when caused by sensitive strains of bacteria. Where considered necessary, therapy may be initiated on the basis of clinical judgment before results of sensitivity testings are available. Continuation of therapy should be reevaluated on the basis of bacteriological findings and of the patient's clinical condition.
Imipenem is active in vitro against a wide range of gram-positive and gram-negative aerobic and anaerobic bacteria, including most strains which are beta-lactamase producing. Patients have responded while under treatment with Primaxin for single or mixed infections of the following body systems, when they were associated with a number of pathogenic species and strains of the genera listed: lower respiratory tract infections, urinary tract infections, intra-abdominal infections, gynecological infections, septicemia, endocarditis caused by S. aureus, bone and joint infections, skin structure infections.
Primaxin is not indicated for the treatment of meningitis.
Gram-positive Aerobes: L. monocytogenes, N. asteroides, Staphylococcus (excluding many strains which are methicillin resistant), Streptococcus (excluding S. faecium).
Gram-negative Aerobes: Acinetobacter, Citrobacter, Enterobacter, E. coli, H. influenzae, H. parainfluenzae, Klebsiella, M. morganii, Neisseria, Proteus (indole positive and indole negative strains), Providencia, P. aeruginosa, S. marcescens.
Gram-positive Anaerobes: Clostridium (excluding C. difficile), Peptococcus, Peptostreptococcus.
Gram-negative Anaerobes: B. fragilis, Bacteroides (non-fragilis).
Contra-Indications: In patients who have shown hypersensitivity to either component of this product. tag_WarningWarnings
Manufacturers' Warnings In Clinical States: Primaxin should be administered with caution to any patient who has demonstrated some form of allergy, particularly to structurally-related drugs. If an allergic reaction to Primaxin occurs, discontinue the drug. Serious hypersensitivity reactions may require epinephrine and other emergency measures.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with the use of Primaxin. Therefore it is important to consider this diagnosis in patients who develop diarrhea during or after therapy. This colitis may range from mild to life-threatening in severity.
Mild cases of pseudomembranous colitis may respond to drug discontinuance alone. In more severe cases, management may include sigmoidoscopy, appropriate bacteriological studies, fluid, electrolyte and protein supplementation, and the use of a drug such as oral vancomycin, as indicated. Other causes of colitis should also be considered.
Precautions: General: Prolonged use may result in overgrowth of resistant organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.
CNS adverse experiences such as myoclonic activity, confusional states, or seizures have been reported especially when recommended dosages based on renal function and body weight were exceeded. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or who have compromised renal function. However, there were rare reports in which there was no recognized or documented underlying CNS disorder. Close adherence to recommended dosage schedules is urged especially in patients with known factors that predispose to seizures (see Dosage).
Anticonvulsant therapy should be continued in patients with a known seizure disorder. 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 dosage should be decreased or discontinued.
Impaired Renal Function: Dosage in patients with impaired renal function is based on the severity of infection but the maximum daily dose varies with the degree of renal functional impairment (see Dosage, Renal Insufficiency).
Pregnancy: Use in pregnant women has not been studied, therefore, Primaxin should be used during pregnancy only if clearly needed. Use of this drug in women of childbearing potential requires that the anticipated benefits be weighed against possible hazards.
Reproduction studies with bolus i.v. doses suggest an apparent intolerance to Primaxin (including emesis, inappetence, body weight loss, diarrhea and death) at doses equivalent to the average human dose in pregnant rabbits and cynomolgus monkeys that is not seen in non-pregnant animals in these or other species. In other studies, Primaxin was well tolerated in equivalent or higher doses (up to 11 times the average human dose) in pregnant rats and mice.
Lactation: It is not known whether Primaxin is excreted in milk. If its use is deemed essential, the patient should stop nursing.
Children: Efficacy and tolerability in infants under the age of 3 months have not yet been established; therefore, Primaxin is not recommended in the pediatric age group below the age of 3 months.
Drug Interactions: Concomitant administration of Primaxin 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 Primaxin.
Primaxin should not be mixed with or physically added to other antibiotics. Primaxin has been administered concomitantly with some antibiotics, such as aminoglycosides.
There is no evidence to suggest that association of Primaxin with any other beta-lactam antibiotics has any therapeutic advantage.
Adverse Reactions: Primaxin is generally well tolerated. The following adverse reactions were reported on 1 723 patients treated in clinical trials. Many of these patients were severely ill and had multiple background diseases and physiological impairments, making it difficult to determine causal relationship of adverse experiences to therapy with Primaxin.
Local: Adverse local clinical reactions that were reported as possibly, probably or definitely related to therapy with Primaxin were: phlebitis/thrombophlebitis 1.7%, infused vein pain 0.6%, vein induration 0.2%, infused vein infection 0.1%.
