Insipim

Insipim uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Xxxxx
• Insipim reviews

1 INDICATIONS AND USAGE

Insipim for Injection is a cephalosporin antibacterial indicated for the treatment of the following infections caused by susceptible strains of the designated microorganisms:

• Pneumonia.
• Empiric therapy for febrile neutropenic patients. (1.2)
• Uncomplicated and complicated urinary tract infections (including pyelonephritis). (1.3)
• Uncomplicated skin and skin structure infections. (1.4)
• Complicated intra-abdominal infections (used in combination with metronidazole) in adults. (1.5)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Insipim for Injection and other antibacterial drugs, Insipim for Injection should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. (1.6)

1.1 Pneumonia

Insipim for Injection is indicated in the treatment of pneumonia (moderate to severe) caused by susceptible strains of Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.

1.2 Empiric Therapy for Febrile Neutropenic Patients

Insipim as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection, antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of Insipim monotherapy in such patients [see Clinical Studies (14.1)].

1.3 Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis)

Insipim is indicated in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by susceptible isolates of Escherichia coli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these bacteria.

1.4 Uncomplicated Skin and Skin Structure Infections

Insipim is indicated in the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus or Streptococcus pyogenes.

1.5 Complicated Intra-abdominal Infections (used in combination with metronidazole)

Insipim is indicated in the treatment of complicated intra-abdominal infections (used in combination with metronidazole) in adults caused by susceptible isolates of Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis [see Clinical Studies (14.2)].

1.6 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Insipim for Injection and other antibacterial drugs, Insipim for Injection should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION

Pediatric Patients (2 months to 16 years)

Recommended dosage in pediatric with CrCL greater than 60 mL/min. (2.2)

• The usual recommended dosage in pediatric patients is 50 mg per kg per dose administered every 12 hours (every 8 hours for febrile neutropenia). (2.2)
• Patients with Renal Impairment: Adjust dose in patients with CrCL less than or equal to 60 mL/min. (2.3)

2.1 Dosage for Adults

The recommended adult dosages and routes of administration are outlined in Table 1 below for patients with creatinine clearance greater than 60 mL/min. Administer Insipim for Injection intravenously over approximately 30 minutes.

2.2 Pediatric Patients

The maximum dose for pediatric patients should not exceed the recommended adult dose.

The usual recommended dosage in pediatric patients up to 40 kg in weight for durations as given above for adults is:

• 50 mg per kg per dose, administered every 12 hours for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia.
• For moderate to severe pneumonia due to P. aeruginosa give 50 mg per kg per dose, every 8 hours.
• 50 mg per kg per dose, every 8 hours for febrile neutropenic patients.

2.3 Dosage Adjustments in Patients with Renal Impairment

Adult Patients

Adjust the dose of Insipim for injection in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination. In these patients, the recommended initial dose of Insipim for injection should be the same as in patients with CrCL greater than 60 mL/min except in patients undergoing hemodialysis. The recommended doses of Insipim for injection in patients with renal impairment are presented in Table 2.

When only serum creatinine is available, the following formula ⁴ may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

Females: 0.85 × above value

In patients undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD), Insipim for injection may be administered at the recommended doses at a dosage interval of every 48 hours.

In patients undergoing hemodialysis, approximately 68% of the total amount of Insipim present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of Insipim for injection for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours.

Insipim for Injection should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days.

Pediatric Patients

Data in pediatric patients with impaired renal function are not available; however, since Insipim pharmacokinetics are similar in adults and pediatric patients [see Clinical Pharmacology (12.3)], changes in the dosing regimen proportional to those in adults are recommended for pediatric patients.

