DIFELIKEFALIN: 363 Adverse Event Reports & Safety Profile

KORSUVA (difelikefalin) is a kappa opioid receptor agonist. Difelikefalin is a synthetic peptide with a single stereoisomer and is present as an acetate salt. Difelikefalin acetate is a white to off-white powder with a molecular formula of C 36 H 53 N 7 O 6 ∙xAcOH (1.0≤ × ≤2.0) and a molecular weight of 679.4 g/mol (mono- isotopic; free base). It is soluble in water. The chemical name of difelikefalin acetate is 4-amino-1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidine-4-carboxylic acid, acetate salt. The chemical structure is: KORSUVA (difelikefalin) injection is supplied in a single-dose vial containing 65 mcg/1.3 mL (50 mcg/mL) of difelikefalin as a sterile, preservative-free, clear and colorless solution for intravenous injection. KORSUVA is formulated as an isotonic 40 mM acetate buffer solution with an osmolality of 250 to 350 mOsm and a pH of 4.5. Each milliliter of KORSUVA injection contains 50 mcg of difelikefalin (equivalent to an average of 58.3 mcg of difelikefalin acetate), 1.3 mg of acetic acid, 2.5 mg of sodium acetate trihydrate, 7.2 mg of sodium chloride (to adjust tonicity), and water for injection.

Chemical

Structure

AND USAGE KORSUVA is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD). 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). ( 1 ) Limitation of Use Korsuva has not been studied in patients on peritoneal dialysis and is not recommended for use in this population. ( 1 ) Limitations of Use KORSUVA has not been studied in patients on peritoneal dialysis and is not recommended for use in this population.

AND ADMINISTRATION Recommended dosage is 0.5 mcg/kg. ( 2.1 ) Administer by intravenous bolus injection into the venous line of the dialysis circuit at the end of each HD treatment. ( 2.1 ) Do not mix or dilute KORSUVA prior to administration. ( 2.2 ) Administer within 4 hours of syringe preparation. ( 2.3 ) See full prescribing information for additional recommendations on preparation and administration of KORSUVA. ( 2.2 , 2.3 )

2.1 Dosage The recommended dosage of KORSUVA is 0.5 mcg/kg administered by intravenous bolus injection into the venous line of the dialysis circuit at the end of each HD treatment <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . If a regularly scheduled HD treatment is missed, resume KORSUVA at the end of the next HD treatment.

2.2 Preparation Instructions Do not mix or dilute KORSUVA prior to administration. Inspect KORSUVA for particulate matter and discoloration prior to administration. The solution should be clear and colorless. Do not use KORSUVA vials if particulate matter or discoloration is observed. KORSUVA is supplied in a single-dose vial. Discard any unused product. Injection volume to be administered is determined by patient&apos;s target dry body weight in kilograms (one patient may use less than the full contents of the vial or use more than one vial).

See Table

1 .

Table

1.

Korsuva

Injection Volumes Based on Target Dry Body Weight Target Dry Body Weight Range (kg)

Injection

Volume (mL)

Total Injection

Volume (mL) = Patient Target Dry Body Weight (kg) x 0.01, rounded to the nearest tenth (0.1 mL). For patient target dry body weight outside of the ranges in Table 1, use this formula. 36 – 44 0.4 45 – 54 0.5 55 – 64 0.6 65 – 74 0.7 75 – 84 0.8 85 – 94 0.9 95 – 104 1 105 – 114 1.1 115 – 124 1.2 125 – 134 1.3 135 – 144 1.4 145 – 154 1.5 155 – 164 1.6 165 – 174 1.7 175 – 184 1.8 185 – 194 1.9 195 – 204 2

2.3 Administration Instructions KORSUVA is removed by the dialyzer membrane and must be administered after blood is no longer circulating through the dialyzer. Administer KORSUVA by intravenous bolus injection into the venous line of the dialysis circuit at the end of each HD session. The dose may be given either during or after rinse back of the dialysis circuit. If the dose is given after rinse back, administer KORSUVA into the venous line followed by at least 10 mL of normal saline flush. If the dose is given during rinse back, no additional normal saline is needed to flush the line. The dose must be administered within 4 hours of the syringe preparation. Discard any unused product.

None None

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances [see Warnings and Precautions (5.1) ] 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. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Vifor (International) Inc. at 1-844-835-8277 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 the 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. A total of 1306 subjects undergoing HD who had moderate-to-severe pruritus were treated with KORSUVA in placebo-controlled and uncontrolled Phase 3 clinical trials. Of these, 711 were treated for at least 6 months and 400 were treated for at least one year. Two placebo-controlled Phase 3 trials (Trial 1 and Trial 2), in subjects undergoing HD who had moderate-to-severe pruritus were pooled to evaluate the safety of KORSUVA in comparison to placebo up to 12 weeks. In total, 848 subjects were evaluated (424 in KORSUVA group and 424 in placebo group). The mean age of the subjects was 59 years (range 22 to 88 years), and 59% of the subjects were male. Of the total subjects, 61% were White, 29% were Black or African American, and 5% were Asian.

