Kathryn Wheeler, PharmD, BCPS, is assistant clinical professor of pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn.

Kathryn Wheeler, PharmD, BCPS

In August 2021, the FDA approved difelikefalin (Korsuva) for the treatment of moderate to severe pruritis associated with chronic kidney disease (CKD) in adults undergoing hemodialysis.

 Uremic pruritis is a common problem for patients with CKD, with limited treatment options. Korsuva is the first FDA-approved treatment for this indication. Difelikefalin is a κ-opioid agonist; the exact mechanism of therapeutic effect is unknown.

Two randomized, placebo-controlled trials (KALM-1, NCT03422653; KALM-2, NCT03636269) demonstrated difelikefalin efficacy in adults with moderate to severe pruritis undergoing hemodialysis (n = 851). Participants received intravenous (IV) injections of either placebo or difelikefalin 0.5 mg/kg of dry body weight at the end of each hemodialysis session 3 times weekly for 12 weeks. Those using medications to treat itch prior to the study were allowed to continue treatment with these medications during the trials.

Prior to randomization, participants kept daily records for 7 days to establish the baseline presence and itch intensity. Mean baseline scores were 7.1 and 7.2 in KALM-1 and KALM-2, respectively. Baseline scores were compared with itch intensity scores assessed at week 12 of therapy. Primary end point was the proportion of patients who achieved a 4-point reduction in itch score at week 12.

In KALM-1, 40% of participants vs 21% in the placebo group met the primary end point (a 19% between-group difference; 95% CI, 9%-28%). In KALM-2, 37% of participants (vs 26% placebo) met the end point for a 12% between-group difference (95% CI, 3%-20%).

Major adverse events (AEs) across both trials included diarrhea (9%), dizziness (6.8%), nausea (6.6%), gait disturbances inclusive of falls (6.6%), hyperkalemia (4.7%), headache (4.5%), somnolence (4.2%), and mental status changes inclusive of confusional state (3.3%). These AEs occurred at higher rates in the difelikefalin group vs placebo.

In the treatment group, dizziness and somnolence were generally transient and occurred within the first 3 weeks of therapy. Somnolence was more common in older adults (age 65 and older; 7.0% vs 2.8%, respectively).

Some patients in the treatment group discontinued therapy due to gait disturbances, dizziness, and mental status changes. Concomitant administration of opioids, antihistamines, or centrally acting depressant drugs may increase AEs. Difelikefalin is not recommended for use in patients undergoing peritoneal dialysis or in patients with severe hepatic impairment.

Korsuva is supplied as a clear colorless solution in a single-dose vial; vials should be stored at room temperature. Recommended dose is 0.5 μg/kg of dry body weight/dose. Bolus injection must be administered within 60 minutes of syringe preparation, administered by IV injection into the venous line of the dialysis circuit at the conclusion of each hemodialysis treatment. Administration of the medication during a dialysis session will result in the removal of the drug by the dialyzer membrane. Any unused medication remaining in the vial after a dose has been prepared should be discarded.

Kathryn Wheeler, PharmD, BCPS, is the associate dean of academic affairs and an associate clinical professor of pharmacy practice in the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy

Korsuva. Prescribing information. Vifor Pharma, Cara Therapeutics; 2022. Accessed March 10, 2022. 

www.accessdata.fda.gov/drugsatfda_docs/label/2021/214916s000lbl.pdf

Articles

Korsuva is approved for treating moderate to severe pruritis associated with chronickidneydisease

FDA Approves Treatment for Uremic Pruritis

Ibrexafungerp is a triterpenoid antifungal that works by inhibiting the formation of the fungal cell wall. Ibrexafungerp (pronounced eye-BREX-ah-FUN- jerp) is the first approved drug of a novel class of antifungals.

Two randomized placebo-controlled positive for 

. Participants clinical trials evaluated the safety and received two 150-mg tablets (300-mg dose) efficacy of ibrexafungerp. Participants were of ibrexafungerp or placebo 12 hours apart postmenarche, nonpregnant females with VVC. In trials, a diagnosis of VVC is defined as a minimum composite vulvovaginal signs and symptoms (VSS) score greater than or equal to 4 and a minimum of 2 moderate signs or symptoms (score of 2 or greater), positive microscopic examination in a sample demonstrating yeast, and a normal vaginal pH. Signs and symptoms were scored along a scale: 0 (absent) to 3 (severe). Median VSS scores at baseline in trials 1 and 2 were 9 and 10, respectively, at baseline; range, 4 to 18. In both trials, the majority of cultures were in a single day, a total daily dose of 600 mg. Participants were reassessed at a test-of-cure (TOC) visit between days 8 to 14 and a follow-up visit between days 21 to 29. Participants with a positive culture for 

who had at least 1 dose of the study drug were included in a modified intention to treat analysis. Compared with placebo, a greater percentage of participants on ibrexafungerp demonstrated negative cultures at the TOC visit (