2.4 Preparation of Insipim for Intravenous Infusion

Vials

• Constitute the 0.5 gram, 1 gram, or 2 grams vial, of Insipim with the one of the following diluents:
  • Sterile Water for Injection
  • 0.9% Sodium Chloride Injection
  • 5% Dextrose Injection
  • 0.5% or 1% Lidocaine Hydrochloride Injection
  • Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol
• Dilute reconstituted solution with one of the following compatible infusion solutions prior to intravenous infusion (Refer to Table 3 below for the amount of diluent to be added to each vial):
  • 0.9% Sodium Chloride Injection
  • 5% and 10% Dextrose Injection
  • M/6 Sodium Lactate Injection
  • 5% Dextrose and 0.9% sodium Chloride Injection
  • Lactated Rings and 5% Dextrose Injection
  • Normosol -R and Normosol -M in 5% Dextrose Injection
• Parenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.
• Administer the resulting intravenous infusion over approximately 30 minutes.
• Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing Insipim, it is desirable to discontinue the other solution.

2.5 Preparation for Intramuscular Administration

Constitute Insipim for injection vials 0.5 gram, 1 gram and 2 grams with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol. Refer to Table 3 below for the amount of diluent to be added to each vial.

Parenteral drugs should be inspected visually for particulate matter before administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.

2.6 Compatibility and Stability

Intravenous Insipim for Injection

Intravenous Infusion Compatibility

Insipim for Injection vials are compatible at concentrations between 1 mg per mL and 40 mg per mL with the following intravenous infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection, Normosol -R, and Normosol -M in 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or 7 days in a refrigerator 2°C to 8°C (36°F to 46°F).

Admixture Compatibility

Insipim for Injection admixture compatibility information is summarized in Table 4.

Insipim for Injection Admixture Incompatibility

Do not add solutions of Insipim for injection, to solutions of ampicillin at a concentration greater than 40 mg per mL, or to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate, or aminophylline because of potential interaction. However, if concurrent therapy with Insipim for injection is indicated, each of these antibiotics can be administered separately.

Intramuscular Insipim for Injection

Insipim for injection constituted as directed is stable for 24 hours at controlled room temperature 20°C to 25°C (68°F to 77°F) or for 7 days in a refrigerator 2°C to 8°C (36°F to 46°F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride.

Intramuscular and Intravenous Insipim for Injection

As with other cephalosporins, the color of Insipim powder, as well as its solutions tend to darken depending on storage conditions; however, when stored as recommended, the product potency is not adversely affected.

3 DOSAGE FORMS AND STRENGTHS

Insipim for Injection, USP is a sterile white to pale yellow powder of Insipim in single-dose vials for reconstitution and it is available in the following strengths:

• 0.5 gram per vial
• 1 g per vial
• 2 g per vial

Insipim for injection, USP is a sterile powder of Insipim in vials for reconstitution, available in the following strengths:

• 0.5 gram per vial, 1 gram per vial and 2 grams per vial. (3)

4 CONTRAINDICATIONS

Insipim for injection is contraindicated in patients who have shown immediate hypersensitivity reactions to Insipim or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.

Patients with known immediate hypersensitivity reactions to Insipim or other cephalosporins, penicillins or other beta-lactam antibacterial drugs. (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Cross-hypersensitivity among beta-lactam antibacterial drugs may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Insipim for Injection occurs, discontinue the drug.
• Neurotoxicity: May occur especially in patients with renal impairment administered unadjusted doses. If neurotoxicity associated with Insipim for Injection therapy occurs, discontinue the drug. (5.2)
• Clostridium difficile Associated Diarrhea (CDAD): Evaluate if diarrhea occurs. (5.3)

5.1 Hypersensitivity Reactions

Before therapy with Insipim for injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to Insipim, cephalosporins, penicillins, or other beta-lactams. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Insipim for injection occurs, discontinue the drug and institute appropriate supportive measures.

5.2 Neurotoxicity

Serious adverse reactions have been reported including life-threatening or fatal occurrences of the following: encephalopathy, aphasia, myoclonus, seizures, and nonconvulsive status epilepticus [see Adverse Reactions (6.2)]. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of Insipim and/or after hemodialysis. If neurotoxicity associated with Insipim therapy occurs, discontinue Insipim and institute appropriate supportive measures.

5.3 Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Insipim, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.4 Development of Drug-Resistant Bacteria

Prescribing Insipim for injection in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

As with other antimicrobials, prolonged use of Insipim may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.

