Specialty Pharmacy Continuum (October 2020) by McMahon Group

Se ee SPEC CIA AL REPORT mon nograph polybagged with this issu ue

Serving managed care, health system and specialty decision makers Volume 9 • Number 5 • September/October 2020 • specialtypharmacycontinuum.com

OPERATIONS & MGMT Cold chain packing patent yields safer drug transit ...........................

A Windfall in Savings From Biosimilars

reating new tiers for lower cost specialty drugs and electronic tools for beneficiaries to check their portion of drug cost sharing were among the items suggested by the Centers for Medicare & Medicaid Services (CMS) in a proposed rule for Medicare Advantage (Part C) and Medicare Prescription Drug Benefit (Part D) programs. Although a final rule issued May 22 addressed only some of the proposed provisions because of a focus on the COVID-19 pandemic, a second final rule expected to be issued later this year may address the others. “Compared to some of the rules from previous years, the proposals set forth

POLICY Capping Medicare out-of-pocket insulin costs ......................................... Civica Rx expands roster of affordable generic drugs ...................

CLINICAL Acute myeloid leukemia: a growing list of treatments ............. Hyperkalemia: management tips for a subtle, deadly condition ............................. PAP programs breathe life into asthma/COPD care .........

Continued on page 8

REVIEW ARTICLE

Immunotherapy Toxicities See page 17.

Big Policy Shifts For Medicare On the Horizon

ransitioning patients taking infliximab to a biosimilar product ucct and improving adherence to imatinib are among the strate-gies specialty pharmacists at Boston Medical Center Health System (BMC) used to help the system better use health care resources, according to a session at the 2020 NASP Annuall Meeting & Expo Virtual Experience. The shift from originator infliximab to an infliximab biosimilar siimilar is forecasted to yield approximately $500,000 in annual savings, vin ngs, with ngs without compromising clinical outcomes, reported Alexander Pham, PharmD, BMC’s director of pharmacy strategy and business development. BMC’s specialty pharmacy successfully led the switch of 146 out of 151 eligible patients (97%) from the originator infliximab (Remicade, Janssen) to infliximab-dyyb (Inflectra, Pfizer) between March 2018 and June 2019 (J Manag Care Spec Pharm 2020;26[4]:410416). As of October 2018, 56 patients (89%) continued with infliximab-dyyb after the transition. Of the 46 patients who had 12 to 15 months of post-transition data, 38 (83%) remained on the biosimilar product. Sixty-three of 75 eligible patients (84%) with inflammatory bowel disease (IBD) transitioned from infliximab to infliximab-dyyb. In a subgroup of 40 patients with IBD who had available scores on the Harvey-Bradshaw Index or the Simple Clinical Colitis Activity Index from both before and after transition, 36 (90%) maintained remission. “This project represents one of many opportunities to reduce costs without

he COVID-19 pandemic has had a major economic impact on the health care system but also offers a number of lessons that providers and payors can use to prepare for future epidemics or a resurgence of COVID-19, experts said during a webinar sponsored by Impact Education. “There is a lot of opportunity to be optimistic about how our health system will improve as a result of COVID,” said Peter Watson, MD, the vice president of care management,

Continued on page 22

Continued on page 10

Role of Specialty Pharmacists in Treating Patients With HIV Access at bit.ly/2GRtI9D

COVID-19

Coping Skills For Payors: What They’ve Learned

For adults with newly-diagnosed secondary AML (sAML) subtypes therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), VYXEOS may offer...

A STRONG START FOR SUPERIOR SURVIVAL

NEW

5-YEAR

1,2

OS DATA

Overall survival more than doubled at 5 years with VYXEOS (18%) vs 7+3a (8%) based on KM estimates1,3 Median overall survival (primary endpoint) of 9.6 months with VYXEOS vs 5.9 months with 7+3 (HR=0.69 [0.52, 0.90], P=0.005b)1 5-YEAR FOLLOW-UP Kaplan-Meier curve for overall survival, ITT population3 100

1-YEAR KM-estimated survival2

Survival (%)

VYXEOS: 42% 7+3: 28%

60 40

5-YEAR KM-estimated survival3

20 0

0 3

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72

VYXEOS: 18% 7+3: 8%

Months from randomization VYXEOS 7+3

153 122 92 79 62 52 49 45 40 35 33 31 30 29 29 29 29 28 28 26 22 6 2

156 110 77 56 43 35 28 25 20 19 17 14 14 13 13 12 12 12 12 11 5 1

0 0

INDICATION VYXEOS is indicated for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

IMPORTANT SAFETY INFORMATION WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS VYXEOS has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors.

Contraindications VYXEOS is contraindicated in patients with a history of serious hypersensitivity reactions to cytarabine, daunorubicin, or any component of the formulation.

Warnings and Precautions Hemorrhage Serious or fatal hemorrhage events, including fatal CNS hemorrhages, associated with prolonged thrombocytopenia, have occurred with VYXEOS. The overall incidence (grade 1-5) of hemorrhagic events was 74% in the VYXEOS arm and 56% in the control arm. The most

frequently reported hemorrhagic event was epistaxis (36% in VYXEOS arm and 18% in control arm). Grade 3 or greater events occurred in 12% of VYXEOS-treated patients and in 8% of patients in the control arm. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and in 0.7% of patients in the control arm. Monitor blood counts regularly and administer platelet transfusion support as required. Cardiotoxicity VYXEOS contains daunorubicin, which has a known risk of cardiotoxicity. This risk may be increased in patients with prior anthracycline therapy, preexisting cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs. Assess cardiac function prior to VYXEOS treatment and repeat prior to consolidation and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS is not recommended in patients with cardiac function that is less than normal. Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit.

In a large, randomized Phase 3 clinical trial, VYXEOS showed proven benefits for secondary AML patients vs 7+31 Median overall survival

CR and CR+CRi

HSCT

Median overall survival (primary endpoint) of 9.6 months with VYXEOS vs 5.9 months with 7+3 (HR=0.69 [0.52, 0.90], P=0.005b)1

38% of patients treated with VYXEOS (n=58/153) achieved CR vs 26% of 7+3 patients (n=41/156) (P=0.036b)1

34% of patients treated with VYXEOS (n=52/153) reached HSCT c vs 25% of 7+3 patients (n=39/156)1

With median follow-up of 60 months, the improvement in OS was maintained with a stable hazard ratio3

48% of patients treated with VYXEOS (n=73/153) achieved CR+CRi vs 33% of 7+3 patients (n=52/156) (P=0.016b)2

Study Design1,3 The Phase 3 study was a randomized, multicenter, open-label, active-controlled superiority study of VYXEOS (N=153) versus cytarabine and daunorubicin (7+3) (N=156) in patients 60 to 75 years of age with newly-diagnosed t-AML or AML-MRC (N=309). Efficacy was established on the basis of overall survival from the date of randomization to death from any cause.1 VYXEOS 44 mg/100 mg per m2 (daunorubicin/cytarabine) was given intravenously on Days 1, 3, and 5 for first induction and on Days 1 and 3 for those needing a second induction. For consolidation, the VYXEOS dose was 29 mg/65 mg per m2 (daunorubicin/cytarabine) on Days 1 and 3. In the 7+3 arm, first induction was cytarabine 100 mg/m2/day on Days 1-7 by continuous infusion + daunorubicin 60 mg/m2/day on Days 1-3. For second induction and consolidation, cytarabine was dosed on Days 1-5 and daunorubicin on Days 1 and 2. Patients could receive up to 2 cycles of induction and 2 cycles of consolidation in each arm. Subsequent induction was highly recommended for patients who did not achieve a response and was mandatory for patients achieving >50% reduction in percent blasts.1 A preplanned overall survival analysis was conducted based on the final 5-year follow-up results from the Phase 3 trial.3

IMPORTANT SAFETY INFORMATION, continued

MOST COMMON ADVERSE REACTIONS

The most common adverse reactions (incidence ≥25%) were hemorrhagic events (74%), febrile neutropenia (70%), rash (56%), edema (55%), nausea (49%), mucositis (48%), diarrhea (48%), constipation (42%), musculoskeletal pain (43%), fatigue (39%), abdominal pain (36%), dyspnea (36%), headache (35%), cough (35%), decreased appetite (33%), arrhythmia (31%), pneumonia (31%), bacteremia (29%), chills (27%), sleep disorders (26%), and vomiting (25%).

Copper Overload VYXEOS contains copper. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with VYXEOS. Monitor total serum copper, serum non-ceruloplasminbound copper, 24-hour urine copper levels, and serial neuropsychological examinations during VYXEOS treatment in patients with Wilson’s disease or other copper-related metabolic disorders. Use only if the benefits outweigh the risks. Discontinue in patients with signs or symptoms of acute copper toxicity.

Please see following pages for Brief Summary of full Prescribing Information, including BOXED Warning.

Tissue Necrosis Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Do not administer by intramuscular or subcutaneous route. Embryo-Fetal Toxicity VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid becoming pregnant while taking VYXEOS. If VYXEOS is used during pregnancy or if the patient becomes pregnant while taking VYXEOS, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS.

Cytarabine 100 mg/m2 and daunorubicin 60 mg/m2.1 bP value is 2-sided.1 c Induction failure, first CR, or as salvage after relapse.1 a

AML=acute myeloid leukemia; CR=complete remission; CRi=complete remission with incomplete recovery; HR=hazard ratio; HSCT=hematopoietic stem cell transplant; ITT=intent to treat; KM=Kaplan-Meier; OS=overall survival. References: 1. VYXEOS [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. 2. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684-2692. 3. Lancet JE, Uy GL, Newell LF, et al. Five-year final results of a phase 3 study of CPX-351 versus 7+3 in older adults with newly diagnosed high-risk/secondary AML. Presented at: American Society of Clinical Oncology ASCO20 Virtual Scientific Program; May 29-31, 2020. Poster 283.

US-VYX-2000237 Rev0820

vyxeospro.com

VYXEOS® (daunorubicin and cytarabine) liposome for injection, for intravenous use BRIEF SUMMARY OF PRESCRIBING INFORMATION: Consult the Full Prescribing Information, including BOXED Warning, for complete product information. Initial U.S. Approval: 2017

Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS treatment is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit. The exposure to daunorubicin following each cycle of VYXEOS is shown in Table 1. Table 1: Cumulative Exposure of Daunorubicin per Cycle of VYXEOS Therapy

Daunorubicin per Dose

Number of Doses per Cycle

Daunorubicin per Cycle

First Induction Cycle

44 mg/m2

132 mg/m2

Second Induction Cycle

44 mg/m2

88 mg/m2

Each Consolidation Cycle

29 mg/m2

58 mg/m2

WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS • VYXEOS has different dosage recommendations than

daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors [see Warnings and Precautions].