Systemic: Adverse clinical reactions that were reported as possibly, probably or definitely related to Primaxin were:
Gastrointestinal: nausea 2.0%, diarrhea 1.7%, vomiting 1.6%, tongue papillar hypertrophy 0.2%, pseudomembranous colitis (see Warnings) 0.1%, hemorrhagic colitis<0.1%, gastroenteritis<0.1%, abdominal pain<0.1%, glossitis<0.1%, heartburn<0.1%, pharyngeal pain<0.1%, increased salivation<0.1%.
CNS: fever 0.4%, dizziness 0.3%, seizures (see Precautions) 0.2%, somnolence 0.2%, confusion 0.2%, myoclonus 0.1%, vertigo 0.1%, headache 0.1%, encephalopathy<0.1%, paresthesia<0.1%.
Special Senses: transient hearing loss in patients with impaired hearing<0.1%, tinnitus<0.1%.
Respiratory: dyspnea 0.1%, hyperventilation<0.1%, thoracic spine pain<0.1%.
Cardiovascular: hypotension 0.4%, palpitations 0.1%, tachycardia<0.1%.
Renal: oliguria/anuria<0.1%, polyuria<0.1%.
Skin: rash 0.9%, pruritus 0.3%, urticaria 0.2%, skin texture changes 0.1%, candidiasis 0.1%, erythema multiforme<0.1%, facial edema<0.1%, flushing<0.1%, cyanosis<0.1%, hyperhidrosis<0.1%, pruritus vulvae <0.1%.
Body as a whole: polyarthralgia<0.1%, asthenia/weakness<0.1%.
Laboratory Changes: Adverse laboratory changes, without regard to drug relationship, that were reported during clinical trials were:
Hepatic: Increased ALT, AST, alkaline phosphatase, bilirubin and LDH.
Hemic: Increased eosinophils, positive Coombs test, decreased WBC and neutrophils, increased WBC, increased platelets, decreased platelets, decreased hemoglobin and hematocrit, increased monocytes, abnormal prothrombin time, increased lymphocytes, increased basophils.
Electrolytes: Decreased serum sodium, increased potassium, increased chloride.
Renal: Increased BUN, creatinine.
Urinalysis: Presence of urine protein, urine red blood cells, urine white blood cells, urine casts, urine bilirubin, and urine urobilinogen.
Marketing Experience: The following reactions have been reported since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians and pharmacists: toxic epidermal necrolysis; hepatitis; acute renal failure. The role of Primaxin in changes in renal function is difficult to assess, since factors predisposing to pre-renal azotemia or to impaired renal function usually have been present; psychic disturbances; anaphylactic reactions; taste perversion.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There are no data available on overdosage. Primaxin is cleared by hemodialysis. tag_DosageDosage
Dosage And Administration: The dosage recommendations represent the quantity of imipenem to be administered by i.v. infusion only. An equivalent amount of cilastatin is also present in the solution.
The dosage should be determined by the severity of the infection, renal function, body weight, the antibiotic susceptibility of the causative organism(s) and the condition of the patient. Doses cited are based on body weight of 70 kg.
The median duration of treatment in clinical trials for infections of the various body systems ranged from 6 to 10 days except for endocarditis and bone and joint infections for which the median duration of treatment was 4 weeks.
Adults: 1 to 2 g daily administered in equally divided doses every 6 to 8 hours
The maximum daily dose should not exceed 4 g or 50 mg/kg, whichever is less.
Geriatrics: In patients with normal renal function the dosage is the same as given for adults above. Renal status of elderly patients may not be accurately portrayed by measurement of BUN or creatinine alone. Determination of creatinine clearance is suggested to provide guidance for dosing in such patients.
Renal Insufficiency: Patients with creatinine clearances of £5 mL/min/1.73 m(£0.08 mL/s/1.73 m should not receive Primaxin unless hemodialysis is instituted within 48 hours. Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive Primaxin after hemodialysis and at 12 hour intervals timed from the end of that hemodialysis session (see Table V). Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, Primaxin is recommended only when the benefit outweighs the potential risk of seizures (see Precautions). Currently, there are inadequate data to recommend the use of Primaxin in patients undergoing peritoneal dialysis.
Males: Weight (kg)x(140-age) / 72xserum creatinine (mg/100 mL)
Females: 0.85xabove value.
When using the International System of units (SI), the estimated creatinine clearance (mL/s) in males can be calculated as follows:
(lean body weight, kg)x(140-age, years)x1.4736 / (72)x(serum creatinine concentration, mmol/L)
and in females the estimated creatinine clearance (mL/s) is:
(lean body weight, kg)x(140-age, years)x1.2526 / (72)x(serum creatinine concentration, mmol/L)
When using the International System of units (SI), the estimated creatinine clearance (mL/s) in males can be calculated as follows: (lean body weight, kg)“(140-age, years)“1.4736 (72)“(serum creatinine concentration, µmol/L) and in females the estimated creatinine clearance (mL/s) is:
(lean body weight, kg)“(140-age, years)“1.2526 (72)“(serum creatinine concentration, µmol/L) Primaxin is cleared by hemodialysis. After each dialysis session the dosage schedule should be restarted.