5.5 Drug/Laboratory Test Interactions

Urinary Glucose

The administration of Insipim may result in a false-positive reaction for glucose in the urine when using some methods (e.g. Clinitest tablets) [see Drug Interactions (7.1)].

Coombs' Tests

Positive direct Coombs' tests have been reported during treatment with Insipim. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy. Positive Coombs' test may be observed in newborns whose mothers have received cephalosporin antibiotics before parturition.

Prothrombin Time

Many cephalosporins, including Insipim, have been associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in the Warnings and Precautions section and below:

• Hypersensitivity Reactions [see Warnings and Precautions ]
• Neurotoxicity [see Warnings and Precautions (5.2)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.3)]

• The most common adverse reactions (incidence ≥ 1%) were local reactions, positive Coombs' test, decreased phosphorous, increased ALT and AST, increased PT and PTT and rash. (6.1)
• At the highest dose (2 g every 8 hours), incidence of adverse reactions was ≥1% for rash, diarrhea, nausea, vomiting, pruritis, fever, and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at-1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials using multiple doses of Insipim, 4137 patients were treated with the recommended dosages of Insipim (500 mg to 2 g intravenous every 12 hours). There were no deaths or permanent disabilities thought related to drug toxicity. Sixty-four (1.5%) patients discontinued medication due to adverse reactions. Thirty-three (51%) of these 64 patients who discontinued therapy did so because of rash. The percentage of cefepime-treated patients who discontinued study drug because of drug-related adverse reactions was similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8%, 1.1%, and 2%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses.

The following adverse reactions (Table 5) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients).

At the higher dose of 2 g every 8 hours, the incidence of adverse reactions was higher among the 795 patients who received this dose of Insipim. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%).

The following (Table 6) adverse laboratory changes, with Insipim, were seen during clinical trials conducted in North America.

A similar safety profile was seen in clinical trials of pediatric patients

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Insipim. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In addition to the adverse reactions reported during the North American clinical trials with Insipim, the following adverse reactions have been reported during worldwide postmarketing experience. Encephalopathy, aphasia, myoclonus, seizures, and nonconvulsive status epilepticus have been reported. [see Warnings and Precautions (5.2)]

Anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia, have been reported.

6.3 Cephalosporin-Class Adverse Reactions

In addition to the adverse reactions listed above that have been observed in patients treated with Insipim, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibacterial drugs:

Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, and pancytopenia.

7 DRUG INTERACTIONS

• Aminoglycosides: increased potential of nephrotoxicity and ototoxicity. Monitor renal function.
• Diuretics: nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide. Monitor renal function. (7.3)

7.1 Drug/Laboratory Test Interactions

The administration of Insipim may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

7.2 Aminoglycosides

Monitor renal function if aminoglycosides are to be administered with Insipim because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs.

7.3 Diuretics

Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide. Monitor renal function when Insipim is concomitantly administered with potent diuretics.

8 USE IN SPECIFIC POPULATIONS

• Geriatric Use: Serious neurologic adverse reactions have occurred in geriatric patients with renal insufficiency given unadjusted doses of Insipim.

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Insipim use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Insipim was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a body surface area basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a body surface area basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a body surface area basis).

8.2 Labor and Delivery

Insipim has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.

8.3 Nursing Mothers

Insipim is excreted in human breast milk. Caution should be exercised when Insipim is administered to a nursing woman [see Clinical Pharmacology ].

8.4 Pediatric Use

The safety and effectiveness of Insipim in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age groups 2 months up to 16 years. Use of Insipim in these age groups is supported by evidence from adequate and well-controlled studies of Insipim in adults with additional pharmacokinetic and safety data from pediatric trials [see Clinical Pharmacology (12.3)].

Safety and effectiveness in pediatric patients below the age of 2 months have not been established. There are insufficient clinical data to support the use of Insipim for injection in pediatric patients for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is H. influenzae type b. In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, an alternate agent with demonstrated clinical efficacy in this setting should be used.