INDICATIONS AND USAGE VYXEOS is indicated for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). CONTRAINDICATIONS The use of VYXEOS is contraindicated in patients with the following: • History of serious hypersensitivity reaction to cytarabine, daunorubicin, or any component of the formulation [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Do Not Interchange With Other Daunorubicin And/Or Cytarabine-Containing Products Due to substantial differences in the pharmacokinetic parameters, the dose and schedule recommendations for VYXEOS are different from those for daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors. Do not substitute other preparations of daunorubicin or cytarabine for VYXEOS. Hemorrhage Serious or fatal hemorrhage events, including fatal central nervous system (CNS) hemorrhages, associated with prolonged severe thrombocytopenia, have occurred in patients treated with VYXEOS. In Study 1 (NCT01696084), the incidence of any grade hemorrhagic events during the entire treatment period was 74% of patients on the VYXEOS arm and 56% on the control arm. The most frequently reported hemorrhagic event was epistaxis (36% in VYXEOS arm and 18% in control arm). Grade 3 or greater events occurred in 12% of VYXEOS treated patients and 8% of patients treated with 7+3. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients on the VYXEOS arm and in 0.7% of patients on the control arm. Monitor blood counts regularly until recovery and administer platelet transfusion support as required [see Adverse Reactions]. Cardiotoxicity VYXEOS contains the anthracycline daunorubicin, which has a known risk of cardiotoxicity. Prior therapy with anthracyclines, pre-existing cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs may increase the risk of daunorubicin-induced cardiac toxicity. Prior to administering VYXEOS, obtain an electrocardiogram (ECG) and assess cardiac function by multi-gated radionuclide angiography (MUGA) scan or echocardiography (ECHO). Repeat MUGA or ECHO determinations of left ventricular ejection fraction (LVEF) prior to consolidation with VYXEOS and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS treatment is not recommended in patients with LVEF that is less than normal. Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum.

Hypersensitivity Reactions Serious or fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine. Monitor patients for hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, interrupt or slow the rate of infusion with VYXEOS and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS permanently, treat symptoms according to the standard of care, and monitor until symptoms resolve. Copper Overload Reconstituted VYXEOS contains 5 mg/mL copper gluconate, of which 14% is elemental copper. There is no clinical experience with VYXEOS in patients with Wilson’s disease or other copper-related metabolic disorders. The maximum theoretical total exposure of copper under the recommended VYXEOS dosing regimen is 106 mg/m2. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with VYXEOS. Monitor total serum copper, serum non-ceruloplasmin bound copper, 24-hour urine copper levels and serial neuropsychological examinations in these patients. Use VYXEOS in patients with Wilson’s disease only if the benefits outweigh the risks. Discontinue VYXEOS in patients with signs or symptoms of acute copper toxicity. Tissue Necrosis Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Do not administer by intramuscular or subcutaneous route. Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies with daunorubicin and cytarabine, VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VYXEOS, daunorubicin, or cytarabine in pregnant women. Daunorubicin and cytarabine are reproductive and developmental toxicants in multiple species (mice, rats, and/or dogs), starting at a dose that was approximately 0.02 times the exposure in patients at the recommended human dose on an mg/m2 basis. Patients should be advised to avoid becoming pregnant while taking VYXEOS. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Cardiotoxicity [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Copper Overload [see Warnings and Precautions] • Tissue Necrosis [see Warnings and Precautions]

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.

Adverse Reaction Pneumonia (excluding fungal) Sleep disorders Bacteremia (excluding sepsis) Vomiting Chills Hypotension Non-conduction cardiotoxicity Dizziness Fungal infection Hypertension Hypoxia Upper respiratory infections (excluding fungal) Chest pain Pyrexia Catheter/device/ injection site reaction Delirium Pleural effusion Anxiety Pruritus Sepsis (excluding fungal) Hemorrhoids Petechiae Renal insufficiency Transfusion reactions Visual impairment (except bleeding)

The safety of VYXEOS was determined in a randomized trial for adults with newly-diagnosed t-AML or AML-MRC which included 153 patients treated with VYXEOS and 151 patients treated with a standard combination of cytarabine and daunorubicin (7+3). At study entry, patients were required to have a LVEF of at least 50% and a prior lifetime cumulative anthracycline exposure less than 368 mg/m2 daunorubicin (or equivalent). On study, the median number of cycles administered was 2 (range, 1–4 cycles) on the VYXEOS arm and 1 (range, 1–4 cycles) on the control arm. The median cumulative daunorubicin dose was 189 mg/m2 (range, 44–337 mg/m2) on the VYXEOS arm and 186 mg/m2 (range, 44–532 mg/m2) on the control arm. Nine patients each on the VYXEOS arm (6%) and the control arm (6%) had a fatal adverse reaction on treatment or within 30 days of therapy that was not in the setting of progressive disease. Fatal adverse reactions on the VYXEOS arm included infection, CNS hemorrhage, and respiratory failure. Overall, all-cause day-30 mortality was 6% in the VYXEOS arm and 11% in the control arm. During the first 60 days of the study, 14% (21/153) of patients died in the VYXEOS arm vs. 21% (32/151) of patients in the 7+3 treatment group. The most common serious adverse reactions (incidence ≥5%) on the VYXEOS arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia and hemorrhage. Adverse reactions led to discontinuation of VYXEOS in 18% (28/153) of patients, and 13% (20/151) in the control arm. The adverse reactions leading to discontinuation on the VYXEOS arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage (GI and CNS), renal insufficiency, colitis, and generalized medical deterioration. The most common adverse reactions (incidence ≥25%) in patients on the VYXEOS arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting. The incidences of common adverse drug reactions during the induction phase in Study 1 are presented in Table 2. Table 2: Common Adverse Reactions (≥10% Incidence in the VYXEOS arm) During the Induction Phase Grades 3 to 5a All Gradesa Adverse VYXEOS 7+3 VYXEOS 7+3 Reaction N=153 N=151 N=153 N=151 n (%) n (%) n (%) n (%) Hemorrhage 107 (70) 74 (49) 15 (10) 9 (6) Febrile Neutropenia 104 (68) 103 (68) 101 (66) 102 (68) Rash 82 (54) 55 (36) 8 (5) 2 (1) Edema 78 (51) 90 (60) 2 (2) 5 (3) Nausea 72 (47) 79 (52) 1 (1) 1 (1) Diarrhea/Colitis 69 (45) 100 (66) 4 (3) 10 (7) Mucositis 67 (44) 69 (46) 2 (1) 7 (5) Constipation 61 (40) 57 (38) 0 0 Musculoskeletal pain 58 (38) 52 (34) 5 (3) 4 (3) Abdominal pain 51 (33) 45 (30) 3 (2) 3 (2) Cough 51 (33) 34 (23) 0 1 (1) Headache 51 (33) 36 (24) 2 (1) 1 (1) Dyspnea 49 (32) 51 (34) 17 (11) 15 (10) Fatigue 49 (32) 58 (38) 8 (5) 8 (5) Arrhythmia 46 (30) 41 (27) 10 (7) 7 (5) Decreased appetite 44 (29) 57 (38) 2 (1) 5 (3)

All Gradesa VYXEOS 7+3 N=153 N=151 n (%) n (%)

Grades 3 to 5a VYXEOS 7+3 N=153 N=151 n (%) n (%)

39 (26)

35 (23)

30 (20)

26 (17)

38 (25)

42 (28)

2 (1)

1 (1)

37 (24)

37 (25)

35 (23)

31 (21)

37 (24) 35 (23) 30 (20)

33 (22) 38 (25) 32 (21)

0 0 7 (5)

0 0 1 (1)

31 (20)

27 (18)

13 (9)

15 (10)

27 (18) 27 (18) 28 (18) 28 (18)

26 (17) 19 (13) 22 (15) 31 (21)

1 (1) 11 (7) 15 (10) 19 (12)

0 9 (6) 8 (5) 23 (15)

28 (18)

19 (13)

4 (3)

1 (1)

26 (17) 26 (17)

22 (15) 23 (15)

5 (3) 1 (1)

0 2 (1)

24 (16)

15 (10)

24 (16) 24 (16) 21 (14) 23 (15)

33 (22) 25 (17) 16 (11) 14 (9)

4 (3) 3 (2) 0 0

9 (6) 2 (1) 0 0

17 (11)

20 (13)

n/a

16 (11) 17 (11) 17 (11) 17 (11)

12 (8) 17 (11) 17 (11) 16 (11)

0 0 7 (5) 3 (2)

0 0 7 (5) 1 (1)

16 (11)

8 (5)

Adverse reactions were graded using NCI CTCAE version 3.0.

During the consolidation phase (both consolidation cycles pooled) the two most common adverse reactions on the VYXEOS arm are the same as those during induction, hemorrhagic events and febrile neutropenia. These occurred at lower rates in the pooled consolidation phase (43% and 29%, respectively), compared to the induction phase. All of the common adverse reactions (≥10% incidence in the VYXEOS arm) seen in the pooled consolidation phase were also seen in the induction phase. These occurred at lower incidence in the consolidation phase, with the exception of chills, dizziness and pyrexia, where the incidences were relatively similar across the induction and consolidation cycles. Other notable adverse drug reactions that occurred in less than 10% of patients treated with VYXEOS during induction or consolidation included: • Ear and labyrinth disorders: Deafness, Deafness unilateral • Eye Disorders: Eye conjunctivitis, Dry eye, Eye edema, Eye swelling, Eye irritation, Eye pain, Ocular discomfort, Ocular hyperemia, Periorbital edema, Scleral hyperemia • Gastrointestinal disorders: Dyspepsia • Psychiatric disorders: Hallucinations • Respiratory, thoracic and mediastinal disorders: Pneumonitis

Laboratory Abnormalities All patients developed severe neutropenia, thrombocytopenia, and anemia. See Table 3 for the incidences of Grade 3 thrombocytopenia and Grade 4 neutropenia that were prolonged in the absence of active leukemia. Table 3: Prolonged Cytopenias for Patients in Study 1 Induction 1 VYXEOS 7+3 N=58 N=34 n (%) n (%) Prolonged thrombocytopeniaa Prolonged neutropeniaa

Consolidation 1b VYXEOS 5+2 N=48 N=32 n (%) n (%)

16 (28)

4 (12)

12 (25)

5 (16)

10 (17)

1 (3)

5 (10)

1 (3)

Platelets <50 Gi/L or neutrophils <0.5 Gi/L lasting past cycle day 42 in the absence of active leukemia. b Patients receiving at least 1 consolidation. a

Grade 3-4 chemistry abnormalities occurring in greater than 5% of VYXEOS treated patients in Study 1 are presented in Table 4. Table 4: Grade 3-4a Chemistry Abnormalities â&#x2030;Ľ5% of VYXEOS Treated Patients in Study 1 Induction 7+3 VYXEOS N=151 N=153 n (%) n (%) Chemistry Abnormalities Hyponatremia 21 (14) 20 (13) Hypokalemia 14 (9) 19 (13) Hypoalbuminemia 11 (7) 19 (13) Hyperbilirubinemia 9 (6) 6 (4) Alanine 7 (5) 8 (5) aminotransferase

Consolidation 5+2 VYXEOS N=32 N=49 n (%) n (%) 3 (6) 3 (6) 1 (2) 1 (2)

0 2 (6) 4 (13) 1 (3)

1 (3)

Graded using NCI CTCAE version 3.0.

