DRUG INTERACTIONS-(summary)

 1. Ganciclovir-                                                                                                          Generalized seizures have been reported in patients who received ganciclovir concomitantly with imipenem/cilastatin, a component of RECARBRIO.

Ganciclovir should not be used concomitantly with RECARBRIO unless the potential benefits outweigh the risks.

2. Valproic Acid-                                                                                                         Based on case reports in the literature concomitant use of carbapenems, including imipenem/cilastatin (components of RECARBRIO) with valproic acid or divalproex sodium may decrease valproic acid concentrations which may increase the risk of breakthrough seizures 

Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that  carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid.

Avoid concomitant use of RECARBRIO with valproic acid or divalproex sodium.

Consider alternative antibacterials other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium.

 ADVERSE REACTIONS

­ The most frequently reported adverse reactions occurring in greater than or equal to 2 % of patients treated with imipenem/cilastatin plus relebactam 250 mg were diarrhea, nausea, headache, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, phlebitis/infusion site reactions, pyrexia, and hypertension. 

CONTRAINDICATIONS

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

 WARNINGS AND PRECAUTIONS-

­ • Hypersensitivity Reactions: Hypersensitivity reactions have been reported in patients receiving beta lactam drugs. Discontinue RECARBRIO immediately if a hypersensitivity reaction occurs.

• 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.

 • 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.

• Clostridium difficile-Associated Diarrhea (CDAD): Has been reported with imipenem/cilastatin plus relebactam. Evaluate if diarrhea occurs.

PATIENT COUNSELING INFORMATION-

Serious Allergic Reactions -                                                                                            Advise patients, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur that require immediate treatment.

Ask them about any previous hypersensitivity reactions to RECARBRIO (imipenem, cilastatin, and relebactam), carbapenems, penicillins, cephalosporins, other beta lactams, or other allergens [see Warnings and Precautions (5.1)].

Seizures and Central Nervous System Reactions-                                                          Counsel patients, their families, or caregivers to inform a healthcare provider if they have central nervous system disorders, such as stroke or history of seizures.

Seizures have been reported during treatment with imipenem especially when recommended dosages were exceeded and with closely related antibacterial drugs 

Drug Interaction with Valproic Acid-                                                                            Counsel patients, their families, or caregivers to inform a healthcare provider if they are taking valproic acid or divalproex sodium.

If treatment with RECARBRIO is necessary, supplemental anti-convulsant medication to prevent and/or treat seizures may be needed 

Potentially Serious Diarrhea -                                                                                         Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including RECARBRIO and usually resolves when the drug is discontinued.

Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection that may require treatment.

If severe watery or bloody diarrhea develops, tell the patient to contact his or her healthcare provider 

Antibacterial Resistance-                                                                                              Patients should be counseled that antibacterial drugs, including RECARBRIO, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).

When RECARBRIO is prescribed to treat a bacterial infection, patients should be told 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 RECARBRIO or other antibacterial drugs in the future 

For patent information: www.merck.com/product/patent/home.html Copyright © 2019 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 17 Reference ID: 446292

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                               RECARBRIO is an antibacterial drug [

.2. Pharmacodynamics -

For imipenem, the % time of dosing interval that unbound plasma concentrations of imipenem exceed the imipenem/relebactam minimum inhibitory concentration (MIC) (% fT > MIC) against the infecting organism best correlates with antibacterial activity in animal and in vitro models of infection.

For relebactam the ratio of the 24-hour unbound plasma relebactam AUC to imipenem/relebactam MIC (fAUC 0 – 24 hr/MIC) best predicts the activity of relebactam in animal and in vitro models of infection.

Cardiac Electrophysiology-

At a dose 4.6 times the recommended dose, relebactam does not prolong the QTc interval to a clinically relevant extent.

3. Pharmacokinetics-                                                                                                    The steady-state pharmacokinetic parameters of imipenem, cilastatin, and relebactam in patients with active bacterial infection with CLcr 90 mL/min or greater following administration of the recommended

Distribution -                                                                                                                    The binding of imipenem and cilastatin to human plasma proteins is approximately 20 % and 40 %, respectively. The binding of relebactam to human plasma proteins is approximately 22 % and is independent of concentration at a range of 5 to 50 µM. The steady-state volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and 19.0 L, respectively, in subjects following multiple doses infused over 30 minutes every 6 hours.

Elimination-                                                                                                           Imipenem and relebactam are eliminated from the body by the kidneys with a mean (± SD) half-life of 1 (± 0.5) hour and 1.2 (± 0.7) hours, respectively.

Metabolism-                                                                                                        Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase, resulting in low levels of imipenem recovered in human urine.

Cilastatin, an inhibitor of this enzyme, effectively prevents renal metabolism so that when imipenem and cilastatin are given concomitantly, adequate concentrations of imipenem are achieved in the urine to enable antibacterial activity.

Relebactam is minimally metabolized. Unchanged relebactam was the only drug-related component detected in human plasma

. Excretion-                                                                                                                 Imipenem, cilastatin, and relebactam are mainly excreted by the kidneys.

Following multiple-dose administration of imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg to healthy male subjects, approximately 63 % of the administered imipenem dose, and 77 % of the administered cilastatin dose are recovered as unchanged parent drugs in the urine.

The renal excretion of imipenem and cilastatin involves both glomerular filtration and active tubular secretion. Greater than 90 % of the administered relebactam dose was excreted unchanged in human urine. The unbound renal clearance of relebactam is greater than the glomerular filtration rate, suggesting that in addition to glomerular filtration, active tubular secretion is involved in the renal elimination, accounting for ~ 30 % of the total clearance.

Specific Populations-                                                                                                     No clinically significant differences in the pharmacokinetics of imipenem, cilastatin, or relebactam were observed based on age, gender, or race/ethnicity.

Patients with Renal Impairment-                                                                                    In a single-dose trial evaluating the effect of renal impairment on the PK of relebactam 125 mg co-infused with imipenem/cilastatin 250 mg (half the recommended dose in patients with normal renal function), mean AUC was higher in subjects with CLcr 60-89, 30-59, and 15-29 mL/min, respectively, compared to healthy 12 Reference ID: 4462927 subjects with CLcr 90 mL/min or greater (Table 5)

. Patients with Hepatic Impairment Imipenem, cilastatin, and relebactam are primarily cleared renally; therefore, hepatic impairment is not likely to have any effect on RECARBRIO exposures.

Drug Interaction Studies-                                                                                         Clinical Studies No drug-drug interaction was observed among imipenem, cilastatin, and relebactam in a clinical study in healthy subjects. No clinically significant differences in the pharmacokinetics of imipenem or relebactam were observed when RECARBRIO was used concomitantly with probenecid (Organic Anion Transporter 3 (OAT3) inhibitor).

 USE IN SPECIFIC POPULATIONS-

1 Pregnancy Risk Summary-                                                                                   Embryonic loss was observed in monkeys treated with imipenem/cilastatin, and fetal abnormalities were observed in relebactam-treated mice; therefore, advise pregnant women of the potential risks to pregnancy and the fetus.

There are insufficient human data to establish whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with RECARBRIO, imipenem, cilastatin, or relebactam in pregnant women.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The estimated background risk of major birth defects is 2 to 4 % and miscarriage is 15 to 20 % of clinically recognized pregnancies within the U.S. general population.

 2. Lactation Risk Summary-                                                                                           There are insufficient data on the presence of imipenem/cilastatin and relebactam in human milk, and no data on the effects on the breastfed child, or the effects on milk production. Relebactam is present in the milk of lactating rats (see Data).

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RECARBRIO and any potential adverse effects on the breastfed child from RECARBRIO or from the underlying maternal condition.

Data Relebactam administered intravenously to lactating rats at a dose of 450 mg/kg/day (GD 6 to LD 14), was excreted into the milk with concentrations of approximately 5 % that of maternal plasma concentrations.

3.Pediatric Use-

 The safety and efficacy of RECARBRIO in patients younger than 18 years of age have not been established. 9 Reference ID: 4462927

4.Geriatric Use-

Of the 216 patients treated with imipenem/cilastatin plus relebactam 250 mg in Trials 1 and 2, 67 (31.0 %) were 65 years of age or older, including 25 (11.6 %) patients 75 years of age and older. RECARBRIO is known to be substantially excreted by the kidney, and the risk of adverse 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 it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [

5.Renal Impairment-                                                                                                           Reduce RECARBRIO dosage in patients with a CLcr less than 90 mL/min

OVERDOSAGE -

In the event of overdose, discontinue RECARBRIO, treat symptomatically, and institute general supportive treatment. Imipenem, cilastatin, and relebactam can be removed by hemodialysis