8.5 Geriatric Use

Of the more than 6400 adults treated with Insipim for injection in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in non-geriatric adult patients.

Serious adverse events have occurred in geriatric patients with renal insufficiency given unadjusted doses of Insipim, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures [see Warnings and Precautions, Adverse Reactions (6.2)].

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored [see Clinical Pharmacology (12.3), Warnings and Precautions (5.2), Dosage and Administration (2.3)].

8.6 Renal Impairment

Adjust the dose of Insipim for injection in patients with creatinine clearance less than or equal to 60 mL/min to compensate for the slower rate of renal elimination. [See Dosage Adjustments in Patients with Renal Impairment (2.3)]

10 OVERDOSAGE

Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis, not peritoneal dialysis, is recommended to aid in the removal of Insipim from the body. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, neuromuscular excitability and nonconvulsive status epilepticus [see Warnings and Precautions (5.2), Adverse Reactions (6.2), Dosage and Administration (2.3)].

11 DESCRIPTION

Insipim hydrochloride, USP is a semi-synthetic, cephalosporin antibacterial for parenteral administration. The chemical name is 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride,7²-(Z)-(O-methyloxime), monohydrochloride, monohydrate, which corresponds to the following structural formula:

Insipim hydrochloride is a white to pale yellow powder. Insipim hydrochloride contains the equivalent of not less than 825 mcg and not more than 911 mcg of Insipim (C₁₉H₂₄N₆O₅S₂) per mg, calculated on an anhydrous basis. It is highly soluble in water.

Insipim for Injection, USP is supplied for intramuscular or intravenous administration in strengths equivalent to 500 mg, 1 g, and 2 g of Insipim. Insipim for injection, USP is a sterile, dry mixture of Insipim hydrochloride and L-arginine. It contains the equivalent of not less than 90 percent and not more than 115 percent of the labeled amount of Insipim (C₁₉H₂₄N₆O₅S₂). The L-arginine, at an approximate concentration of 725 mg/g of Insipim, is added to control the pH of the constituted solution at 4 to 6. Freshly constituted solutions of Insipim for Injection, USP will range in color from pale yellow to amber.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Insipim is a cephalosporin antibacterial drug [See Microbiology ].

12.2 Pharmacodynamics

Similar to other beta-lactam antimicrobial agents, the time that the unbound plasma concentration of Insipim exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamics relationship for Insipim has not been evaluated in patients.

12.3 Pharmacokinetics

Pharmacokinetic parameters for Insipim in healthy adult male volunteers following single 30-minute infusions (IV) of Insipim 500 mg, 1 g, and 2 g are summarized in Table 7. Elimination of Insipim is principally via renal excretion with an average (±SD) half-life of 2 (±0.3) hours and total body clearance of 120 (±8) mL/min in healthy volunteers. Insipim pharmacokinetics are linear over the range 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.

Pharmacokinetic parameters for Insipim following a single intramuscular injection are summarized in Table 8. The pharmacokinetics of Insipim are linear over the range of 500 mg to 2 g intramuscularly and do not vary with respect to treatment duration.

Absorption

Following intramuscular (IM) administration, Insipim is completely absorbed.

Distribution

The average steady-state volume of distribution of Insipim is 18 (±2) L. The serum protein binding of Insipim is approximately 20% and is independent of its concentration in serum.

Insipim is excreted in human milk at a concentration of 0.5 mcg/mL. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of Insipim per day [see Use in Specific Populations (8.3)].

Concentrations of Insipim achieved in specific tissues and body fluids are listed in Table 9.

Data suggest that Insipim does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.

Metabolism and Excretion

Insipim is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged Insipim accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of Insipim. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment [see Dosage and Administration (2.3)].

Specific Populations

Patients with Renal impairment

Insipim pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysis was 19 (±2) hours. Insipim total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients [see Dosage and Administration (2.3)].

Patients with Hepatic impairment

The pharmacokinetics of Insipim were unaltered in patients with hepatic impairment who received a single 1 g dose (n=11).