DRUG INTERACTIONS Cardiotoxic Agents Concomitant use of cardiotoxic agents may increase the risk of cardiotoxicity. Assess cardiac function more frequently when VYXEOS is coadministered with cardiotoxic agents [see Warnings and Precautions]. Hepatotoxic Agents Concomitant use with hepatotoxic agents may impair liver function and increase the toxicity of VYXEOS. Monitor hepatic function more frequently when VYXEOS is coadministered with hepatotoxic agents. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on anecdotal data of cytarabine in pregnant women and results of studies of daunorubicin and cytarabine in animals, VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VYXEOS, daunorubicin, or cytarabine in pregnant women. Daunorubicin and cytarabine are reproductive and developmental toxicants in multiple species (mice, rats, and/or dogs), starting at a dose that was approximately 0.02 times the exposure in patients at the recommended human dose on a mg/m2 basis [see Animal Data]. Patients should be advised to avoid becoming pregnant while taking VYXEOS. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential harm to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Data Human Data Cytarabine can cause fetal harm if a pregnant woman is exposed to the drug. Four anecdotal cases of major limb malformations have been reported in infants after their mothers received intravenous cytarabine, alone or in combination with other agents, during the first trimester. Animal Data A liposomal formulation of daunorubicin was administered to rats on gestation days 6 through 15 at 0.3, 1.0, or 2.0 mg/kg/day (about 0.04, 0.14, or 0.27 the recommended human dose on a mg/m2 basis) and produced severe maternal toxicity and embryolethality at 2.0 mg/kg/day and was embryotoxic and caused fetal malformations (anophthalmia, microphthalmia, incomplete ossification) at 0.3 mg/kg/day. Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes. Cytarabine was teratogenic in mice (cleft palate, phocomelia, deformed appendages, skeletal abnormalities) when doses â&#x2030;Ľ2 mg/kg/day were administered IP during the period of organogenesis (about 0.06 times the recommended human dose on a mg/m2 basis), and in rats (deformed appendages) when 20 mg/kg was administered as a single IP dose on day 12 of gestation (about 1.2 times the recommended human dose on a mg/m2 basis). Single IP doses of 50 mg/kg in rats (about 3 times the recommended human dose on a mg/m2 basis) on day 14 of gestation reduced prenatal and postnatal brain size and permanent impairment of learning ability. Cytarabine was embryotoxic in mice when administered during the period of organogenesis. Embryotoxicity was characterized by decreased fetal weight at 0.5 mg/kg/day (about 0.02 times the recommended human dose on a mg/m2 basis), and increased early and late resorptions and decreased live litter sizes at 8 mg/kg/day (about 0.24 times the recommended human dose on a mg/m2 basis). Lactation Risk Summary There are no data on the presence of daunorubicin, cytarabine, or their metabolites in human milk, their effects on the breastfed infant, or their effects on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with VYXEOS and for at least 2 weeks after the last dose. Females and Males of Reproductive Potential Pregnancy Testing VYXEOS can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Verify the pregnancy status of females of reproductive potential prior to initiating VYXEOS. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with VYXEOS and for at least 6 months after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with VYXEOS and for at least 6 months after the last dose. Infertility Based on findings of daunorubicin and cytarabine in animals, male fertility may be compromised by treatment with VYXEOS.

Pediatric Use Safety and effectiveness of VYXEOS in pediatric patients have not been established.

Specialty Pharmacy Continuum • September/October 2020

OPERATIONS & MANAGEMENT

Geriatric Use Of the 375 patients who received VYXEOS (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) liposome in clinical studies, 57% were 65 years and over. No overall differences in safety were observed between these patients and younger patients, with the exception of bleeding events, which occurred more frequently in patients 65 years and older compared to younger patients (77% vs. 59%). Renal Impairment Dosage adjustment is not required for patients with mild (creatinine clearance [CLCR] 60 mL/min to 89 mL/min by Cockcroft Gault equation [C-G]) or moderate (CLCR 30 mL/min to 59 mL/min) renal impairment. VYXEOS has not been studied in patients with severe renal impairment (CLCR 15 mL/min to 29 mL/min) or end-stage renal disease. Hepatic Impairment Dosage adjustment is not required for patients with a bilirubin level less than or equal to 3 mg/dL. VYXEOS has not been studied in patients with bilirubin level greater than 3 mg/dL. PATIENT COUNSELING INFORMATION Hemorrhage Inform patients of the risk of fatal bleeding. Advise patients of the need for periodic monitoring of blood counts and of the importance of keeping scheduled appointments for blood work and necessary transfusions. Advise patients to contact a healthcare provider for new onset fever or symptoms of infection or if they notice signs of bruising or bleeding [see Warnings and Precautions and Adverse Reactions]. Cardiotoxicity Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions]. Hypersensitivity Reactions Inform patients of the risk of hypersensitivity reactions, including anaphylaxis. Describe the symptoms of hypersensitivity reactions, including anaphylaxis, and instruct the patient to seek medical attention immediately if they experience such symptoms [see Warnings and Precautions]. Embryo-Fetal Toxicity VYXEOS can cause fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS and to inform their healthcare provider of a known or suspected pregnancy before and during treatment with VYXEOS [see Warnings and Precautions and Use in Specific Populations]. Lactation Advise patients not to breastfeed during treatment with VYXEOS and for at least 2 weeks after the last dose [see Use in Specific Populations]. Infertility Advise males of reproductive potential that VYXEOS may cause temporary or permanent infertility [see Use in Specific Populations].

VYX-0083(3)

From AllianceRx Walgreens Prime:

Rx Packing Patent Yields Safer Cold Chain Transit By the end of 2020, AllianceRx Walgreens Prime will roll out its patented process to customize packing configurations for the safe transit and delivery of refrigerated specialty medications, adhering to drug manufacturers’ requirements of 2° to 8° C. At an AllianceRx Walgreens Prime lab in Pittsburgh, a team has designed, tested and validated the predictive process via dataintensive research in environmental simulation chambers and on actual shipments since July 2017. The patent granted in March 2020 culminated an effort begun by Walgreen Co. in 2014 to “expedite our ability to find opportunities to improve our cold chain process,” said Ed Musisko, AllianceRx Walgreens Prime’s senior director of data science and analytics, a co-inventor and patent holder. Since 2018, more than 98% of refrigerated orders in the Pittsburgh beta site have used, and continue to use, the predictive process. “To date, no orders shipped [this way] required reshipment due to instability,” said Luke Holbrook, AllianceRx Walgreens Prime’s manager of engineering and logistics, a co-inventor of the new process and patent holder. Although the predictive packout process is able to protect temperature integrity of frozen and room temperature medication shipments as well, AllianceRx Walgreens Prime has, so far, devoted its use to refrigerated medications, which account for approximately 60% of its shipments to patients, noted Joe Renna, AllianceRx Walgreens Prime’s senior director of facilities management and logistics and engineering. These customized packouts help reduce the reshipping of spoiled medications and save on materials and shipping expenses versus the universal packouts typically used by specialty pharmacies, Mr. Musisko said.

‘A Breakthrough’

Concomitant Medications Advise patients to speak with their physicians about any other medication they are currently taking [see Drug Interactions].

Rev0919

“This is a breakthrough for our pharmacists because we can see the same visual as our packout technicians,” said Ojas Sampat, PharmD, AllianceRx Walgreens Prime’s logistics manager. “As a result, our pharmacists have more confidence in the packout; they can see the trail of temperatures along the path to delivery (not while in transit but after); they can reassure patients when they speak with them; and they’re very excited because they can assist with

any temperature-stability questions.” Jeff Reichard, PharmD, BCOP, the director of pharmacy at UNC Health–Home Delivery and Specialty Pharmacy, in Chapel Hill, N.C., an expert on cold chain management, said, “This sounds like an algorithm they’ve validated that could provide better guidance to reduce their supply costs without any impact on patients or the quality of goods. The big savings opportunity would be in potentially mitigating medication replacement costs, which could be thousands of dollars at a time, if a package doesn’t maintain cold chain integrity. “Reshipping has risen in the COVID era because national couriers are stretched beyond their normal shipping schedules, placing a real strain on delivery turnaround times. That requires specialty pharmacies to pack out longer to maintain cold chain, and use more expedited shipping schedules,” Dr. Reichard said. “The clinical value of this program could help to support the timely delivery of medications,” he added. “If patients don’t get their medications, they can’t be on their medications.”

How the Patented Process Works The patented process uses a series of algorithms and thermal equations that predict how a medication will fare along its shipping path. “We map out the route to destination, carrier and vehicle type, weather reports and expected temperatures across our shipping window,” Mr. Musisko explained. “We’ve developed an array of packout configurations for minimally 36-hour shipping windows, and tested and validated them against respective outputs of the algorithms.” Several AllianceRx Walgreens Prime specialty pharmacies will ship nationally using its predictive packout application. The company said it has no plans to license the technology. —Al Heller The sources reported no relevant financial relationships other than stated employment.

Specialty Pharmacy Continuum • September/October 2020

POLICY

A Big Medicare Shift continued from page 1

in the 2021-2022 policy and technical rule are perhaps less disruptive, but still certainly signal some major policy shifts from CMS and have a number of implications for managed care pharmacies,” said Ross Margulies, JD, MPH, an attorney with Foley Hoag LLP in Washington, D.C., during an AMCP webinar this spring. Here are some changes that are part of the May final rule or are expected as part of a rule later this year that pharmacists should be aware of, Mr. Margulies said: Changes to Star Ratings. CMS proposed an increase in the impact that patient experience and access measures have on a Medicare Advantage and Part D plan’s Star Rating, a system that helps beneficiaries and caregivers compare the quality of health and drug plans being offered. CMS would increase the calculated weight of patient experience and complaints in determining a Part D plan’s Star Rating from a 2 to a 4, making the beneficiary-reported experience in a Part D plan worth more in future years. “Despite a large number of commenters not being supportive of this proposal, CMS argued this move is in support of its goal of ‘listening to the voice of the patient to identify opportunities to improve care delivery,’” Mr. Margulies said. The May final rule stated that this measure will be enacted by Jan. 1, 2021.

