Difelikefalin

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# Overview
Difelikefalin is a kappa opioid receptor agonist that is FDA approved for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in certain populations.   Common adverse reactions include dizziness, somnolence, diarrhea, hyperkalemia, nausea, gait disturbances, and mental status change.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- At the end of each HD treatment, 0.5 mcg/kg is the recommended dosage of Difelikefalin through intravenous bolus injection into the venous line of the dialysis circuit for patients.
- Patient dry body weight in kg is used to determine the injection volume.
Table 1 displays the amount of injection volume of Difelikefalin given based on the patients dry body weight.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Difelikefalin in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Difelikefalin in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Difelikefalin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Difelikefalin in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Difelikefalin in pediatric patients.

# Contraindications
There are no contraindications associated with Difelikefalin.

# Warnings
Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances
- Patients treated with Difelikefalin have experienced mental status changes, dizziness, gait disturbances, and somnolence.
- Trial studies have shown how 12% of patients receiving a placebo reported at least one of the adverse reactions mentioned above compared to 17% of patients receiving Difelikefalin.
- Patients with an age of 65 years of age and older receiving Difelikefalin were more likely to report experiencing somnolence compared to patients less than 65 years of age.
- Adverse reactions chances increases in patients who concomitant use Difelikefalin with either sedating antihistamines, centrally-acting depressant medications, and opioid analgesics.
Risk of Driving and Operating Machinery
- Physical or mental abilities may be impaired when treated with Difelikefalin which can impact a patients ability to conduct hazardous activities.
- Advise patients to not operate a vehicle when treated with Difelikefalin.

# Adverse Reactions

## Clinical Trials Experience
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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.
- Placebo controlled and uncontrolled Phase 3 clinical trials was conducted on 1306 patients treated with Difelikefalin that had moderate-to-severe pruritus who are undergoing HD.
- Trial 1 and Trial 2 are two placebo-controlled Phase 3 trials conducted on 848 subjects that tested the safety of Difelikefalin for 12 weeks when compared to a placebo. 424 patients received Difelikefalin while 424 patients received a placebo. The patient population has a mean age of 59 years, largely Caucasian (61%), and included 59% males.
- Trial 1 and 2 data showed that 0.7% of patients receiving the placebo had to discontinue treatment due to adverse reactions compared to 2.6% of patients receiving Difelikefalin that needed to discontinue their treatment. Mental status change, headache, nausea, and dizziness were the most common adverse reactions leading to discontinuation of treatment. 4.5% of patients receiving Difelikefalin reported serious adverse reactions in comparison to the 2.8% of patients part of the placebo group.
Table 2 displays the Adverse Reactions reported in the Trial 1 and 2 Studies.
Description of Selected Adverse Reactions
Gait Disturbances, including Falls
- 6.6% of patients in the Difelikefalin group reported gait disturbances compared to the 5.4% of patients in the placebo group who reported it.
- < 1% of patients in either group reported falls as a serious adverse reaction.
Dizziness
- 6.8% of patients receiving Difelikefalin reported dizziness compared to the 3.8% of patients in the placebo group that reported it.
- 0.2% of patients receiving Difelikefalin reported serious dizziness compared to the 0% of patients in the placebo group that reported it.
- 0.9% of patients discontinued use of Difelikefalin due to dizziness while 0.2% discontinued placebo use to dizziness.
Somnolence
- 4.2% of patients receiving Difelikefalin reported somnolence compared to the 2.4% of patients in the placebo group that reported it.
- 0.2% of patients receiving Difelikefalin reported serious somnolence compared to the 0% of patients in the placebo group that reported it.
- No discontinuation of either treatment occurred due to somnolence.
Mental Status Change
- 3.3% of patients receiving Difelikefalin reported mental status change compared to the 1.4% of patients in the placebo group that reported it.
- 1.4% of patients receiving Difelikefalin reported serious mental status change compared to the 0.5% of patients in the placebo group that reported it.
- 0.7% of patients discontinued use of Difelikefalin due to mental status change while 0.2% discontinued placebo use to dizziness.
Hyperkalemia
- 4.7% of patients receiving Difelikefalin reported hyperkalemia change compared to the 3.5% of patients in the placebo group that reported it.

## Postmarketing Experience
There is limited information about "Postmarketing Experiance" in the drug label.

# Drug Interactions
There is limited information regarding Difelikefalin Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Data is limited on human birth defects or miscarriage in pregnant women when treated with Difelikefalin. No adverse effects were seen on pregnant rat studies when given intravenous injection of Difelikefalin that was 711 times the maximum recommended human dose. During the period of organogenesis, fetal malformations and embryofetal lethality  were not seen in pregnant rats receiving doses of 0.25, 2.5, and 25 mg/kg/day of Difelikefalin. Decrease in food consumption, maternal body weight gain, and maternal body weigh were reported in pregnant rat prenatal and postnatal development studies when given doses greater than or equal to 2.5 mg/kg/day. Decrease in food consumption, maternal body weight gain, and maternal body weigh were not seen in pregnant rats receiving 0.6 mg/kg/day of Difelikefalin.
No adverse effects were seen on pregnant rabbits studies when given intravenous injection of Difelikefalin that was 10 times the maximum recommended human dose. 
During the period of organogenesis, fetal malformations and embryofetal lethality were not seen in pregnant rabbits receiving doses up to 0.1 mg/kg/day of Difelikefalin. Pregnant rabbits do show decreased maternal body weight gain which can be evidence for maternal toxicity
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Difelikefalin in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Difelikefalin during labor and delivery.

