RECARBRIO -imipenem, cilast., relebactam

RECARBRIO (imipenem, cilastatin, and relebactam)

Usual Diluents

• 0.9 % Sodium Chloride Injection, USP
• 5 % Dextrose Injection, USP
• -----------------------------------
• 5 % Dextrose Injection, USP + 0.9 % Sodium Chloride Injection, USP
• 5 % Dextrose Injection, USP + 0.45 % Sodium Chloride Injection, USP
• 5 % Dextrose Injection, USP + 0.225 % Sodium Chloride Injection, USP

Standard Dilutions   [Amt of drug] [Infusion vol] [Infusion rate]

RECARBRIO has low aqueous solubility. To ensure complete dissolution of RECARBRIO it is important to adhere to the following instructions:

Basically, 10mL is added to the same vial twice in order to ensure all of the drug is transferred.

Step 1) For diluents available in 100 mL prefilled infusion bags, proceed to step 2. For diluents not available in 100 mL prefilled infusion bags, aseptically withdraw 100 mL of the desired diluent and transfer it to an empty infusion bag, then proceed to step 2.

Step 2) Withdraw 20 mL (as two 10 mL aliquots) of diluent from the appropriate infusion bag and constitute the vial with one 10 mL aliquot of the diluent. The constituted suspension is for intravenous infusion only after dilution in an appropriate infusion solution.

Step 3) After constitution, shake vial well and transfer resulting suspension into the remaining 80 mL of the infusion bag.

Step 4) Add the second 10 mL aliquot of infusion diluent to the vial and shake well to ensure complete transfer of vial contents; repeat transfer of the resulting suspension to the infusion solution before administering. Agitate the resulting mixture until clear.

Constituted solutions of RECARBRIO range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

Storage of Constituted Solution

RECARBRIO, as supplied in single-dose glass vials upon constitution with the appropriate diluent and following further dilution in the infusion bag, maintains satisfactory potency for at least 2 hours at room temperature (up to 30 °C) or for at least 24 hours under refrigeration at 2 °C to 8 °C (36 °F to 46 °F). Do not freeze solutions of RECARBRIO.

See complete dosing info.
DOSAGE AND ADMINISTRATION

WARNINGS 

DESCRIPTION 

RECARBRIO (imipenem, cilastatin, and relebactam) for injection is an antibacterial combination product consisting of imipenem, a carbapenem antibacterial drug, cilastatin, a renal dehydropeptidase inhibitor, and relebactam, a diazabicyclooctane beta lactamase inhibitor, for intravenous administration.

Imipenem
Imipenem is a beta lactam antibacterial drug. Imipenem (N-formimidoylthienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya. The 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, sparingly soluble in water. The empirical formula is C12H17N3O4S.H2O and the molecular weight is 317.37.

Cilastatin
Cilastatin sodium is the sodium salt of a derivatized heptenoic acid. The chemical name is sodium (Z)-7- [[(R)-2-amino-2-carboxyethyl]thio]-2-[(S)-2,2-dimethylcyclopropanecarboxamido]-2-heptenoate. It is an off-white to white, hygroscopic, amorphous compound, very soluble in water. The empirical formula is C16H25N2NaO5S and the molecular weight is 380.44.

Relebactam
Relebactam is a beta lactamase inhibitor. It is a crystalline monohydrate. The chemical name is (1R,2S,5R)-7-oxo-2-(piperidin-1-ium-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate hydrate. It is a white to off-white powder, soluble in water. The empirical formula is C12H20N4O6S.H2O and the molecular weight is 366.39.

RECARBRIO is supplied as a white to light yellow sterile powder for constitution in a single-dose vial containing 500 mg imipenem (equivalent to 530 mg imipenem monohydrate), 500 mg cilastatin (equivalent to 531 mg cilastatin sodium), and 250 mg relebactam (equivalent to 263 mg relebactam monohydrate). Each vial of RECARBRIO is buffered with 20 mg sodium bicarbonate to provide solutions in the pH range of 6.5 to 7.6. The total sodium content of the mixture in the vial is 37.5 mg (1.6 mEq). Solutions of RECARBRIO range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

CLINICAL PHARMACOLOGY:

RECARBRIO is a combination of imipenem/cilastatin and relebactam. Imipenem is a penem antibacterial drug, cilastatin sodium is a renal dehydropeptidase inhibitor, and relebactam is a beta lactamase inhibitor. Cilastatin limits the renal metabolism of imipenem and does not have antibacterial activity. The bactericidal activity of imipenem results from binding to PBP 2 and PBP 1B in Enterobacteriaceae and Pseudomonas aeruginosa and the subsequent inhibition of penicillin binding proteins (PBPs). Inhibition of PBPs leads to the disruption of bacterial cell wall synthesis. Imipenem is stable in the presence of some beta lactamases. Relebactam has no intrinsic antibacterial activity. Relebactam protects imipenem from degradation by certain serine beta lactamases such as Sulhydryl Variable (SHV), Temoneira (TEM), Cefotaximase-Munich (CTX-M), Enterobacter cloacae P99 (P99), Pseudomonas-derived cephalosporinase (PDC), and Klebsiella-pneumoniae carbapenemase (KPC).

INDICATIONS AND USAGE 

Complicated urinary tract infections, including pyelonephritis (cUTI) (1.1)

Complicated intra-abdominal infections (cIAI) (1.2)

Approval of these indications is based on limited clinical safety and efficacy data for RECARBRIO. (1.1, 1.2, 14) To reduce the development of drug-resistant bacteria and maintain the effectiveness of RECARBRIO and other antibacterial drugs, RECARBRIO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.3)

CONTRAINDICATIONS

RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity to any component of RECARBRIO.

PRECAUTIONS

• Hypersensitivity Reactions: Hypersensitivity reactions have been reported in patients receiving beta lactam drugs. Discontinue RECARBRIO immediately if a hypersensitivity reaction occurs. (5.1)
• Seizures and Central Nervous System Adverse Reactions: CNS adverse reactions such as seizures have been reported with imipenem/cilastatin, a component of RECARBRIO. If focal tremors, myoclonus, or seizures occur, evaluate patients, to determine whether RECARBRIO should be discontinued. (5.2)
• Increased Seizure Potential Due to Interaction with Valproic Acid: Concomitant use of RECARBRIO with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid which may increase the risk of breakthrough seizures. Avoid concomitant use or consider alternative antibacterial drugs other than carbapenems. (5.3, 7.2)
• Clostridium difficile-Associated Diarrhea (CDAD): Has been reported with imipenem/cilastatin plus relebactam. Evaluate if diarrhea occurs. (5.4)

ADVERSE REACTIONS

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide. Drug information (pdf)

DOSAGE AND ADMINISTRATION 

Administer RECARBRIO 1.25 grams (imipenem 500 mg, cilastatin 500 mg, relebactam 250 mg) by intravenous (IV) infusion over 30 minutes every 6 hours in patients 18 years of age and older with creatinine clearance (CLcr) 90 mL/min or greater. (2.1)

Dosage adjustment in patients with renal impairment. (2.2)

Recommended Dose of RECARBRIO (imipenem/cilastatin/relebactam) (mg) administered by IV infusion over 30 minutes every 6 hours

Estimated Creatinine
Clearance (mL/min)*

60 to 89 mL/min: 1 gram (imipenem 400 mg, cilastatin 400 mg, and relebactam 200 mg)
---------
30 to 59 mL/min: 0.75 grams (imipenem 300 mg, cilastatin 300 mg, and relebactam 150 mg)
---------
15 to 29 mL/min: 0.5 grams (imipenem 200 mg, cilastatin 200 mg, and relebactam 100 mg)
---------
End Stage Renal Disease on Hemodialysis: 0.5 grams (imipenem 200 mg,cilastatin 200 mg, and relebactam 100 mg)

*CLcr calculated using the Cockroft-Gault formula.

Patients with CLcr less than 15 mL/min should not receive RECARBRIO unless hemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of RECARBRIO for patients undergoing peritoneal dialysis. Imipenem, cilastatin, and relebactam are cleared from the circulation during hemodialysis. For patients maintained on hemodialysis, administer RECARBRIO after hemodialysis and at intervals timed from the end of that hemodialysis session.

2.3 Preparation of RECARBRIO Solution for Intravenous Administration
RECARBRIO is supplied as a dry powder in a single-dose vial that must be constituted and further diluted using aseptic technique prior to intravenous infusion. To prepare the infusion solution, contents of the vial must be constituted with the appropriate diluent as instructed below. A list of appropriate diluents is as follows:

• 0.9 % Sodium Chloride Injection, USP
• 5 % Dextrose Injection, USP
• 5 % Dextrose Injection, USP + 0.9 % Sodium Chloride Injection, USP
• 5 % Dextrose Injection, USP + 0.45 % Sodium Chloride Injection, USP
• 5 % Dextrose Injection, USP + 0.225 % Sodium Chloride Injection, USP

RECARBRIO has low aqueous solubility. To ensure complete dissolution of RECARBRIO it is important to adhere to the following instructions:

Step 1) For diluents available in 100 mL prefilled infusion bags, proceed to step 2. For diluents not available in 100 mL prefilled infusion bags, aseptically withdraw 100 mL of the desired diluent and transfer it to an empty infusion bag, then proceed to step 2.

Step 2) Withdraw 20 mL (as two 10 mL aliquots) of diluent from the appropriate infusion bag and constitute the vial with one 10 mL aliquot of the diluent. The constituted suspension is for intravenous infusion only after dilution in an appropriate infusion solution.

Step 3) After constitution, shake vial well and transfer resulting suspension into the remaining 80 mL of the infusion bag.

Step 4) Add the second 10 mL aliquot of infusion diluent to the vial and shake well to ensure complete transfer of vial contents; repeat transfer of the resulting suspension to the infusion solution before administering. Agitate the resulting mixture until clear.

Constituted solutions of RECARBRIO range from colorless to yellow. Variations of color within this range do not affect the potency of the product.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if discoloration or visible particles are observed.

The above instructions for preparation of RECARBRIO solution for intravenous administration must be followed for all patients, irrespective of the intended patient’s renal function. The volume of this prepared RECARBRIO solution to be administered to patients is determined based on renal function [see Dosage and Administration (2.4)].

2.4 Preparation of RECARBRIO Solution for Intravenous Administration in Patients with Renal Impairment

For patients with renal impairment, prepare a reduced dose of RECARBRIO (1 gram, 0.75 grams, or 0.5 grams) [see Dosage and Administration (2.2)] by preparing a 100 mL solution containing 1.25 grams (as described above in Section 2.3) then withdrawing and discarding the excess according to Table 2.

Table 2: Preparation of Reduced RECARBRIO Doses for Intravenous Administration in Patients with Renal Impairment:

Creatinine Clearance (mL/min): 60 to 89 mL/min
Dosage of RECARBRIO: 1 gram (imipenem 400 mg, cilastatin 400 mg, and relebactam 200 mg)       After preparation as instructed above, remove from the 100 mL prepared bag the volume indicated below and discard:  20 mL.    Resulting volume that provides the indicated reduced dose:  80mL.
----------------
Creatinine Clearance (mL/min): 30 to 59 mL/min
Dosage of RECARBRIO: 0.75 grams (imipenem 300 mg, cilastatin 300 mg, and relebactam 150 mg).     After preparation as instructed above, remove from the 100 mL prepared bag the volume indicated below and discard:  40 mL.    Resulting volume that provides the indicated reduced dose:  60mL.
----------------
Creatinine Clearance (mL/min): 15 to 29 or ESRD on hemodialysis.
Dosage of RECARBRIO: 0.5 grams (imipenem 200 mg, cilastatin 200 mg, and relebactam 100 mg).     After preparation as instructed above, remove from the 100 mL prepared bag the volume indicated below and discard:  60 mL.    Resulting volume that provides the indicated reduced dose:  40mL.

2.5 Storage of Constituted Solution

RECARBRIO, as supplied in single-dose glass vials upon constitution with the appropriate diluent and following further dilution in the infusion bag, maintains satisfactory potency for at least 2 hours at room temperature (up to 30 °C) or for at least 24 hours under refrigeration at 2 °C to 8 °C (36 °F to 46 °F). Do not freeze solutions of RECARBRIO.

2.6 Incompatible Injectable Drug Products

RECARBRIO for injection for intravenous infusion is physically incompatible with propofol in 5 % Dextrose USP or 0.9 % Sodium Chloride USP.

HOW SUPPLIED 

RECARBRIO 1.25 grams for injection is supplied as sterile powder for constitution in a single-dose vial containing imipenem 500 mg (anhydrate equivalent), cilastatin 500 mg (free acid equivalent), and relebactam 250 mg (anhydrate equivalent)

Storage and Stability

The vials are supplied as a single-dose glass vial (NDC 0006-3856-01) and in cartons containing 25 vials (NDC 0006-3856-02).

Store RECARBRIO vials at 20 °C to 25 °C (68°F to 77°F), excursions permitted between 15 °C to 30 °C (between 59 °F to 86 °F) [See USP Controlled Room Temperature]. Keep vials in the carton.