< .001) and VSS scores of 0 (ie, complete clinical response) at the TOC (

In trials, a total of 545 participants were exposed to a dose of ibrexafungerp. The most common adverse effects (AEs) noted in participants administered ibrexafungerp are diarrhea (16.7%), nausea (11.9%), abdominal pain (11.4%), dizziness (3.3%), and vomiting (2.0%). For comparison, the most common AE noted in participants administered placebo in trials is abdominal pain (5.1%). Ibrexafungerp is metabolized by cytochrome P450 (CYP3A). Concomitant administration of strong inhibitors or moderate to strong inducers of CYP3A may alter the patient’s exposure to ibrexafungerp. A reduced dose of ibrexafungerp, 150 mg (1 tablet), should be given when concomitantly administered with strong CYP3A inhibitors. Ibrexafungerp is potentially teratogenic. The use of ibrexafungerp is contraindicated in pregnant women. A patient’s pregnancy status should be confirmed prior to use. The manufacturer recommends the use of contraception for 4 days after the last dose of ibrexafungerp for all women of reproductive potential. If a woman is pregnant or pregnancy is detected within 4 days after the last dose of ibrexafungerp, patients should report the pregnancy to the manufacturer to include in an ongoing safety analysis by calling 1-888- 982-7299.

The recommended dosage of ibrexafungerp for treatment of VVC is 300 mg. This dose is provided as two 150-mg tablets. To complete a full course of therapy, patients should take two 150-mg tablets for the first dose and two 150-mg tablets 12 hours later. This medication may be taken with or without food.

1. Brexafemme. Prescribing Information. Scynexis, Inc; 2021. Accessed June 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214900s000lbl.pdf

On June 2,2021, ibrexafungerp (Brexafemme; Scynexis, Inc) was approved by the FDA for vulvovaginal candidiasis (VVC) in adult women and girls who have begun menstruating.




Novel Antifungal Treatment Approved for Vaginal Candidiasis    

On April 2, 2021, the FDA approved viloxazine (Qelbree; Supernus Pharmaceuticals, Inc) for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children aged 6 to 17 years. Viloxazine is a selective norepinephrine reuptake inhibitor and is the first new nonstimulant medication for treatment of ADHD in children in more than 10 years. 

The FDA evaluated the safety of viloxazine in 3 randomized, placebo-controlled trials. Studies 1 and 2 included participants aged 6 to 11 years and lasted either 6 or 8 weeks that included a titration period to achieve maintenance dosing of 100 mg, 200mg, or placebo daily (study 1) and 200mg, 400mg, or placebo daily (study 2). Participants aged 12 to 17 years were titrated to either 200 mg or 400 mg or placebo in study 3. The primary end point in each study is a change in total score on the ADHD Rating Scale (AHD-RS-5), comparing baseline to the end of the maintenance period assessments. The change in Clinical Global Impression-Improvement (CGI-I) score from baseline served as a secondary end point in each study. In all 3 studies, patients administered viloxazine demonstrated statistically significant improvements in ADHD rating scale scores and in CGI-I scores compared with participants administered placebo. 

In trials, 826 participants were exposed to a dose of viloxazine that ranged from 100 mg to 400 mg. In this group, the most common adverse effects (AEs) included nausea, vomiting, insomnia, irritability, decreased appetite, and somnolence. The most common AEs leading to discontinuation of the medication included somnolence, nausea, fatigue, decreased appetite, headache, tachycardia, and irritability. Viloxazine carries a boxed warning regarding higher rates of suicidal thoughts and behaviors among participants administered viloxazine in clinical trials compared with participants administered placebo. Patients treated with viloxazine should be monitored for suicidal ideation or behaviors, particularly when initiating or increasing therapy. Patients experiencing these symptoms may require a discontinuation of viloxazine therapy. Viloxazine may activate mania in patients at risk for bipolar disorder. Patients should be screened prior to initiating therapy for a history of suicide, depression, or bipolar disorder. 

Viloxazine may also cause an increase in blood pressure and heart rate. A patient’s blood pressure and heart rate should be assessed at baseline when initiating therapy and periodically throughout treatment. Somnolence and fatigue associated with viloxazine administration may affect a patient’s mental alertness. Until a patient knows how viloxazine will affect them, they should avoid operating machinery or driving. Concomitant administration of viloxazine with monoamine oxidase inhibitors is contraindicated due to an increased risk of hypertensive crisis. Viloxazine strongly inhibits cytochrome P450 1A2 (CYP1A2) and will increase exposure to concomitant CYP1A4 substrates and increase the risk of AEs to those medications. In addition, viloxazine weakly inhibits CYP2D6 and CYP3A4. Patients should be monitored for AEs associated with any additional medications they take that may be impacted by this interaction.

In patients aged 6 to 11 years, the recommended starting dosage of viloxazine is 100 mg once daily and may be titrated in 100-mg increments weekly to a maximum dosage of 400 mg once daily. The recommended starting dosage for patients aged 12 to 17 years is 200 mg once daily. In this age group, the dosage may be titrated up in 1 week to the maximum recommended dosage of 400 mg once daily. Capsules may be swallowed whole with or without food or may be opened and contents sprinkled on applesauce. The capsule or applesauce with sprinkled medication must not be chewed. Medication mixed with applesauce must be used within 2 hours of mixing and cannot be stored for later use.

Qelbree. Prescribing information. Supernus Pharmaceuticals Inc; 2021. Accessed May 11, 2021. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/211964s000lbl.pdf

Viloxazine is a selective norepinephrine reuptake inhibitor and is the first new nonstimulant medication for treatment of ADHD in children in more than 10 years.  

New Nonstimulant Medication Is Approved for ADHD in Children

On January 22, 2021, the FDA approved voclosporin (Lupkynis; Aurinia Pharmaceuticals) for the treatment of adult patients with active lupus nephritis (LN) in combination with a background immunosuppressive therapy regimen. Voclosporin is an oral calcineurin inhibitor immunosuppressant. Its activity results in inhibition of lymphocyte proliferation, production of T-cell cytokines, and expression of T-cell activation surface antigens. This is the first FDA-approved oral therapy for LN, a condition that can cause irreversible kidney damage and increase risk of kidney failure, cardiac events, and death.

The results of a 52-week randomized, double-blind, placebo-controlled trial (NCT03021499) demonstrate the efficacy of voclosporin in participants with a diagnosis of systemic lupus erythematosus and class III or IV LN (alone or in combination with class V LN) or class V LN. Renal biopsy was performed to classify LN based on the International Society of Nephrology/Renal Pathology Society’s standards. A total of 357 participants were randomized to receive either voclosporin 23.7 mg twice daily (n = 179) or placebo (n = 178). All participants received background immunosuppressant therapy (ie, oral mycophenolate mofetil [MMF] targeted to a dose of 1 gram twice daily and corticosteroid therapy adjusted to achieve a dose of 2.5 mg/d by week 16 of the study). The primary efficacy end point of the study is the proportion of patients achieving complete renal response at week 52; urine protein/creatinine ratio (UPCR) of less than or equal to 0.5 mg/mg and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of greater than 20% or no treatment- or disease-related eGFR-associated event (ie, decrease in renal creatinine clearance or glomerular filtration rate, or increase in blood creatinine, serum creatinine, renal impairment, renal failure, or acute renal failure) at time of assessment. At week 52, a higher proportion of participants achieved complete renal response in the voclosporin arm than the placebo arm (40.8% vs 22.5%; OR, 2.7; 95% CI, 1.6-4.3; 

 < .001). Moreover, administration of voclosporin compared with placebo is associated with a reduction in the time to UPCR of less than or equal to 0.5 mg/mg (median time of 169 days vs 372 days; HR, 2.0; 95% CI, 1.5-2.7). Overall, a greater proportion of participants who received voclosporin for 1 year in addition to background therapy achieved a reduction in kidney inflammation in comparison with those who received background therapy alone.

Prior to initiating therapy with voclosporin, obtain a baseline eGFR and blood pressure. Monitor renal function and blood pressure regularly throughout treatment with voclosporin. The most common adverse effects (AEs) include decreased eGFR (26%), hypertension (19%), diarrhea (19%), headache (15%), anemia (12%), and cough (11%). Other potential AEs include lymphoma, serious infections, nephrotoxicity, neurotoxicity, hyperkalemia, corrected QT interval prolongation, and pure red cell aplasia.

Voclosporin is a CYP3A4 substrate. Coadministration with moderate and strong CYP3A4 inducers should be avoided. Voclosporin is a P-glycoprotein inhibitor; other medications may require a dose reduction when used in combination with voclosporin. Dose adjustments are recommended in severe renal impairment and mild to moderate hepatic impairment. Voclosporin should be avoided in pregnant patients because of the alcohol content of the drug formulation. Patients taking voclosporin should avoid live vaccines.

Voclosporin is administered as a 7.9-mg capsule. It must be swallowed whole on an empty stomach. Recommended starting dose is 23.7 mg orally every 12 hours. Voclosporin is approved in combination with MMF and corticosteroids. Concomitant administration of voclosporin and cyclophosphamide should be avoided; further study is required to establish safety and efficacy of the combination. Do not stop or change the dose of voclosporin without consulting a health care provider.

Lupkynis. Prescribing information. Aurinia Pharmaceuticals; 2021. Accessed March 8, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213716s000lbl.pdf

New Drug Review: Voclosporin for Lupus Nephritis

On February 27, 2020, the FDA approved an intravenous solution of amisulpride (Barhemsys; Acacia Pharma) to treat and prevent postoperative nausea and vomiting (PONV). For prevention, amisulpride can be used alone or with another antiemetic. For PONV treatment, it may be administered to patients who received no prophylactic therapy or received a different drug during prophylaxis. Amisulpride, a selective D2/D3 dopamine receptor antagonist, is the first of Acacia Pharma’s pipeline medications to be approved after showing positive results in 4 phase 3 clinical trials.

Data from 4 randomized double-blind, placebo-controlled, multicenter trials supported the approval of amisulpride for prevention and treatment of PONV.

Two studies evaluated the agent’s use for prevention of PONV in patients undergoing general anesthesia and elective surgery. In both studies, treatment groups were matched for PONV risk factors. In study 1, participants (n = 342) received 5 mg of amisulpride (n = 176) or placebo (n = 166). In study 2, participants (n = 1147) received amisulpride plus standard therapy of ondansetron, betamethasone, or dexamethasone (n = 572) or placebo plus a standard antiemetic (n = 575). The primary outcome in both studies was complete response (CR), defined as no emesis and no use of rescue medication in the 24-hour postoperative period. In both studies, groups receiving amisulpride demonstrated increased rates of CR: study 1, 44% in the amisulpride treatment group vs 33% in the placebo group (difference, 12%; 95% CI, 2%-22%); study 2, 58% in the amisulpride plus standard antiemetic group vs 47% in the placebo plus standard antiemetic group (difference, 11%; 95% CI, 5%-17%).

Amisulpride’s effectiveness for treating PONV was demonstrated in 2 studies using the agent as a 10-mg single dose. In study 3
(n = 369), participants did not receive prior prophylaxis. Participants in study 4 (n = 465) received prior prophylaxis therapy with a nondopaminergic antiemetic (77%, 5-HT3 receptor antagonist; 65%, dexamethasone; 10%, other medication). Both studies evaluated the CR rates within 24 hours after administration with amisulpride excluding emesis within the first 30 minutes. Groups receiving amisulpride demonstrated increased rates of CR: study 3, 31% in the amisulpride treatment group vs 22% in the placebo group (difference, 10%; 95% CI, 1%-19%); study 4, 42% in the amisulpride treatment group vs 29% in the placebo group (difference, 13%; 95% CI, 5%-22%).

Overall, participants given amisulpride experienced significantly lower incidence of emesis, nausea, and rescue medication use compared with placebo, as monotherapy, and combined with other antiemetics.

Among all the studies of amisulpride, the adverse event (AE) profile was similar to that of the placebo groups. The most common AEs include infusion-site pain (6%), increased serum prolactin (5%), hypokalemia (4%), chills (4%), procedural hypotension (3%), and abdominal distention (2%). QT prolongation is a dose- and concentration-dependent AE associated with amisulpride use. It is unlikely to contribute to a meaningful QT prolongation at approved doses, but monitoring is recommended in patients who are at higher risk; have preexisting arrhythmia or cardiac conduction disorders, congestive heart failure, hypokalemia, hypomagnesemia; or receive concurrent medications that can prolong the QT interval (such as ondansetron). Amisulpride is extensively renally eliminated; its use should be avoided in patients who have severe renal dysfunction, with an estimated glomerular filtration rate less than 30 mL/min/1.73m2, because these patients may be at increased risk of AEs.

For prevention of PONV, amisulpride is given as a 5-mg, single-dose infusion over 1 to 2 minutes at the induction of anesthesia. This may be administered as monotherapy

or with another antiemetic medication. For treatment of PONV, amisulpride is infused as a 10-mg dose over 1 to 2 minutes in the event of nausea or vomiting after surgery.

Barhemsys. Acacia Pharma; 2020. Accessed May 19, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2020/209510s000lbl.pdf

On February 27, 2020, the FDA approved an intravenous solution of amisulpride (Barhemsys; Acacia Pharma) to treat and prevent postoperative nausea and vomiting. 

Barhemsys (Amisulpride) for Postoperative Nausea and Vomiting

On December 20, 2019, the FDA approved lumateperone tosylate (Caplyta™, Intra-Cellular Therapies) for treatment of schizophrenia in adult patients. Lumateperone is an atypical antipsychotic. The exact mechanism of action is unknown. However, lumateperone demonstrates binding affinity and antagonistic activity at central serotonin 5-HT2A receptors and postsynaptic central dopamine D2 receptors.

The efficacy of lumateperone was studied in 2 randomized, double-blind placebo-controlled multicenter trials (study 1 and study 2). The primary efficacy measure in both studies is the Positive and Negative Syndrome Scale (PANSS) total score. This scale scores patients’ symptoms associated with schizophrenia on a scale of 1 (absent) to 7 (severe).

In study 1, a total of 335 patients participated, with an age range of 20 to 55 years old. All participants met diagnosis criteria of schizophrenia, according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV). Patients were randomized to receive lumateperone 42 mg, lumateperone 84 mg (double the recommended dose), an active comparator, or a placebo. Compared with the placebo group, participants randomly assigned lumateperone 42 mg demonstrated a statistically significant reduction from baseline to day 28 in the PANSS total score, compared with participants who were administered the placebo.

Participants administered lumateperone 84 mg did not demonstrate a statistically significant difference in PANSS total score compared with those taking the placebo. A total of 450 participants, ranging from 19 to 60 years old, are included in study 2. All participants met diagnosis criteria of schizophrenia, according to the DSM-IV. Participants were randomized to receive lumateperone 28 mg, lumateperone 42 mg, or a placebo. Participants randomized to lumateperone 42 mg demonstrated a statistically significant reduction from baseline to day 28 in total PANSS score, compared with participants administered the placebo. The group receiving treatment with lumateperone 28 mg was not statistically significant compared with those receiving the placebo.

In studies, the most common adverse reactions occurring with greater frequency than placebo are: somnolence/sedation (24%), nausea (9%), dry mouth (6%), dizziness (5%), an increase in creatinine phosphokinase (4%), fatigue (3%), vomiting (3%), decreased appetite (2%), and an increase in hepatic transaminases (2%). In studies, extrapyramidal symptoms occurred at rates of 6.7% for lumateperone and 6.3% for placebo. Metabolic changes, such as hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain, have been associated with antipsychotic drugs. A patient’s fasting plasma glucose, weight, and fasting lipid profile should be monitored before or soon after starting therapy and throughout treatment. Leukopenia, neutropenia, and agranulocytosis have been associated with antipsychotic medications. Patients demonstrating clinically significant

neutropenia must be monitored for signs of infection. Discontinue lumateperone in patients with an absolute neutrophil count <1000/mm3 and monitor the patient’s white blood cell count until recovery. Patients with hypotension, with cardiovascular disease, or with cerebrovascular disease should be monitored for orthostatic hypotension.

The use of lumateperone is not recommended in patients with moderate (Child-Pugh class B) to severe hepatic impairment (Child-Pugh class C). No dose adjustment is recommended in patients with mild hepatic impairment (Child-Pugh A). Concomitant use of lumateperone with a moderate or strong CYP3A4 inhibitor or a UGT inhibitor increases lumateperone exposure, which may increase the risk of adverse effects. Concomitant use of lumateperone with a CYP3A4 inducer should be avoided.

In adult patients with schizophrenia, lumateperone should be administered 42 mg orally once daily. Lumateperone does not require any dose titration. Lumateperone should be given with food. Lumateperone is available only in 42-mg strength capsules.

1. Caplyta [package insert]. Hamilton, Bermuda: Intra-Cellular Therapies, Inc; 2019.

The FDA has approved lumateperone tosylate (Caplyta™, Intra-Cellular Therapies) for treatment of schizophrenia in adults.