### Nursing Mothers
The effects on the breastfed infant, human milk and milk production caused by Difelikefalin are not present. Rat studies show that Difelikefalin was transferred through milk in nursing rats. Advise pregnant mothers taking Difelikefalin about the potential adverse effects when nursing.

### Pediatric Use
There is no FDA guidance on the use of Difelikefalin in pediatric settings.

### Geriatic Use
A placebo-controlled study was done to tested the safety and effectiveness of Difelikefalin where 278 patients who were 65 years of age or older receiving Difelikefalin while 98 patients who were 75 years of age or older also received Difelikefalin. The were no differences in the safety and effectiveness of Difelikefalin when comparing young and patients 65 years of age or older except in incidences of somnolence. 7.0% of patients 65 years of age or older reported somnolence while 2.8% of patients younger than 65 years of age reported this when treated with Difelikefalin. Plasma concentrations were no different when comparing patients 65 years of age or older to patients younger than 65 years of age.

### Gender
There is no FDA guidance on the use of Difelikefalin with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Difelikefalin with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Difelikefalin in patients with renal impairment.

### Hepatic Impairment
No dosage changes were needed in patients that had mild-to-moderate hepatic impairment when receiving Difelikefalin. Patients with severe hepatic impairment should be advised to not be treated with Difelikefalin due to the limited data contained.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Difelikefalin in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Difelikefalin in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Administration Instructions
- Difelikefalin is administered when blood is no longer circulating through the dialyzer.
- At the end of each HD Session, an intravenous bolus injection of Difelikefalin is injected into the venous line of the dialysis circuit.
- Difelikefalin can be given during or after rinse back of the dialysis circuit.
- If given after rinse back, 10 mL of normal saline flush must be given after Difelikefalin is administered.
- If given during rinse back, no saline flush is required after Difelikefalin is administered.
- Within 60 minutes of the syringe preparation, Difelikefalin dosage must be given.

### Monitoring
There is limited information regarding Difelikefalin Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Difelikefalin and IV administrations.

# Overdosage
- During overdosage, give medical attention based on the patients clinical status.
- In dialysis patients, 23% to 28% is the low plasma protein binding of Difelikefalin when eliminated through the kidney.
- 70% to 80% of Difelikefalin from plasma was cleared after 4 hours of hemodialysis using a high-flux dialyzer.
- At the end of the second of two dialysis cycles, the plasma showed no signs of Difelikefalin.

# Pharmacology

## Mechanism of Action
- Difelikefalin is a kappa opioid receptor agonist.

## Structure
- Difelikefalin is a kappa opioid receptor agonist. It has an empirical formula of C36H53N7O6 and a molecular weight of 679.4 g/mol.

## Pharmacodynamics
- For the pharmacodynamic response of Difelikefalin, time course and exposure-response relationships are not known.
Cardiac Electrophysiology
- At any clinically relevant extent, QTc interval is not prolonged due to Difelikefalin at 6 times the recommended dosage.