Geriatric patients

Insipim pharmacokinetics have been investigated in elderly (65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74 (±15) mL/min. There appeared to be a decrease in Insipim total body clearance as a function of creatinine clearance. Therefore, dosage administration of Insipim in the elderly should be adjusted as appropriate if the patient's creatinine clearance is 60 mL/min or less [see Dosage and Administration (2.3)].

Pediatric patients

Insipim pharmacokinetics have been evaluated in pediatric patients from 2 months to 11 years of age following single and multiple doses on every 8 hours (n=29) and every 12 hours (n=13) schedules. Following a single intravenous dose, total body clearance and the steady-state volume of distribution averaged 3.3 (±1) mL/min/kg and 0.3 (±0.1) L/kg, respectively. The urinary recovery of unchanged Insipim was 60.4 (±30.4)% of the administered dose, and the average renal clearance was 2 (±1.1) mL/min/kg. There were no significant effects of age or gender (25 male vs. 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seen when Insipim was given at 50 mg per kg every 12 hours (n=13), while C_max, AUC, and t_½ were increased about 15% at steady state after 50 mg per kg every 8 hours. The exposure to Insipim following a 50 mg per kg intravenous dose in a pediatric patient is comparable to that in an adult treated with a 2 g intravenous dose. The absolute bioavailability of Insipim after an intramuscular dose of 50 mg per kg was 82.3 (±15)% in eight patients.

12.4 Microbiology

Mechanism of Action

Insipim is a bactericidal drug that acts by inhibition of bacterial cell wall synthesis. Insipim has a broad spectrum of in vitro activity that encompasses a wide range of Gram-positive and Gram-negative bacteria. Within bacterial cells, the molecular targets of Insipim are the penicillin binding proteins (PBP).

Antimicrobial Activity

Insipim has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the Indications and Usage section (1).

Gram-negative Bacteria

Enterobacter spp.

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa

Gram-positive Bacteria

Staphylococcus aureus (methicillin-susceptible isolates only)

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans group streptococci

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for Insipim against isolates of similar genus or organism group. However, the efficacy of Insipim in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Staphylococcus epidermidis (methicillin-susceptible isolates only)

Staphylococcus saprophyticus

Streptococcus agalactiae

NOTE: Most isolates of enterococci, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to Insipim.

Gram-negative Bacteria

Acinetobacter calcoaceticus subsp. lwoffii

Citrobacter diversus

Citrobacter freundii

Enterobacter agglomerans

Haemophilus influenzae

Hafnia alvei

Klebsiella oxytoca

Moraxella catarrhalis

Morganella morganii

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Serratia marcescens

NOTE: Insipim is inactive against many isolates of Stenotrophomonas maltophilia.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method ^1,2 (broth and/or agar). The MIC should be interpreted according to criteria provided in Table 10.

Diffusion techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method ^2,3. This procedure uses paper discs impregnated with 30 mcg Insipim to test the susceptibility of microorganisms to Insipim. The disk diffusion interpretive criteria are provided in Table 10.

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test ^1,2,3. Standard Insipim powder should provide the following range of MIC values noted in Table 11. For the diffusion technique using the 30 mcg disc, the criteria in Table 11 should be achieved.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal carcinogenicity studies have been conducted with Insipim. In chromosomal aberration studies, Insipim was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), Insipim was negative for genotoxic effects. Moreover, in vivo assessments of Insipim in mice (2 chromosomal aberration and 2 micronucleus studies) were negative for clastogenicity. No untoward effects on fertility were observed in rats when Insipim was administered subcutaneously at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a body surface area basis).

14 CLINICAL STUDIES

14.1 Febrile Neutropenic Patients

The safety and efficacy of empiric Insipim monotherapy of febrile neutropenic patients have been assessed in two multicenter, randomized trials comparing Insipim monotherapy to ceftazidime monotherapy (at a dose of 2 g intravenously every 8 hours). These studies comprised 317 evaluable patients. Table 12 describes the characteristics of the evaluable patient population.