Establishing pharmacy performance standards. CMS has proposed new reporting requirements in which Part D plan sponsors will need to disclose the measures they use to evaluate pharmacy performance in their network agreements. The agency plans to report this information publicly to increase transparency related to the process and to inform industry about efforts to develop a set of standard performance measures. Going forward, Mr. Margulies said, Part D plan sponsors may be limited in their ability to develop their own pharmacy performance measures and, instead, will have to use a set of predefined measures developed by a group such as the Pharmacy Quality Alliance. Although not in the May final rule, this provision is expected to be addressed in a separate final rule to be published later in 2020, he said. Implementing a Beneficiary RealTime Benefit Tool (RTBT). CMS proposes to require Part D plans to implement an RTBT by Jan. 1, 2022, through which beneficiaries can view real-time formulary and benefit information, including their share of costs of a recommended drug and its alternatives. Plans also would be allowed to offer nominal gifts to enrollees to encourage them to use the tool. Previously, CMS had required plans to support an RTBT for prescribers as of Jan. 1, 2021, to supply prescribers with information on

Capping Out-of-Pocket Insulin Costs for Medicare CMS is capping out-of-pocket insulin costs for Medicare beneficiaries at $35 per month as of Jan. 1, 2021.. The cap applies to both pen and vial dosage forms for rapid-acting, acting, short-acting, intermediate-acting and long-acting insulin. n. It will extend from the beginning of the year and through h the Part D coverage gap. Participation by Medicare Part art D prescription drug and Medicare Advantage (MA) MA) plans with prescription drug coverage has been robust. More than 1,750 stand-alone Medicare Part D and d MA prescription drug plans will offer the lower insulin ulin copays through the Part D Senior Savings Model for or the 2021 plan year. (To familiarize yourself with this new innovation model, visit bit.ly/3cPTVQ3.) The change to insulin copays in 2021 forr beneficiaries in participating plans will cover “all common forms of insulin,” CMS Administrator Seema ma Verma said during a recent press conference. “If itt goes well, we’ll extend that to other drugs. We’re starting arting with insulin, but depending on the progress of this, we will consider offering this flexibility to manufacturers cturers and plans with other drugs. We think that this creates a foundation and a platform to fix ... some of the problems that we have in the Part D plans. It’s time for that at program to be updated. A lot of the provisions just don’t work anymore, and it’s standing in the way of free-marree-market competition and negotiation that can lower prices for seniors.” —Bonnie Kirschenbaum m

cost-sharing for formulary drugs and any necessary prior authorizations or utilization management strategies. The new RTBT also is expected to be addressed in a later 2020 final rule, Mr. Margulies said. Permitting a Second Preferred Specialty Tier. All drugs that fall in a Part D plan’s specialty tier (with the highest cost drugs) have the same level of cost sharing for enrollees: $670 per month. CMS proposes to allow plans to establish a second specialty tier with lower cost-

drug management programs by Jan. 1, 2022, for beneficiaries at risk for abuse or misuse of frequently abused drugs. Such programs place beneficiaries at risk for abuse into programs, limiting them to one or a small number of pharmacies to discourage inappropriate pharmacy shopping. These programs historically have been voluntary, and are used by about 80% of plans, Mr. Margulies said. Additional measures propose to modify the definition of a potentially at-risk beneficiary to include a Part D-eligible

Changes to Medicare’s Star Rating system are ‘in support of its goal of “listening to the voice of the patient to identify opportunities to improve care delivery.”’ —Ross Margulies, JD, MPH sharing drugs, with the agency setting standards for the maximum cost share for each tier. Sponsors could determine which drugs would fit which tiers. “This proposal probably got the most news after it came out, likely due to the implications for negotiations between plans, pharmacy benefit managers and manufacturers,” Mr. Margulies said, noting that this proposal also likely will be addressed in the rule expected later in 2020. SUPPORT Act Implementation. The proposed rule would implement several provisions of the federal Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) Act signed in 2018. They include a potential requirement for Part D plan sponsors to start

individual who has a history of opioidrelated overdose through a recent claim, and to automatically forward to the independent review entity information about an enrollee appealing their enrollment in a drug management program. Furthermore, it requires implementation of a provision requiring Part D plans to suspend payments to pharmacies for reasons such as credible allegations of fraud.

Second Specialty Tier Could Have Benefits CMS has been focused on addressing high drug prices, high out-of-pocket insulin costs (sidebar) and drug price transparency, so suggesting an RTBT for beneficiaries was not surprising, said Carrie Monks, the session moderator and director of regulatory affairs for AMCP. d The second specialty tier proposal was T more surprising, she said, but if finalized, m it has the potential to reduce prescription drug costs in the Medicare program ti by allowing the design of Part D drug b formularies “that are even more effective fo aat recommending the most appropriate drug choice for patients, while limiting d out-of-pocket costs. o “We do expect that CMS will issue Part 2 of this final rule later this year, though when it will be published is unknown at w this time,” Ms. Monks added. “The focus th on the COVID-19 public health emergeno ccy is vital and likely appropriately redirecting some agency attention. However, re Medicare Advantage and Part D plans do M need final guidance on the provisions not finalized in Part 1 of the rule to prepare for future plan years.” For an overview of the final rule on Parts C and D, see the Federal Register at go.aws/3cWgSkU. —Karen Blum The sources reported no relevant financial relationships.

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Specialty Pharmacyy Continuum • September/October 2020

POLICY

COVID-19 Lessons continued from page 1

quality and outcomes for the Health Alliance Plan, a nonprofit plan based in Michigan. Many areas within health care systems struggled with the unexpected during the pandemic surge this spring; all can be looked at as opportunities for improvement going forward, said Dr. Watson, who also is an attending staff hospitalist at Henry Ford Medical Group, in Michigan.

Hospitals had a lot of extended delays for COVID-19 test results in the beginning of the pandemic. As a result, they had to act in a manner that presumed patients were positive and use personal protective equipment, and it was difficult to group infected and noninfected patients because it was unclear who was who, he said. There also were issues with shortages of specialized providers

needed to manage patients. At Henry Ford, the graduate medical education director repurposed all training staff to care for COVID-19, which demonstrated that health systems can be nimble. “As payors, we have to be very supportive of our health systems that are trying to react very quickly in these situations,” Dr. Watson said. Hospitals also faced shortages of certain equipment, such as ventilators and infrared thermometers. “These are things all facilities are now rethinking, and as health plans, we will have to partner with

I N T R O DUC ING ™ ™ F UN G I T E L L STAT FU NG

our facilities to make sure they have the resources they need to take care of our membership,” Dr. Watson said. In addition, health systems have been working to try to stay financially viable, he said, continuing to provide needed care and working to make sure staff were paid and deployed properly. Many had to make changes in their lines of credit or apply for government or other loans. Some hospital groups have since started working together to pool supplies and ensure they have enough inventory on hand for the next epidemic, including adequate supplies of low-cost generic medications (sidebar). The pandemic opened discussions

Civica Rx Takes A Seat at Drug Supply Chain Table

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ivica Rx has earned a key role in a new federally funded public–private partnership to maintain adequate supplies of essential medications during pandemics and other future public health emergencies. The collaboration was announced soon after the company relieved critical shortages of generic sterile injectables for more than 1,200 member hospitals during the COVID-19 pandemic’s crushing first wave. At the Department of Health and Human Services (HHS), teams are involving Civica Rx in their build of “a 100% U.S.-owned and operated, endto-end domestic drug manufacturing infrastructure to secure essential sterile injectable drugs and prevent future shortages of these vital medicines,” said Martin VanTrieste, RPh, the president and CEO of the nonprofit company. Already, Civica Rx has provided 1.6 million doses of critical medicines to the Strategic National Stockpile for the COVID-19 response. The neuromuscular blocking agents, pain relievers and sedatives for intubation, broad-spectrum antibiotics for secondary infections, and other drugs to treat comorbidities were supplied in partnership with the Phlow Corporation, in Richmond, Va. Civica Rx’s role will be to make the finished dosage forms of essential medications, including vials and syringes, using its established network of manufacturing partners. Civica Rx also will build its own finished dosage-form

Specialty Spe p cialty Pharmacy Continu Continuum • September/October 2020

POLICY

about fair allocation of resources, Dr. Watson said. While much of that had to do with ventilators, it opens the door for conversations about how COVID-19 vaccines should be distributed if and when they are approved and appropriate. “Getting the vaccine is just one step,” he said. “Getting the vaccine to the people who need it will be an entirely different issue. As health plans, we will have to partner with health care organizations to make sure it’s done fairly and appropriately for our population.”

Multiple Points of Support

health plans can be involved in, he said, including testing for their members and the broader community, and supporting member needs outside of clinical care, such as providing food benefits. It also highlighted opportunities for health plans to partner with clinical systems to address risky chronic conditions—such as obesity, hypertension and diabetes—that exacerbated COVID-19 clinical outcomes and deaths. “These should be areas of intense focus as we prepare for future epidemics,” Dr. Watson said. Health

systems and plans also have to look at social determinants of health to identify at-risk populations ahead of time, and consider remote management or other technologies to detect epidemics before they happen, he noted. The COVID-19 pandemic accelerated a trend in digital technologies, Dr. Watson said, and health plans need to be in a position to support their use. As the venue of care for more conditions shifts from hospital to home, devices will be a big piece of that, and more biometric data can be aggregated and

segmented within populations to identify trends in geographic areas. The pandemic will change the way we think about access to care, he added. “We have to think about how our members can access care through a variety of channels, with even social media as a clinical tool for those with lower-risk health care needs.” —By Karen Blum Dr. Watson reported no relevant financial relationships.

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manufacturing facility on the same site as Phlow’s other partners, Virginia Commonwealth University’s Medicines for All Institute and AMPAC Fine Chemicals. The pandemic that exposed America’s medication supply vulnerabilities was Civica Rx’s toughest challenge in only its second full year of operation. “Generics are treated like commodities, so there’s no real inventory in the pipeline. It was a big body blow to the supply chain when demand surged 300% during COVID-19 for some of the medications we deliver to members,” Mr. VanTrieste said. Yet “we were able to serve all of their day-to-day needs” because Civica Rx maintains a sixmonth inventory stockpile, has redundant suppliers and safety stock, had daily contact with hospital members in hot spot cities and manufacturer partners, and closely tracked FDA and ASHP drug shortage lists and IQVIA sales data and patterns, he noted. Mr. VanTrieste said attuned “members can be the first ones to identify demand surges and also possible shortages, through something as simple as two orders in a row that weren’t full. By trying to connect the dots with them, we have a higher probability of understanding what’s going to happen.” Such a proactive approach is key, he noted, because “once a house is on fire, you can’t buy fire insurance. And you can’t develop robust supplies in a pandemic. Every day at Civica, we measure risk and manage our business model around the potential risk we see. We are preparing for ongoing COVID-19 waves.”

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Specialty Pharmacy Continuum • September/October 2020

CLINICAL

AML Rx Evolves With Growing List of Options In acute myeloid leukemia (AML), newer options, such as a FLT3 inhibitor for relapsing-remitting disease and several therapies for patients who are ineligible for intensive chemotherapy, are pushing out old standards, according to data recently presented at the 2020 virtual annual meetings of the American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA). After decades of little progress, the options in AML are evolving quickly. ADMIRAL Trial: Long-Term Survivors New data from the phase 3 ADMIRAL trial presented at ASCO show that in a subset of patients who achieved an overall survival (OS) of 18 months or longer after treatment with the FLT3 inhibitor gilteritinib (Xospata, Astellas), the median duration of complete response (CR) has not been reached (abstract 7514).

Extended gilteritinib is feasible because it has been well tolerated despite substantial initial rates of cytopenias, Dr. Perl said, noting that the most common grade 3 or higher adverse events (AEs) occurring during the first 12 months of gilteritinib therapy were febrile neutropenia (45%), anemia (40%) and thrombocytopenia (23%). After 12 months, the incidences of

improve OS in older AML patients who are ineligible for more intensive chemotherapy regimens. One of the trials, called VIALE-A, was presented as a latebreaker at EHA (abstract LB2601). The other, VIALE-C, was presented at ASCO (abstract 7511). In VIALE-A, investigators enrolled 433 treatment-naive AML patients who were not eligible for intensive chemotherapy based on an age greater than 75 years or the presence of comorbidities, such as heart failure, lung dysfunction or poor performance status. The patients were randomly assigned, in a 2:1 ratio, to receive azacitidine combined with either venetoclax or placebo. To improve tolerability, they used a ramp-up schedule of venetoclax in the first cycle. Median OS, a co-primary end point with CR, was 14.7 months in the

These new data from

ADMIRAL confirm a

persistent mortality benefit at 24 months (20% vs. 14%). In VIALE-A, the rate of CR or CR plus partial hematologic recovery was

66.4% with venetoclax versus 28.3% without it.