## Pharmacokinetics
Pharmacokinetics
- In chronic kidney disease patients undergoing HD, multiple intravenous dosage range from 0.5 to 2.5 mcg/kg and a single dosage range from 1 to 3 mcg/kg are dose proportional.
- 1.6 is the mean accumulation ratio after the second administered dosage of Difelikefalin.
- After the second administered dosage of Difelikefalin, steady state was reached.
Distribution
- 238 mL/kg is the mean volume of distribution when patients are given Difelikefalin.
- In dialysis patients, 23% to 28% is the human plasma protein binding to Difelikefalin.
Elimination
- In HD patients prior to dialysis, the half life ranges from 23 and 31 hours for Difelikefalin.
- >99% of circulating radioactivity was seen in the plasma after the administration of radiolabeled Difelikefalin.
- Plasma concentrations were of Difelikefalin were reduced 70% to 80% after hemodialysis.
- After 2 dialysis cycles, there were no signs in the plasma of Difelikefalin.
Metabolism
- In hepatocytes or human hepatic microsomes during vitro studies showed that CYP2C19, CYP3A, CYP2C8, CYP2D6, CYP1A2, and CYP2C9 did not metabolize Difelikefalin.
Excretion
- 11% of Difelikefalin was excreted in urine in HD patients after the administration of Difelikefalin.
- 59% of Difelikefalin was excreted in feces in HD patients after the administration of Difelikefalin.
- 20% of Difelikefalin was excreted in dialysate fluid in HD patients after the administration of Difelikefalin.
Specific Populations
- When looking at patients treated with Difelikefalin, sex, mild-to-moderate hepatic impairment, age, or race/ethnicity had no significant differences on the pharmacokinetics.
- Pharmacokinetics are unknown in patients with severe hepatic impairment when looking at Difelikefalin.
Drug Interaction Studies
Clinical Studies
- Difelikefalin clinical studies on drug interactions have not been conducted.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes:
- CYP enzymes were not inhibited by Difelikefalin.
- CYP enzymes are not induced by Difelikefalin.
- Difelikefalin is not a substrate of CYP450 enzymes.
Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes:
- UGT1A9, UGT1A3, or UGT2B7 is not inhibited by Difelikefalin.
Transporter Systems:
- OAT1, BCRP, Pgp, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, or, MATE2-K human transporters are not inhibited by Difelikefalin.
- Difelikefalin is not a substrate of OATP1A2, OCT2, Pgp, BCRP, OST/, OCT3, LAT1, PEPT1, PEPT2, ASBT, BSEP, MRP2, OATP1B1, OATP1B3, OATP2B1, OCT1, OCTN1, OAT1, OAT2, OAT3, OCTN2, MATE1, or, MATE2-K.

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- At doses up to 1.0 mg/kg/day given to rats part of a 2-year carcinogenicity study, Difelikefalin was not carcinogenic.
- At doses up to 30 mg/kg/day given to transgenic rasH2 mice part of a 6-month carcinogenicity study, Difelikefalin was not carcinogenic.
- In a vitro mammalian chromosomal aberration assay, Difelikefalin was negative for genotoxicity.
- In a vivo mouse micronucleus assay, Difelikefalin was negative for genotoxicity.
- In a bacterial reverse mutation assay, Difelikefalin was negative for genotoxicity.
- At doses greater than or equal to 2.5 mg/kg/day given to female rats, a decrease was seen in the number of estrous cycles per 14 days when given Difelikefalin.
- There were no effects when female rats were given Difelikefalin doses of up to 25 mg/kg/day on fertility index, any ovarian or uterine parameters, or mating index.
- Difelikefalin doses of up to 25 mg/kg/day did not impair male fertility.

# Clinical Studies
Trial 1 and 2
- Two randomized, multicenter, double-blind, placebo-controlled trials were conducted to look into the efficacy of Difelikefalin. The study included 851 patients undergoing HD who had moderate-to-severe pruritus that was older than 18 years of age. For 12 weeks, patients either received a placebo 3 times a week or 0.5 mcg per kilogram of dry body weight of Difelikefalin at the end of each hemodialysis session. A 24-hour Worst Itching Intensity Numerical Rating Scale was used to create a baseline of itch intensity.
- In trial 1, the patient population was mostly Caucasian (49%), included 61% men, and had a mean age of 57 years old. The mean baseline score of the 24-hour Worst Itching Intensity Numerical Rating Scale is 7.1.
- In trial 2, the patient population was mostly Caucasian (70%), included 58% men, and had a mean age of 60 years old. The mean baseline score of the 24-hour Worst Itching Intensity Numerical Rating Scale is 7.2.
- Efficacy of Difelikefalin in each trial was based on a 4-point or greater improvement from baseline in the weekly mean of the daily 24-hour WI-NRS score at Week 12.
Table 3 shows the Trial 1 and 2 Results testing the Efficacy of Difelikefalin.

# How Supplied
- Difelikefalin injection contains a colorless solution that is clear and sterile.
- Difelikefalin injections are glass vials that contain a single mL dose.

## Storage
- Store vials at 20C to 25C (68F to 77F) .
- Excursions of vials are permitted to 15C to 30C (59F to 86F) .
- Do not freeze Difelikefalin vials.
- Advise patients that within 60 minutes of syringe preparation, Difelikefalin must be administered into the patient.
- Discard any unused Difelikefalin that is remaining in the syringe.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances
- Advise patients about potentially experiencing somnolence, gait disturbances (including falls), dizziness, and mental status changes.
- Advise patients in the age group of 65 years of age or above are more prone to experiencing somnolence.
- Advise patients that likelihood of facing potential adverse reactions increases with concomitant use of sedating antihistamines, opioid analgesics, and centrally-acting depressants with Difelikefalin treatment.
Driving or Operating Machinery
- Advise patients that the ability to conduct hazardous activities such as operating heavy machinery or driving a vehicle may be impaired when taking Difelikefalin.
- Advise patients who are treated with Difelikefalin to not operate heavy machinery or drive a vehicle.

# Precautions with Alcohol
Alcohol-Difelikefalin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Korsuva

# Look-Alike Drug Names
There is limited information regarding Difelikefalin Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price