Infants and Children: In children and infants 3 months of age and older, the dosage is 60 to 100 mg/kg body weight divided into 4 equal doses given at 6-hour intervals. The higher dosages should be used for infants and young children. The total daily dosage should not exceed 2 g. Clinical data are insufficient to recommend an optimum dose for infants and children with impaired renal function.
Primaxin is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used.
Primaxin may be used in children with sepsis as long as they are not suspected of having meningitis.
Caution: Contents of vials not for direct infusion.
Each reconstituted 250 mg or 500 mg dose should be given by i.v. infusion over 20 to 30 minutes. Each 1 000 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.
Reconstitution: Vials: Contents of the vials must be suspended and transferred to 100 mL of an appropriate infusion solution.
A suggested procedure is to transfer approximately 10 mL from the 100 mL of the appropriate infusion solution to the vial (see Compatibility and Stability, List of Diluents). Shake well. Return the resulting 10 mL of suspension to the remaining 90 mL of the infusion solution.
Repeat, using 10 mL of the diluted suspension, to ensure complete transfer of the contents of the vial to the infusion solution.
Caution: Contents of vials not for direct infusion.
ADD-Vantage Vials: When administering Primaxin using the ADD-Vantage drug delivery system, the sterile powder is added directly to a single-dose flexible plastic ADD-Vantage diluent container.
Solutions for Reconstitution: Use Abbott Laboratories' ADD-Vantage diluent containers containing 100 mL or 250 mL of either: 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
Special Instructions (ADD-Vantage): To Open Diluent Container: Peel overwrap from the corner and remove container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.
To Assemble Vial and Flexible Diluent Container (use aseptic technique): See package insert for figures.
1. Remove the protective covers from the top of the vial and the vial port on the diluent container as follows: a) To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening. Pull the ring approximately half way around the cap and then pull straight up to remove the cap. b) To remove the vial port cover, grasp the tab on the pull ring, pull up to break the 3 tie strings, then pull back to remove the cover.
2. Screw the vial into the vial port until it will go no further. The vial must be screwed in tightly to assure a seal. This occurs approximately 1/2 turn (180°) after the first audible click. The clicking sound does not assure a seal; the vial must be turned as far as it will go. Note: Once vial is seated, do not attempt to remove.
3. Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.
4. Label appropriately.
To Prepare Admixture:
1. Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.
2. With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container.
3. Pull the inner cap from the drug vial. Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.
4. Mix container contents thoroughly and use within the specified time.
Preparation for Administration (use aseptic technique):
1. Confirm the activation and admixture of vial contents.
2. Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
3. Close flow control clamp of administration set.
4. Remove cover from outlet port at bottom of container.
5. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. Note: See full directions on administration set carton.
6. Lift the free end of the hanger loop on the bottom of the vial, breaking the 2 tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.
7. Squeeze and release drip chamber to establish proper fluid level in chamber.
8. Open flow control clamp and clear air from set. Close clamp.
9. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
10. Regulate rate of administration with flow control clamp.
Warning: Do not use flexible containers in series connections.
Compatibility and Stability: List of Diluents: Sodium Chloride 0.9% Injection, Dextrose 5% or 10% Injection, Dextrose 5% Injection with 0.02% sodium bicarbonate solution, Dextrose 5% and Sodium Chloride 0.9% Injection, Dextrose 5% Injection with 0.225% or 0.45% saline solution, Normosol-M in D5-W, Dextrose 5% Injection with potassium chloride 0.15% solution, mannitol 2.5%, 5% and 10%.
Reconstituted Solutions: Solutions range from colorless to yellow. Variations of color within this range do not affect the potency of the product.
Primaxin, as supplied in vials or in ADD-Vantage vials and reconstituted as above maintains satisfactory potency for 4 hours at room temperature and for 24 hours under refrigeration (4°C). Primaxin has been found to be stable in Sodium Chloride 0.9% Injection for 10 hours at room temperature and 48 hours under refrigeration.
Availability And Storage: 250 mg: Each vial of sterile powder mixture contains: imipenem anhydrous equivalent to imipenem 250 mg and cilastatin sodium equivalent to cilastatin 250 mg. Also contains sodium bicarbonate buffer. ADD-Vantage vials also available.
500 mg: Each vial of sterile powder mixture contains: imipenem anhydrous equivalent to imipenem 500 mg and cilastatin sodium equivalent to cilastatin 500 mg. Also contains sodium bicarbonate buffer. ADD-Vantage vials also available.
Store the dry powder between 15 and 30°C.