In the trial, 371 patients with FLT mutation–positive AML were randomly assigned to receive gilteritinib or standard therapy. When the trial results were published last year (N Engl J Med 2019;381[18]:1728-1740), gilteritinib had demonstrated an OS advantage (9.3 vs. 5.6 months; P<0.001), but the new data show very long periods of disease control, particularly in patients who continued to take gilteritinib. The focus of this analysis was on the 63 patients who had survived at least 18 months, reported Alexander E. Perl, MD, an associate professor of medicine at the University of Pennsylvania, in Philadelphia. Of the 35 patients who underwent hematopoietic cell transplant (HCT), 25 (71%) remained on gilteritinib after transplant. Of the 28 patients who did not undergo HCT, 15 (54%) have received gilteritinib for at least 18 months, and some remain on this therapy.

these AEs decreased to 8%, 10% and 0%, respectively, he added. When the ADMIRAL trial was published, Dr. Perl said the OS benefit coupled with the drug’s greater tolerability established gilteritinib as a standard for treatment of FLT3-positive relapsingremitting AML. These new data from ADMIRAL confirm a persistent mortality benefit at 24 months (20% vs. 14%). Dr. Perl associated the improved longterm survival with the ongoing remissions, improvement in the proportion of patients receiving HCT and post-HCT administration of gilteritinib.

Phase 3 Venetoclax Data Broaden Role in Older Patients With AML Two phase 3 studies have expanded the evidence that venetoclax (Venclexta, AbbVie/Genentech) can be combined with other well-tolerated agents to

venetoclax arm versus 9.6 months in the placebo arm. Venetoclax reduced the risk for death by 34% (hazard ratio [HR], 0.66; P<0.001) reported Courtney DiNardo, MD, an associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, in Houston. The rate of CR or CR plus partial hematologic recovery (CRh) was 66.4% with venetoclax versus 28.3% without it (P<0.001). Venetoclax also was favored for the combined end point of CR plus CR with incomplete blood count recovery (CRi) in the FLT3-positive patients (72% vs. 36%; P=0.021) as well as in the IDH1/2-positive patients (75% vs. 11%; P<0.001). Several grade 3 or higher cytopenias, including neutropenia (42% vs. 29%) and febrile neutropenia (42% vs. 19%) were more common in the group receiving venetoclax. Gastrointestinal events

also were more common in patients receiving venetoclax, but most were grade 2 or lower, and no early deaths were associated with the combination. Tumor lysis syndrome (TLS), which has been associated with venetoclax in the past and is the reason that a rampup strategy is used when this drug is started, was not a significant issue in this study. Although there were three cases of minor TLS, no patient required a modified course of venetoclax. An inhibitor of the B-cell lymphoma-2 (or BCL-2) protein, venetoclax is approved in combination with azacitidine or decitabine, another hypomethylating agent, for the types of patients enrolled in the VIALE-A trial. It also is approved in combination with low doses of cytarabine, which was the focus of VIALE-C. In VIALE-C, 211 patients were randomly assigned in a 2:1 ratio to receive oral venetoclax plus a low dose of subcutaneous cytarabine or low-dose cytarabine alone. As in VIALE-A, venetoclax was initiated in a ramp-up strategy in the first cycle. In both groups, 20 mg/m2 of cytarabine was administered on the first 10 days of each 28-day cycle. For the primary end point of OS, venetoclax plus cytarabine was superior to cytarabine alone (8.4 vs. 4.1 months; HR, 0.70; P=0.04), according to investigator Andrew Wei, MBBS, PhD, an adjunct associate professor at the Australian Centre for Blood Diseases at Monash University, in Melbourne. Several secondary end points also favored venetoclax in combination with low-dose cytarabine, including CR/CRh (48% vs. 15%) and CR/CRi (48% vs. 13%). The median event-free survival was nearly twice as long in the group receiving both venetoclax and cytarabine (4.9 vs. 2.1 months). Grade 3 or higher neutropenia was twice as common with the combination (49% vs. 18%), but Dr. Wei called the safety profile of the combination “tolerable and manageable.” He concluded that these data support this combination as an option for newly diagnosed AML patients who are unfit for intensive chemotherapy.

5-Year Data With CPX-351 Support Survival Benefit Five-year data with CPX-351 (Vyxeos, Jazz), a liposomal encapsulation of cytarabine and daunorubicin, confirm a long-time OS benefit in newly diagnosed patients with high-risk or secondary AML. An OS benefit in this phase 3 trial of CPX-351 versus 7+3 chemotherapy was reported earlier (J Clin Oncol 2018;36:2684-2692), but these updated

Specialty Pharmacy Continuum • September/October 2020

CLINICAL

For patients who are ineligible for intensive chemotherapy, ‘the treatment options really come down to side effects, treatment schedules and, ultimately, whether the characteristics of their disease might better match one study’s cohort of patients versus another.’ —Martina Fraga, PharmD results show the proportion of AML patients aged 60 to 75 years who are alive five years after randomization is twice as great in the group treated with CPX-351 compared with the group treated with 7+3 chemotherapy (18% vs. 8%). The 7+3 regimen (seven days of cytarabine and three days of daunorubicin or another anthracycline) was a standard for AML for decades before the head-to-head comparison that established the superiority of CPX-351 led to its approval. The updated results of that trial were presented at ASCO (abstract 7510). The median follow-up now exceeds 60 months. Ultimately, 53 of the 153 patients randomly assigned to receive CPX-351 (35%) and 39 of the 156 patients assigned to 7+3 (25%) received HCT. Even among these patients, survival at five years ears was longer for those randomized to o CPX-351 (52% vs. 23%). “The study shows that CPX351 has the ability to produce orr contribute to long-term remission on and survival in these older patients,” reported investigator Jeffrey E. Lancet, MD, a senior member in the Department of Malignant Hematology at Moffitt Cancer Center, in Tampa, Fla. Dr. Lancet and his co-investigators concluded that these long-term results strengthen the conclusion that CPX351 is a superior treatment for relatively fit patients.

ASCO (abstract 7507), magrolimab was combined with azacitidine, which Dr. Sallman said has been shown to synergize with magrolimab. The median age of the 68 patients enrolled in this study was 72 years, and 68% had poor-risk cytogenetics. The CR/CRi rate was 56% in the 25 evaluable AML patients. In the 12 patients with TP53-mutated AML, the CR/CRi rate was 75%, even though this is regarded as a treatment-refractory form. In the 39 MDS patients, the CR rate was 42%. Although there was no control arm,

Progress in AML Means Challenging Choices

the response rates are impressive, according to Dr. Sallman. He reported that the median response has not yet been reached for AML or MDS. Importantly for this older patient population unfit for intensive chemotherapy, magrolimab was well tolerated. The types and severity of AEs were similar to those expected with azacitidine alone, Dr. Sallman reported. A phase 3 trial is planned. Although the study will be limited to high-risk MDS patients, Gilead has reported that the FDA has granted fast track designation to this drug for other B-cell malignancies, such as non-Hodgkin lymphoma and diffuse large B-cell lymphoma, and that trials in these other malignancies are underway.

specialist in hematology/oncology at the University of Michigan in Ann Arbor. “Traditionally, the treatment decision revolved around whether the patient could tolerate intensive chemotherapy. That is definitely still part of the discussion, but the newer options have allowed clinicians to target specific disease characteristics, such as molecular and cytogenetic aberrations.” For patients who are ineligible for intensive chemotherapy, “the treatment options really come down to side effects, treatment schedules and, ultimately, whether the characteristics of their disease might better match one study’s cohort of patients versus another,” Dr. Fraga added. “The presence of the FLT3 and IDH2 mutations

In AML patients, the expanding number of treatment options associated with improved OS relative to previous standards is good news, but it also creates challenges for clinicians. There are limited or no data comparing many of the newer treatments. Many factors, such as the mutational profile of the AML and the ability of AML patients to tolerate treatment, are important to consider. “This is definitely an interesting time in the treatment of AML,” suggested Martina Fraga, PharmD, a pharmacy

and other targetable molecular characteristics can also help further guide therapy decisions.” More head-to-head studies will facilitate these decisions, but Dr. Fraga said many choices could be made on the basis of disease characteristics and patient preference. “As it stands right now, the newer agents all tend to be fairly tailored to be used within specific subtypes,” she said. When more than one choice is reasonable, “it comes down to weighing the different side effect profiles, drug interactions and routes of administration to figure out

Promising AML Strategy: Novel CD47-Targeted Therapy Other new drugs are in the pipeline. A monoclonal antibody called magrolimab (Gilead) that targets CD47 on cancer cells also showed uncommon activity in newly diagnosed AML patients who were unable to receive intensive chemotherapy. The study included patients with highrisk myelodysplastic syndrome (MDS), who obtained similar benefits. “The six-month overall survival estimate was 100% in MDS and 91% in TP53-mutation AML patients,” reported David A. Sallman, MD, an assistant professor in the Department of Malignant Hematology at Moffitt Cancer Center. By blocking CD47, magrolimab acts as an immunotherapy. The CD47 protein on cancer cells generates a “do not eat me” signal to macrophages, but when CD47 is blocked, phagocytosis can proceed, according to Dr. Sallman. In this phase 1b trial presented at

which would be the best fit for the lifestyle and goals of the patient.” Dr. Fraga noted, however, that “as more drugs are approved and they start to be moved up in the treatment algorithms, these decisions are going to get more complex.” —Ted Bosworth The sources reported the following financial relationships: Dr. Perl: AbbVie, Actinium, Agios, Astellas, Daiichi Sankyo, Jazz, Newlink Genetics, Novartis, Takeda; Dr. DiNardo: AbbVie, Agios, Celgene, Daiichi Sankyo, Immune-Onc, Notable Labs, Novartis; Dr. Wei: AbbVie, Amgen, Celgene, Genentech, Janssen, Novartis, Pfizer, Roche, Servier; Dr. Sallman: AbbVie, Agios, Argenx, Celgene, Celyad, Incyte, Novartis; Dr. Lancet: Agios, Daiichi Sankyo, Jazz, Pfizer; Dr. Fraga: None.

Specialty Pharmacy Continuum • September/October 2020

CLINICAL

Newer Therapies for Subtle, Deadly Hyperkalemia Hyperkalemia is an easily missed, life-threatening condition that can recur frequently in high-risk populations, including patients with chronic kidney disease (CKD), heart failure and diabetes. “This is a condition that is commonly underappreciated,” said Jeff Dunn, PharmD, in a webinar on the condition hosted by the AMCP and sponsored by Relypsa, manufacturer of the potassiumbinding agent patiromer (Veltassa). Hyperkalemia can be classified as mild (serum potassium concentrations in mEq/L of 5.0-5.5), moderate (5.5-6.0) or severe (6.0 and above). “Serum potassium can elevate quickly and unexpectedly, and arrhythmias and sudden death may occur, so it needs to be addressed quickly,” said Dr. Dunn, who was the vice president for clinical strategy and programs and industry relations at Magellan Rx Management at the time of the webinar but is not head of clinical pharmacy at Haven. The condition can be deceptive, said Frank Peacock, MD, a professor of emergency medicine at the Baylor College of Medicine, in Houston, in an interview with Specialty Pharmacy Continuum. “A person with 6.8 serum potassium can look normal and be sitting there talking to you. They have no idea how severe their condition is, and just by looking at them, you don’t either. They can look fine one moment and drop dead from an arrhythmia the next. “Once you hit 5-5.5 or 6, the risk for mortality significantly increases, and

failure, as well as medications that inhibit potassium excretion, such as potassiumsparing diuretics and nonsteroidal antiinflammatory drugs (NSAIDs). Other common risk factors include diabetes and heart failure. “Patients with multiple risk factors are more likely to have high potassium, compounding the complexity of management of these patients,” Dr. Dunn said. “One study found that 13% to 32% of patients with CKD had been diagnosed with hyperkalemia. Another population-based study found that, among CKD patients diagnosed with hyperkalemia for the first time, 25.4% had diabetes, compared with only 14.6% of those with normal potassium levels, and 19.8% had heart failure, compared with 8.5% of those who had normal potassium levels” (Nephrol Dial Transplant 2018;33[9]:1610-1620; Clin J Am Soc Nephrol 2016;11[1]:90-100). Risk for hyperkalemia increases significantly as renal function declines, with an estimated glomerular filtration rate (GFR) of 30 mL/min/1.73 m2 or less considered a threshold for a substantial increase in risk, Dr. Dunn said. He pointed to a study in veterans which showed that 20.7% of patients with stage 3 CKD (GFR, 30-59) had hyperkalemia, compared with 42.1% of stage 4 CKD

Based on disease recurrences after discontinuation of patiromer, ‘the take home is that these patients, in a lot of cases, need to be chronically treated.’ —Jeff Dunn, PharmD it’s exponential,” said Dr. Dunn, who is also an associate chair and the research director for the Department of Emergency Medicine at Baylor. “That can be stratified and worsened among patients who have other comorbidities. If someone has diabetes, CKD and elevated potassium, their risk for sudden death is higher. If they have heart failure and CKD and elevated potassium, it’s even higher. If somebody has all of those things—heart failure, CKD and diabetes—which is not actually uncommon— their risk is higher still.” The two most common causes of hyperkalemia are CKD and certain medications, including renin-angiotensin-aldosterone system (RAAS) inhibitors such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), commonly used to treat heart

patients (GFR, 15-29), and 56.7% of stage 5 patients (GFR <15) (Arch Intern Med 2009;169[12]:1156-1162).

Vigilance Needed Among Clinicians, Managed Care Providers, case managers and payors should be particularly vigilant for hyperkalemia associated with medications, which in addition to RAAS inhibitors such as ACE inhibitors and ARBs can include mineralocorticoid receptor agonists (MRAs), NSAIDs, beta blockers, cyclosporin, heparin, digoxin, trimethoprim and pentamidine. “This is a really important intervention point—managing these potential drug interactions,” Dr. Dunn said. Prior to the introduction of new potassium-binding agents in the late 2010s, hyperkalemia associated with RAAS inhibitor medications often required dosing adjustments

to those medications, which posed a serious challenge. The first step in emergency treatment of hyperkalemia is to stabilize the membranes to protect the myocardium, typically by administering IV calcium gluconate. Within the next few minutes, the priority is to quickly and temporarily redistribute potassium back

a low-potassium diet is actually quite hard to do, and we want those patients on those RAAS inhibitors and achieving the outcome benefit of those drugs,” Dr. Dunn said. Two newer potassium-binding agents have proven to be effective at lowering serum potassium with minimal side effects: patiromer, first approved by the

Hyperkalemia By the Numbers Up to 32% of patients with CKD are diagnosed with hyperkalemia Among CKD patients diagnosed with hyperkalemia for the first time, 25.4% had diabetes, compared with 14.6% of those with normal potassium levels

19.8% of hyperkalemia patients had heart failure, compared with 8.5% of those with normal potassium levels CKD, chronic kidney disease Source: Nephrol Dial Transplant 2018;33(9):1610-1620; Clin J Am Soc Nephrol 2016;11(1):90-100.

into the cells. “In minutes, I can jam that potassium back in your cells and life is grand again—for a while. Because that doesn’t remove the potassium, it’s just hidden it,” Dr. Peacock said. Insulin paired with glucose, with or without a beta-2 adrenergic receptor agonist, is the treatment of choice at this stage. “Insulin opens the door and glucose pours into the cells and takes potassium with it,” he explained. “That works very quickly, too. But too much insulin can cause a fatal drop in blood sugar, which means that you have to pair insulin with glucose.” These two initial treatments work quickly and well, but they are temporary. “They don’t actually change your total body potassium amount at all,” Dr. Peacock said. “The next phases of treatment are focused on removing potassium from the body, [best done with] dialysis; you’re done in a couple of hours. But that can be a logistical nightmare in the emergent setting and is very expensive and invasive.” The historical standard of care for hyperkalemia was a low-potassium diet and discontinuing/modifying RAAS inhibitors. “That’s not ideal, because

FDA for hyperkalemia in 2015, and sodium-zirconium cyclosilicate (Lokelma, AstraZeneca), first approved in 2018.

Evidence Supports Long-Term Therapy In the OPAL-HK trial, one of several trials that led to the approval of patiromer, the drug provided significant reductions in serum potassium in CKD patients receiving RAAS inhibitors and reduced the rapid recurrence of hyperkalemia during a placebocontrolled withdrawal phase (N Engl J Med 2015;372[3]:211–221). “Everybody got to below 5, and that was maintained over the four weeks of the study,” Dr. Dunn said. “In the second phase of the study, which assessed what would happen if patients were withdrawn from the drug, 60% of patients who switched to placebo experienced a recurrence of hyperkalemia, compared with 15% who were maintained on patiromer (P<0.001). So the take home [message] is that these patients, in a lot of cases, need to be chronically treated.” The FDA’s approval for sodium-zirconium cyclosilicate was primarily based on data from the HARMONIZE trial, in

Specialty Pharmacy Continuum • September/October 2020

CLINICAL

which 258 patients with hyperkalemia received 10 g of the drug three times daily during an initial 48-hour openlabel phase; 98% of participants achieved normal serum potassium levels within 48 hours. During the randomized phase, the 237 patients who achieved normokalemia were assigned to either 5, 10, or 15 g of the drug daily or placebo. Compared with placebo, all three doses of sodium-zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days (JAMA 2014;312[21]:2223-2233). More recent data from an open-label extension trial showed that all patients taking sodium-zirconium cyclosilicate maintained potassium levels at or below 5.5 for at least 11 months, and 88.3% maintained potassium levels at or below 5.0 (Am J Nephrol 2019;570:473-480). N Both agents appear to be well tolerated, Dr. Peacock said, with sodium-zirconium cyclosilicate’s side effects including edema and hypokalemia, and patiromer’s including gastrointestinal symptoms such as constipation, diarrhea and nausea. “From everything we have seen to date, both of these drugs are effective and safe, and patients can be comfortable taking them daily on a long-term basis,” said Dr. Peacock, who noted that both have a preferable side effect profile compared with a previous potassium binder, sodium polystyrene sulfonate (Kayexalate, Concordia Pharmaceuticals), which has been associated with debilitating diarrhea as well as intestinal bleeding and necrosis and upper GI tract injury (Surgery 1987;101[3]:267-272; Am J Surg Pathol 1997;21[1]:60-69; Am J Surg Pathol 2001;25[5]:637-644).

normal but not scary, from 5.5-6, this approach might be effective. That’s what we want to figure out.” —Gina Shaw Dr. Peacock reported financial relationships with Abbott, AseptiScope, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Brainbox, Braincheck, CSL Behring, Comprehensive Research Associates, Daiichi-Sankyo, ImmunArray, Ischemia DX, Instrument Labs, Janssen, Johnson & Johnson, Nabriva, Ortho, Portola, Quidel, Relypsa, Roche, Salix and Siemens, Dr. Dunn reported no relevant financial relationships other than his stated employment.

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online: Catch us binutrition.com

www.fre

seniuska

Choose the alternative with M.O.R.E. SMOFlipid is the only alternative lipid injectable emulsion (ILE) for adults with FOUR oil sources for MORE alternatives.

Watch Out for Elevated Sodium No head-to-head studies have been conducted between sodium-zirconium cyclosilicate and patiromer. “The biggest difference between the two drugs is that patiromer uses calcium as the exchange ion, while [sodium-zirconium cyclosilicate] exchanges sodium for potassium,” Dr. Dunn said. “So you have to be careful with [sodium-zirconium cyclosilicate] in patients who are at risk for issues with elevated sodium.” Neither of these drugs is indicated for use in emergent control of hyperkalemia, but, given that they take some time to have an effect. Dr. Peacock is pursuing trials to assess higher doses of potassium binders as possible emergency treatments. “Rather than giving IV insulin plus glucose and then a binder, could we give four times the recommended dose of the binder and be able to send the patient home? That’s what we would like to investigate. I suspect that there’s a level of effect. If your patient is at 6.5-7, there’s no binder that can bring potassium down quickly enough, but if they are above

Monounsaturated, fatty acid-olive oil, which is immune neutral1 Omega-3s, which may have less pro-inflammatory effects than other lipid sources1 Rapidly available energy from MCTs2 Essential fatty acids delivered from soybean oil SMOFlipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use: The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in SMOFlipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions. Contraindications: Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the active ingredients or excipients. Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1,000 mg/dL.

Please see Brief Summary of Prescribing Information including Boxed Warning for SMOFlipid on the next page.

Specialty Pharmacy Continuum • September/October 2020

CLINICAL

PAPs Breathe Life Into Asthma/COPD Care Patients with asthma and chronic obstructive pulmonary disease (COPD) who are enrolled in patient assistance programs (PAPs) for long-term medications are less likely to be hospitalized or visit the emergency department (ED), according to a study by Georgia pharmacists. Looking at records from 56 patients with COPD or asthma at Piedmont Athens Regional Medical Center who obtained medication through a PAP from January

2018 through March 2019, researchers found that the number of cumulative ED visits decreased from 54 in the six months before PAP enrollment to seven in the

SMOFLIPID (lipid injectable emulsion), for intravenous use BRIEF SUMMARY OF PRESCRIBING INFORMATION This brief summary does not include all the information needed to use SMOFlipid safely and effectively. Please see full prescribing information, including Boxed Warning for Smoflipid (lipid injectable emulsion), for intravenous use at www.freseniuskabinutrition.com/products/smoflipid.

>(9505.! +,(;/ 05 79,;,94 05-(5;: +LH[OZ PU WYL[LYT PUMHU[Z HM[LY PUM\ZPVU VM PU[YH]LUV\Z SPWPK LT\SZPVUZ OH]L ILLU YLWVY[LK PU [OL TLKPJHS SP[LYH[\YL (\[VWZ` ÄUKPUNZ PUJS\KLK PU[YH]HZJ\SHY MH[ HJJ\T\SH[PVU PU [OL S\UNZ 7YL[LYT PUMHU[Z HUK SV^ IPY[O ^LPNO[ PUMHU[Z OH]L WVVY JSLHYHUJL VM PU[YH]LUV\Z SPWPK LT\SZPVU HUK PUJYLHZLK MYLL MH[[` HJPK WSHZTH SL]LSZ MVSSV^PUN SPWPK LT\SZPVU PUM\ZPVU INDICATIONS AND USAGE SMOFlipid is indicated in adults as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. Limitations of Use: The omega-6: omega-3 fatty acid ratio and Medium Chain Triglycerides in SMOFlipid have not been shown to improve clinical outcomes compared to other intravenous lipid emulsions. Cumulative ED

six months after enrollment. Cumulative hospitalizations during the same time frame dropped from 13 to zero. “Having access to the medication was a huge contributor” to the results, said lead author Brooke Gallman, PharmD, a PGY-1 resident at the 360-bed nonprofit hospital and referral center. “Most of these patients were not able to afford inhalers prior to enrolling in the program, so they were having a lot of exacerbations. Every

aluminum at greater than 4 to 5 mcg/kg/day can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of PN products. • Risk of Parenteral Nutrition-Associated Liver Disease (PNALD): PNALD has been reported in patients who receive PN for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD, although a causal relationship has not been established. If SMOFlipid-treated patients develop liver test abnormalities, consider discontinuation or dose reduction. • Hypertriglyceridemia: Impaired lipid metabolism with hypertriglyceridemia may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. • Monitoring/Laboratory Tests: Routinely monitor serum triglycerides, fluid and electrolyte status, blood glucose, liver and kidney function, blood count including platelets, and coagulation parameters throughout treatment. Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended. • Interference with Laboratory Tests: Content of vitamin K may counteract anticoagulant activity. The lipids contained in this emulsion may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase [LDH], bilirubin, and oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream.

Piedmont Athens PAP Successes:

ADVERSE REACTIONS

visits decreased Most common adverse drug reactions >1% of patients who received SMOFlipid from clinical trials were nausea, vomiting, hyperglycemia, flatulence, pyrexia, from 54 to seven

DOSAGE AND ADMINISTRATION abdominal pain, increased blood triglycerides, hypertension, sepsis, dyspepsia, The recommended daily dosage in adults is 1 to 2 grams/kg per day and should not urinary tract infection, anemia and device-related infection. Cumulative exceed 2.5 grams/kg per day. SMOFlipid 1000 mL is supplied as a Pharmacy Bulk hospitalizations Package for admixing only and is not for direct infusion. Prior to administration, Less adverse reactions in ) 1% of patients who received SMOFlipid were dropped from 13common to zero transfer to a separate PN container. dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased Median amount billed per patient CONTRAINDICATIONS C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritis, Known hypersensitivity to fish, egg, soybean, or peanut protein, or to any of the fromdizziness, decreased $4,683rash toand $0thrombophlebitis. active ingredients or excipients. The following adverse reactions have been identified during post-approval use of Severe hyperlipidemia or severe disorders of lipid metabolism with serum Median hospital acquisition cost per SMOFlipid in countries where it is registered. Infections and Infestations: infection. triglycerides > 1,000 mg/dL. person dropped from $351Thoracic to $0and Mediastinal Disorders: dyspnea. Respiratory, WARNINGS AND PRECAUTIONS To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, • Death in Preterm Infants: (see BLACK BOX WARNING) LLC, at 1-800-551-7176, option 5, or FDA at 1-800-FDA-1088 or • Hypersensitivity Reactions: SMOFlipid contains soybean oil, fish oil, and egg www.fda.gov/medwatch. phospholipids, which may cause hypersensitivity reactions. Cross reactions DRUG INTERACTIONS have been observed between soybean and peanut oil. Signs or symptoms Coumarin and Coumarin Derivatives, Including Warfarin: Anticoagulant activity of a hypersensitivity reaction may include: tachypnea, dyspnea, hypoxia, may be counteracted; monitor laboratory parameters. bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, USE IN SPECIFIC POPULATIONS pyrexia, or chills. If a hypersensitivity reaction occurs, stop infusion of SMOFlipid • Pregnancy and Lactation: There are no available data on risks associated with immediately and undertake appropriate treatment and supportive measures. SMOFlipid when used in pregnant or lactating women. • Risk of Catheter-Related Infections: Lipid emulsions, such as SMOFlipid, can • Pediatric Use: The safety and effectiveness of SMOFlipid have not been support microbial growth and is an independent risk factor for the development established in pediatric patients. of catheter-related bloodstream infections. The risk of infection is increased in • Hepatic Impairment: Parenteral nutrition should be used with caution in patients patients with malnutrition-associated immunosuppression, long-term use and with hepatic impairment. Hepatobiliary disorders are known to develop in some poor maintenance of intravenous catheters, or immunosuppressive effects of patients without preexisting liver disease who receive PN, including cholestasis, other concomitant conditions or drugs. hepatic steatosis, fibrosis and cirrhosis (PN associated liver disease), possibly • Fat Overload Syndrome: This is a rare condition that has been reported with leading to hepatic failure. intravenous lipid emulsions. A reduced or limited ability to metabolize lipids accompanied by prolonged plasma clearance may result in a syndrome OVERDOSE characterized by a sudden deterioration in the patient’s condition including fever, In the event of an overdose, fat overload syndrome may occur. Stop the SMOFlipid anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, infusion until triglyceride levels have normalized. The effects are usually reversible fatty liver infiltration (hepatomegaly), deteriorating liver function, and central by stopping the lipid infusion. If medically appropriate, further intervention may be nervous system manifestations (e.g., coma). indicated. Lipids are not dialyzable from serum. • Refeeding Syndrome: Reintroducing calories and protein to severely undernourished patients with PN may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. • Aluminum Toxicity: SMOFlipid contains no more than 25 mcg/L of aluminum. During prolonged PN administration in patients with renal impairment, the 9,-,9,5*,:! Vanek VW, et al. A.S.P.E.N. position paper: Clinical role for alternative intravenous aluminum levels in the patient may reach toxic levels. Preterm infants are at fat emulsions. Nutr Clin Pract. 2012;27(2):150-192. Deckelbaum RJ, et al. Medium-chain versus greater risk because their kidneys are immature, and they require large amounts long-chain triacylglycerol emulsion hydrolysis by lipoprotein lipase and hepatic lipase: implications for of calcium and phosphate solutions, which contain aluminum. Patients with the mechanisms of lipase action. Biochemistry (Mosc). 1990;29(5):1136-1142. renal impairment, including preterm infants, who receive parenteral intakes of

Fresenius Kabi USA, LLC Three Corporate Drive, Lake Zurich, IL 60047 Phone: 1.888.386.1300 www.fresenius-kabi.com/us

hospital encounter that I included in this study was related to a COPD or asthma visit,” she said. A lot of these patients were set up with primary care during the study period, which could be another factor contributing to the positive findings, she added. The median amount billed per patient decreased from $4,683 before PAP enrollment to $0 (P<0.001), and the median hospital acquisition cost per person dropped

Piedmont Athens PAP Successes: Cumulative ED visits decreased from 54 to seven Cumulative hospitalizations dropped from 13 to zero Median amount billed per patient decreased from $4,683 to $0 Median hospital acquisition cost per person dropped from $351 to $0

from $351 to $0 (P=0.002), according to the study (No. 5) presented at the American College of Clinical Pharmacy’s 2020 virtual poster symposium. “I knew there was a benefit for the patient; however, I wasn’t expecting to see that much of a monetary decrease as well as seeing ED visits decrease by almost 90% in these patients,” said Dr. Gallman, who added that a pharmacy buyer who is a certified pharmacy technician helps enroll patients in the PAP. “We were really happy with our results, and we think that it justifies continuing this program.”

Some Caveats It would have been helpful to see patient medication compliance information before and after participation in the program to confirm the validity of the conclusions and learn whether the PAP provided medications or coupons, commented Mark Malesker, PharmD, a professor of pharmacy practice at Creighton University, in Omaha, Neb., who works with pulmonary critical care patients. He noted that it’s also unusual to put asthma and COPD patients together in one study, he said, because those populations tend to have different demographics. —Karen Blum The sources reported no relevant financial relationships.

Specialty Pharmacy Continuum • September/October 2020

CLINICAL

Immunotherapy Toxicities: Early Recognition, Management, And Concerns in the COVID-19 Pandemic SAMANTHA SPENCER, PHARMD, BCPS Clinical Assistant Professor University of Illinois at Chicago Drug Information Group Chicago, Illinois

mmune checkpoint inhibitors and adoptive cell transfer therapies have unlocked new avenues to treat cancer, but they are associated with immune-related adverse events (irAEs).

Pharmacists can play an integral role in managing these irAEs and educating patients and other health care professionals about them. The immune system recognizes tumors and eradicates cancerous cells through T cells and natural killer cells,1 but to ensure that T cells do not autoreact to normal cells, the body has mechanisms that downregulate their activity as needed.2 Checkpoint pathways regulate T cells to prevent autoimmunity through a process called peripheral tolerance. To evade detection by T cells, cancer cells hijack this mechanism. Checkpoint inhibitors enable the immune system to better recognize and eliminate cancerous cells that are evading the immune system this way.2 Several checkpoint pathways regulate T cells, including the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death-1 (PD-1) pathways.2 The CTLA pathway regulates the early stages of T-cell activation, and most expression is found in lymphoid tissue. In contrast, PD-1 regulates previously activated T cells in the later stages of the immune system response and is found mostly in peripheral tissues. Inhibition of CTLA-4 and PD-1—or its ligand, programmed death ligand-1 (PD-L1)— restores the immune system’s ability to respond to tumors. These pathways have been successfully targeted and have led to the approval of several checkpoint inhibitors (Table 1).3-12 Adoptive cell transfer therapy is another approach that has been developed to increase the immune system’s ability to target tumors.1 Specifically, in chimeric antigen receptor (CAR) T-cell therapy, T cells are harvested from a patient, genetically modified to express CARs, multiplied, and reinfused into the patient. Three such therapies are approved by the FDA: axicabtagene ciloleucel (Yescarta, Kite) tisagenlecleucel (Kymriah, Novartis), and brexucabtagene autoleucel (Tecartus, Kite) (Table 1). All express a CAR with an anti-CD19 chain, which allows the modified T cells to recognize and eliminate CD19-expressing cells.3,4,12