Table

2 summarizes the adverse reactions that occurred at a rate of ≥2% in the KORSUVA group and ≥1% higher than that of the placebo group during the 12-week placebo-controlled period of Trials 1 and 2. The percentage of subjects who discontinued treatment due to any adverse reaction was 2.6% for subjects taking KORSUVA and 0.7% for subjects taking placebo. The most common adverse reactions (≥0.5% of subjects) leading to discontinuation were dizziness (0.9% for KORSUVA and 0.2% for placebo), mental status change (0.7% and 0.2%, respectively), nausea (0.5% and 0%, respectively), and headache (0.5% and 0%, respectively). The percentage of subjects who developed serious adverse reactions was 4.5% in the KORSUVA group and 2.8% in the placebo group.

Table

2: Adverse Reactions in ≥ 2% of KORSUVA-Treated Subjects with Moderate-to-Severe CKD-aP Undergoing HD and ≥ 1% Higher Than Placebo in Trials 1 and 2 Adverse Reactions Placebo (N=424) n (%) KORSUVA (N=424) n (%)

Diarrhea

24 (5.7) 38 (9.0)

Dizziness

16 (3.8) 29 (6.8)

Nausea

19 (4.5) 28 (6.6)

Gait Disturbances

Gait disturbances includes: preferred terms of falls and gait disturbances 23 (5.4) 28 (6.6)

Hyperkalemia

15 (3.5) 20 (4.7)

Headache

11 (2.6) 19 (4.5)

Somnolence

10 (2.4) 18 (4.2)

Mental Status Change Mental Status

Change includes: preferred terms of confusional state and mental status change. 6 (1.4) 14 (3.3) Description of Selected Adverse Reactions Gait Disturbances, including Falls Gait disturbances, including falls, were reported in 6.6% of subjects receiving KORSUVA compared to 5.4% of subjects who received placebo. Falls were reported as serious adverse reactions in < 1% of subjects receiving KORSUVA and placebo, with one subject discontinuing KORSUVA due to gait disturbance.

Dizziness

Dizziness was reported in 6.8% of subjects randomized to KORSUVA compared to 3.8% of subjects who received placebo. Dizziness occurred within the first 3 weeks of treatment and was generally transient. Dizziness was serious in 0.2% of KORSUVA-treated subjects compared to 0% of subjects who received placebo and led to discontinuation in 0.9% of KORSUVA-treated subjects compared to 0.2% of subjects who received placebo.

Somnolence

Somnolence was reported in 4.2% of subjects randomized to receive KORSUVA compared to 2.4% of subjects who received placebo. Somnolence occurred within the first 3 weeks of treatment and tended to subside with continued dosing. Somnolence was serious in 0.2% of KORSUVA-treated subjects compared to 0% of subjects who received placebo. There were no subjects who discontinued KORSUVA due to an adverse reaction of somnolence.

Mental Status Change

Mental status change (including confusional state) was reported in 3.3% of subjects randomized to receive KORSUVA compared to 1.4% of subjects who received placebo. Most events tended to subside with continued dosing. Mental status change adverse reactions were serious in 1.4% of KORSUVA-treated subjects compared to 0.5% of subjects who received placebo and led to discontinuation in 0.7% of KORSUVA-treated subjects compared to 0.2% of subjects who received placebo.

Hyperkalemia

Hyperkalemia was found in 4.7% of subjects who received KORSUVA compared to 3.5% of subjects who received placebo. The incidence of hyperkalemia was higher in subjects who took concomitant opioids regardless of treatment and was almost doubled in the KORSUVA group (11.7%) compared to the placebo group (6.2%). The clinical relevance of this is unknown.

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. ( 5.1 ) 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. ( 5.2 )

5.1 Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances Dizziness, somnolence, mental status changes, and gait disturbances, including falls, have occurred in patients taking KORSUVA and may subside over time with continued treatment <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

In Trial

1 and Trial 2, 17.0% of patients randomized to receive KORSUVA reported at least one of these adverse reactions, compared to 12.0% of patients who received placebo. The incidence of somnolence was higher in KORSUVA-treated subjects 65 years of age and older (7.0%) than in KORSUVA-treated subjects less than 65 years of age (2.8%). Concomitant use of centrally-acting depressant medications, sedating antihistamines and opioid analgesics may increase the likelihood of these adverse reactions and should be used with caution during treatment with KORSUVA.

5.2 Risk of Driving and Operating Machinery Dizziness, somnolence, and mental status changes have occurred in patients taking KORSUVA. KORSUVA may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car and operating machinery. Advise patients not to drive or operate dangerous machinery until the effect of KORSUVA on a patient&apos;s ability to drive or operate machinery is known .