Table 13 describes the clinical response rates observed. For all outcome measures, Insipim was therapeutically equivalent to ceftazidime.

Insufficient data exist to support the efficacy of Insipim monotherapy in patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia). No data are available in patients with septic shock.

14.2 Complicated Intra-abdominal Infections

Patients hospitalized with complicated intra-abdominal infections participated in a randomized, double-blind, multicenter trial comparing the combination of Insipim (2 g every 12 hours) plus intravenous metronidazole (500 mg every 6 hours) versus imipenem/cilastatin (500 mg every 6 hours) for a maximum duration of 14 days of therapy. The study was designed to demonstrate equivalence of the two therapies. The primary analyses were conducted on the population consisting of those with a surgically confirmed complicated infection, at least one pathogen isolated pretreatment, at least 5 days of treatment, and a 4 to 6 week follow-up assessment for cured patients. Subjects in the imipenem/cilastatin arm had higher APACHE II scores at baseline. The treatment groups were otherwise generally comparable with regard to their pretreatment characteristics. The overall clinical cure rate among the primary analysis patients was 81% (51 cured/63 evaluable patients) in the Insipim plus metronidazole group and 66% (62/94) in the imipenem/cilastatin group. The observed differences in efficacy may have been due to a greater proportion of patients with high APACHE II scores in the imipenem/cilastatin group.

15 REFERENCES

• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-sixth Informational Supplement, CLSI document M100-S26. CLSI document M100-S26, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2016.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
• Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16:31-41.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Insipim for injection, USP is supplied as follows: Insipim for Injection, USP in the dry state, is a white to pale yellow powder. Constituted solution of Insipim for Injection, USP can range in color from pale yellow to amber.

Storage and Handling

Insipim for injection, USP in the dry state should be stored at 2° to 25° C (36° to 77° F) and protected from light.

17 PATIENT COUNSELING INFORMATION

• Counsel patients that antibacterial drugs including Insipim for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Insipim for injection is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Insipim for injection or other antibacterial drugs in the future.
• Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibiotic is discontinued. Inform patient that they may develop watery and bloody stools (with or without stomach cramps and fever) during treatment and as late as two or more months after having taken the last dose of the antibiotic. Inform patients that they should contact their physician as soon as possible if this occurs.
• Advise patients of neurological adverse events that could occur with Insipim for injection use. Instruct patients or their caregivers to inform their healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia (disturbance of speaking and understanding spoken and written language), myoclonus, seizures and nonconvulsive status epilepticus, for immediate treatment, dosage adjustment, or discontinuation of Insipim for injection.

Mfg. by: Mfg. for:

Hospira Healthcare India Pvt. Ltd. Apotex Corp.

Irungattukottai - 602 105, India Weston, FL 33326

LAB-1002-1.0

9491xxxxx

Single-Dose Vial

NDC 60505-0834-1

Insipim

for Injection, USP

1 gram*

For IV or IM Use

after constitution.

Rx Only

APOTEX CORP.

949119364

949119430

Carton NDC 60505-0834-0 60505-0834-4

Single-Dose Vial

NDC 60505-0681-1

Insipim

for Injection, USP

2 grams*

For IV Use

after constitution.

Rx Only

APOTEX CORP.

949119366

949119431

Carton NDC 60505-0681-0 60505-0681-4

Insipim pharmaceutical active ingredients containing related brand and generic drugs:

• Cefepime

Insipim available forms, composition, doses:

• Injectable; Injection; Cefepime 1 g
• Injectable; Injection; Cefepime 250 mg

Insipim destination | category:

• Human:
• Cephalosporins fourth-generation

Insipim Anatomical Therapeutic Chemical codes:

• J01DE01 - Cefepime

Insipim pharmaceutical companies:

• Hos & Ins

References

1. Dailymed."CEFEPIME INJECTION, POWDER, FOR SOLUTION [APOTEX CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."CEFEPIME HYDROCHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "cefepime". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Insipim after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Insipim not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology