BRIEF SUMMARY

DIFELIKEFALIN- (Aug 2021)

Indn-     To treat moderate to severe Pruritus associated  with certain kidney disaese in certain population   

Comp-   ­ Injection: 65 mcg /1.3 mL (50 mcg/mL) of difelikefalin.                                         • Recommended dosage is 0.5 mcg/kg.                                                                               • Administer by intravenous bolus injection into the venous line of the dialysis circuit at the end of each HD treatment.                      

ADR-   The most common adverse reactions (incidence =2% and =1% higher than placebo) were diarrhea, dizziness, nausea, gait disturbances, including falls, hyperkalemia, headache, somnolence, and mental status change.

CI-   None

WARNINGS-

 • Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances: Dizziness, somnolence, mental status changes, and gait disturbances, including falls, have occurred. Centrally-acting depressant medications, sedating antihistamines, and opioid analgesics should be used with caution during treatment 

Pat Inform-

Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances-                  Inform patients that dizziness, somnolence, mental status changes, and gait disturbances, including falls, can occur during treatment

Somnolence is more likely to happen to patients who are age 65 years or older. Inform patients that concomitant treatment with centrally-acting depressants, sedating antihistamines.

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 36

Name of the Drug-    KORSUVA

Active Ingredient -   Difellikefalin

Pharmacological Classification- To treat moderate to severe Pruritus associated                                                             with certain kidney disaese in certain population                                                                                                                                                                                                                                            

 Date of Approval-          8/23/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                           KORSUVA safely and effectively.

See full prescribing information for KORSUVA. KORSUVA™ (difelikefalin) injection, for intravenous use

Initial U.S. Approval: 2021- 

INDICATIONS AND USAGE-

­ KORSUVA is a kappa opioid receptor agonist indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD).

 Limitation of Use Korsuva has not been studied in patients on peritoneal dialysis and is not recommended for use in this population.

ADVERSE REACTIONS-

­ The most common adverse reactions (incidence =2% and =1% higher than placebo) were diarrhea, dizziness, nausea, gait disturbances, including falls, hyperkalemia, headache, somnolence, and mental status change.

CONTRAINDICATIONS-

­ None

WARNINGS AND PRECAUTIONS-

 • Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances: Dizziness, somnolence, mental status changes, and gait disturbances, including falls, have occurred. Centrally-acting depressant medications, sedating antihistamines, and opioid analgesics should be used with caution during treatment with KORSUVA.

 • Risk of Driving and Operating Machinery:                                                                     May impair mental or physical abilities. Advise patients not to drive or operate dangerous machinery until the effect of KORSUVA on a patient’s ability to drive or operate machinery is known.

DOSAGE AND ADMINISTRATION-

­ • Recommended dosage is 0.5 mcg/kg.                                                                               • Administer by intravenous bolus injection into the venous line of the dialysis circuit at the end of each HD treatment.                                                                                                        • Do not mix or dilute KORSUVA prior to administration.                                                    • Administer within 60 minutes of syringe preparation.                                                              • See full prescribing information for additional recommendations on preparation and administration of KORSUVA.

DOSAGE FORMS AND STRENGTHS-

­ Injection: 65 mcg /1.3 mL (50 mcg/mL) of difelikefalin

PATIENT COUNSELING INFORMATION-

Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances-                  Inform patients that dizziness, somnolence, mental status changes, and gait disturbances, including falls, can occur during treatment with KORSUVA 

Somnolence is more likely to happen to patients who are age 65 years or older. Inform patients that concomitant treatment with centrally-acting depressants, sedating antihistamines and opioid analgesics may increase the likelihood of these adverse reactions and these medications should be used with caution during treatment with KORSUVA 

Driving or Operating Machinery-                                                                                      Inform patients that KORSUVA may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery.

Advise patients not to drive or operate machinery until they know how they will react to KORSUVA 

Manufactured for: Cara Therapeutics, Inc. Stamford, CT 06902 Marketed by: Vifor (International) Inc., Rechenstrasse 37, 9014 St. Gallen, Switzerland KORSUVA is a trademark of Cara Therapeutics, Inc. For patent information: www.caratherapeutics.com/innovation/patents

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                              KORSUVA is a kappa opioid receptor (KOR) agonist. The relevance of KOR activation to therapeutic effectiveness is not known.

2 Pharmacodynamics-                                                                                         Difelikefalin exposure-response relationships and the time course of pharmacodynamic response are unknown.

Cardiac Electrophysiology- At a dose 6 times the recommended dosage, difelikefalin does not prolong the QTc interval to any clinically relevant extent.

3 Pharmacokinetics-                                                                                                     The pharmacokinetics of difelikefalin is dose proportional over a single dosage range from 1 to 3 mcg/kg (2 to 6 times the recommended dosage) and multiple intravenous dosage range from 0.5 to 2.5 mcg/kg (1 to 5 times the recommended dosage) in chronic kidney disease patients undergoing HD.

Steady-state was reached after the second administered dosage and the mean accumulation ratio was up to 1.6.

Distribution- The mean volume of distribution of difelikefalin is approximately 238 mL/kg. Difelikefalin binding to human plasma protein in dialysis patients is 23% to 28%.

Elimination- The half-life of difelikefalin in HD subjects prior to dialysis ranged between 23 and 31 hours. Following administration of radiolabeled difelikefalin, >99% of circulating radioactivity was present in plasma as parent.

Hemodialysis reduced the difelikefalin plasma concentrations by 70% to 80% and difelikefalin was not detectable in plasma after 2 dialysis cycles.

Metabolism- Difelikefalin is not metabolized by cytochrome P450 (CYP) enzymes CYP1A2, CYP2C19, CYP2C8, CYP2C9, CYP2D6 or CYP3A observed in human hepatic microsomes or hepatocytes, in vitro.

Excretion- Following administration of difelikefalin to HD patients, 11% of the dosage was excreted in urine, 59% in feces, and 20% in dialysate fluid.

Specific Populations-                                                                                                        No clinically significant differences in the pharmacokinetics of difelikefalin were observed based on age (25 to 80 years of age), sex, race/ethnicity, or mild-to-moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of difelikefalin is unknown 

Drug Interaction Studies-                                                                                                 Clinical Studies- No clinical studies evaluating the drug interaction potential of difelikefalin were conducted.

In Vitro Studies Cytochrome P450 (CYP) Enzymes: Difelikefalin did not inhibit CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, or CYP2D6), or induce CYP enzymes (CYP1A2, CYP2B6, or CYP3A) and is not a substrate of CYP450 enzymes (CYP1A2, CYP2C19, CYP2C8, CYP2C9, CYP2D6 or CYP3A).

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Difelikefalin is not an inhibitor of UGT1A3, UGT1A9, or UGT2B7. 

Transporter Systems: Difelikefalin did not inhibit BCRP, Pgp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or, MATE2-K human transporters and is not a substrate of OAT1, OAT2, OAT3, OATP1A2, OCT2, OCT3, LAT1, PEPT1, PEPT2, ASBT, BSEP, MRP2, OATP1B1, OATP1B3, OATP2B1, OCT1, OCTN1, OCTN2, Pgp, BCRP, OSTa/ß, MATE1, or, MATE2-K.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                       The limited human data on use of KORSUVA in pregnant women are not sufficient to evaluate a drugassociated risk for major birth defects or miscarriage.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

2. Lactation Risk Summary-                                                                                         There are no data regarding the presence of KORSUVA in human milk or effects on the breastfed infant or on milk production. Studies in rats showed difelikefalin was transferred into the milk in lactating rats.

When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KORSUVA and any potential adverse effects on the breastfed child from KORSUVA or from the underlying maternal condition.

3. Pediatric Use-                                                                                                            The safety and effectiveness of KORSUVA in pediatric patients have not been established.

4. Geriatric Use-                                                                                                                   Of the 848 subjects in the placebo-controlled studies who received KORSUVA, 278 subjects (32.8%) were 65 years of age and older and 98 subjects (11.6%) were 75 years of age and older.

No overall differences in safety or effectiveness of KORSUVA have been observed between patients 65 years of age and older and younger adult subjects, with the exception of the incidence of somnolence which was higher in KORSUVA-treatedsubbjects 5 years of age and older (7.0%) than in KORSUVA-treated subjects less than 65 years of age (2.8%), and was comparable in both placebo age groups (3.0% and 2.1%, respectively).

No differences in plasma concentrations of KORSUVA were observed between subjects 65 years of age and older and younger adult subjects

5.Hepatic Impairment-                                                                                                     The influence of mild-to-moderate hepatic impairment on the pharmacokinetics of KORSUVA was evaluated in a population pharmacokinetic analysis which concluded that no KORSUVA dosage adjustments are needed in these populations

OVERDOSAGE-

Single doses of KORSUVA up to 12 times and multiple doses of KORSUVA up to 5 times the recommended dosage of 0.5 mcg/kg were administered in clinical studies in subjects undergoing HD.

A dose-dependent increase in adverse reactions, including dizziness, somnolence, mental status changes, paresthesia, fatigue, hypertension, and vomiting, were observed. In the event of overdosage, provide the appropriate medical attention based on patient’s clinical status.

Difelikefalin is primarily eliminated by the kidneys with a low plasma protein binding of approximately 23% to 28% in dialysis patients. Hemodialysis for 4 hours using a high-flux dialyzer effectively cleared approximately 70% to 80% of difelikefalin from plasma, and difelikefalin was not detectable in plasma at the end of the second of two dialysis cycles.