Checkpoint Inhibitors Immune-Related Adverse Events Due to their novel mechanism of action, checkpoint inhibitors are not associated with the

traditional AEs seen with cytotoxic chemotherapy.13 However, inhibition of CTLA-4, PD-1, and PD-L1 can lead to excessive immune system activation with upregulation of T-cell proinflammatory responses.13-15 This activation of the immune system can result in irAEs. The exact mechanism of irAEs has not been elucidated fully, but it is hypothesized that T-cell activity, autoantibodies, and proinflammatory cytokines may contribute to their development. Dermatologic, gastrointestinal, endocrine, and pulmonary-related irAEs are the most common irAEs, but they can manifest in any organ system. The CTLA-4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb) is associated with the highest rates of irAEs; 75% of patients will experience an irAE and one-fourth will have a high-grade irAE.13,15 Dermatologic and gastrointestinal events have been reported most commonly.13 Phase 3 trials of the PD-1/PD-L1 inhibitors reported lower rates, with no more than 30% of patients experiencing an irAE.13,15 In patients receiving combination checkpoint inhibitor therapy (ie, nivolumab [Opdivo, Bristol-Myers Squibb] with ipilimumab), almost all experience an irAE (96%) and over half (59%) develop a high-grade irAE. The rates of irAEs also vary based on the underlying cancer, and for ipilimumab and pembrolizumab (Keytruda, Merck) the toxicity is dose dependent. Most irAEs experienced by patients receiving checkpoint inhibitors are mild to moderate, but severe events, including fatal ones, can occur with these agents. Rash and pruritus are the most common dermatologic irAEs, and they typically present as a lowgrade reaction.13 Dermatologic toxicities occur in approximately 30% to 40% of patients receiving PD-1/PD-L1 inhibitors and 50% of those receiving ipilimumab.15 Patients with melanoma have been observed to experience more dermatologic irAEs than patients with other underlying cancers.16 Diarrhea is another frequent irAE, with ipilimumab associated with the highest rates of occurrence (23%-41%). Additionally, colitis occurs in 7% to 16% of patients receiving ipilimumab and in 1% to 3% of patients receiving PD-1/PD-L1 inhibitors. Endocrine irAEs occur less frequently, but hypothyroidism,

hyperthyroidism, and hypophysitis have been reported most frequently among the endocrinopathies. Pneumonitis is rare (<1% with ipilimumab; 1%-3% with PD-1/PD-L1 inhibitors) but can lead to serious consequences. A number of additional irAEs have been reported, but many occur at a much lower incidence. The average onset of these irAEs varies, with dermatologic reactions presenting within 2 to 3 weeks and gastrointestinal, hepatic, and endocrine toxicities occurring after 2 to 3 months of therapy.14,16 However, the range for onset is broad, with some irAEs taking up to 2 years to appear,16 and they sometimes occur weeks or months after discontinuation of the medication.14 Management of irAEs Patients increasingly are presenting with irAEs outside of the oncology space.14 Recognition of irAEs generally begins with a detailed medication history, including past medications because irAEs can occur even after discontinuation of a checkpoint inhibitor. A recent study reported that diarrhea was the most common irAE that led to patient presentation in an emergency department (ED).17 Other irAEs frequently observed in the ED included colitis, pneumonitis, dermatitis, hypophysitis, and hepatitis. Mild irAEs typically can be managed while the patient continues checkpoint inhibitor therapy, with a few exceptions.13,17 More severe toxicities generally require discontinuation of therapy. Corticosteroids are a cornerstone of irAE management and are recommended in the treatment of most reactions.13,16 Thyroid-related irAEs are a notable exception; clinicians do not use corticosteroids as part of the management of thyroid-related irAEs, except in cases of severe hyperthyroidism that may progress to thyroid storm.18 Guidance on steroid dosing can be found in clinical guidelines and the prescribing information for individual drugs.5-13,18 Generally, higher corticosteroid doses are reserved for moderate and severe irAEs.13 Additionally, the decision to use corticosteroids must consider patient-specific factors, such as see IMMUNOTHERAPY, page 18

Specialty Pharmacy Continuum • September/October 2020

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IMMUNOTHERAPY

Table 1. FDA-Approved Immunotherapies

continued from page 17

comorbid conditions, type and number of irAEs, concurrent immunosuppressive therapies, and the ability to tolerate corticosteroids. Specific guidance on irAE management can be found in practice guidelines by the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network.13,18 The ASCO guideline has detailed information about the grading and management of irAEs.18 A few examples outlining the recognition and management of irAEs are presented in Table 2.13,18 For high-grade toxicities, more aggressive management is needed and should be provided in conjunction with a specialist referral.13,18

Class

CTLA-4 inhibitor

Ipilimumab (Yervoy, BristolMyers Squibb)

2011

• CRC, metastatic or metastatic MSI-H • HCC • Melanoma • Metastatic NSCLC • RCC, advanced

PD-1 inhibitor

Cemiplimab (Libtayo, Regeneron)

2018

• Cutaneous SCC, metastatic or locally advanced

Nivolumab (Opdivo, BristolMyers Squibb)

2014

• Classic Hodgkin lymphoma, relapsed • CRC, metastatic MSI-H • Esophageal SCC • HCC • HNSCC, recurrent or metastatic • Melanoma • NSCLC, metastatic • RCC, advanced • SCLC, metastatic • UCC, recurrent or metastatic

Pembrolizumab (Keytruda, Merck)

2014

• Cervical cancer, recurrent or metastatic • Classic Hodgkin lymphoma, refractory • CRC, MSI-H • Cutaneous SCC • Endometrial carcinoma, advanced • Esophageal cancer, recurrent or metastatic • Gastric cancer, recurrent or metastatic • HCC • HNSCC • Melanoma • Merkel cell carcinoma, recurrent or metastatic • MSI-H cancers, unresectable or metastatic • NSCLC • PMBCL, refractory • RCC, advanced • SCLC, metastatic • TMB-H solid tumors, unresectable or metastatic • UCC

Atezolizumab (Tecentriq, Genentech)

2016

• Breast cancer, triple-negative • HCC, unresectable or metastatic • Melanoma • SCLC, extensive-stage • NSCLC, metastatic • UCC, locally advanced or metastatic

Avelumab (Bavencio, EMD Serono)

2017

• Merkel cell carcinoma, advanced • RCC, advanced • UCC, locally advanced or metastatic

Durvalumab (Imfinzi, AstraZeneca)

2017

• NSCLC, unresectable stage III • SCLC, extensive-stage • UCC, advanced or metastatic

Axicabtagene ciloleucel (Yescarta, Kite)

2017

• B-cell lymphoma, relapsed or refractory

Brexucabtagene autoleucel

2020

• Mantle cell lymphoma, relapsed or refractory

Tisagenlecleucel (Kymriah, Novartis)

2017

• B-cell ALL, relapsed or refractory • Large B-cell lymphoma, relapsed or refractory

The novel 2019 coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has introduced potential complications in patients with cancer. Particularly relevant to checkpoint inhibitor therapy is the overlap of symptoms of COVID-19 with immunerelated pneumonitis.19 Appropriate recognition of symptoms is imperative to ensure patients receive optimal treatment. While the clinical presentation of COVID-19 still is being characterized, the most common symptoms are fever, cough, and dyspnea.20 With pneumonitis, dyspnea and cough are common, with fever occurring less frequently.19,21 Given these overlapping symptoms, it is critical for patients taking checkpoint inhibitors to quickly recognize and contact their health care provider about any of these core symptoms. COVID-19 testing and radiological findings can aid in the differential diagnosis to quickly determine the appropriate course of therapy and whether corticosteroids, which have a controversial role in COVID-19 treatment outside of severe cases, should be initiated.

CAR T-Cell Therapy

PD-L1 inhibitor

Cytokine Release Syndrome

see IMMUNOTHERAPY, page 20

Current FDA Indicationsa

Checkpoint inhibitors

IrAEs Considerations With COVID-19

Axicabtagene ciloleucel, brexucabtagene autoleucel, and tisagenlecleucel contain boxed warnings in their prescribing information and are only available through a Risk Evaluation and Mitigation Strategies (REMS) program to moderate the risks of therapy, including cytokine release syndrome (CRS).3,4,22,23 Infusion of CAR T cells leads to a state of increased circulating proinflammatory cytokines coupled with suppression of anti-inflammatory cytokines.1,24 This imbalance causes CRS and, specifically, the activation of interleukin (IL)-6 contributes to capillary leak syndrome. CRS presents as fever, myalgias, and malaise that can progress to potentially fatal or life-threatening manifestations, including hypoxia, pulmonary edema, hemodynamic instability, renal and/or hepatic dysfunction, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.1,13 Almost all patients receiving axicabtagene ciloleucel (94%) had CRS (any grade) in its clinical trial.3 Any grade of CRS was reported in 79% and 74% of patients receiving tisagenlecleucel for relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory diffuse large B-cell lymphoma in clinical trials,

Drug

Initial Approval Date

CAR T-cell therapy CD-19 T-cell immunotherapy

As of August 3, 2020; see prescribing information for details on the specific place in therapy within these indications. ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CRC, colorectal cancer; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; MSI-H, microsatellite instability-high; NSCLC, non-small cell lung cancer; PMBCL, primary mediastinal B-cell lymphoma; RCC, renal cell carcinoma; SCC, cutaneous squamous cell carcinoma; SCLC, small cell lung cancer, TMB-H, tumor mutational burden-high; UCC, urothelial carcinoma

Based on references 3-12.

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Specialty Pharmacy Continuum • September/October 2020

CLINICAL

IMMUNOTHERAPY continued from page 18

respectively.4 Most often, CRS presents within 2 to 3 days after CAR T-cell infusion and persists for approximately a week.13 However, patients should be monitored for signs and symptoms of CRS for 4 weeks after CAR T-cell therapy.22,23 Management of CRS Management of CRS is critically dependent on early recognition of symptoms to reduce the risk for a fatal outcome.1 The IL-6 receptor antagonist tocilizumab (Actemra, Genentech) is an important component in treating CRS.25 In an analysis of clinical trials for axicabtagene ciloleucel and tisagenlecleucel, 53% to 69% of patients with severe or life-threatening CRS resolved their fever and need for vasopressors within 14 days after 1 or 2 doses of tocilizumab.26 For patients presenting with a fever not attributable to another cause, symptomatic management and administration of empirical antibiotics is appropriate.13 For prolonged (>3 days) or higher-grade CRS (grade 2 or higher), tocilizumab is recommended. The dosing is 8 mg/kg (maximum, 800 mg) given via IV infusion over 1 hour.13,25 For patients weighing less than 30 kg, a dose of 12 mg/kg should be used instead.25 Tocilizumab can be repeated as needed every 8 hours, with a

maximum of 3 doses in 24 hours or 4 doses overall. For grades 3 and 4, IV corticosteroids should be given with tocilizumab therapy.13 Vasopressors and other therapies to manage hypotension and hypoxia also should be used when needed.

The Pharmacist’s Role Pharmacists are in a unique position to educate providers and patients about potential AEs, recognition of symptoms, and management of immunotherapy toxicities.27 Early recognition and management of irAEs is critical for patients. Patient education for checkpoint inhibitors should focus on potential signs and symptoms and encourage patients to report any concerning symptoms quickly.28 Patterns of irAE incidence, including the type of irAE, prescribed checkpoint inhibitor, and underlying risk factors, should be considered.27 In addition, as corticosteroids are a foundation of treatment, pharmacists can assist in initial prescribing and tapering strategies. Tapers should last at least 4 weeks but should be individualized, as patients with corticosteroid-refractory disease may require a longer taper (6-12 weeks).27 There is no universal recommended tapering strategy, but the length of the taper is dependent on the severity and type of irAE.29 During any tapering strategy, close monitoring is warranted because the irAE can rebound. In addition, to help mitigate the risk

Table 2. Management of Selected Low-Grade Immune-Related AEs Toxicity Rash

Diarrhea/ colitis

Signs and Symptoms

Other Considerations

Management

• Erythematous or maculopapular rash, frequently affecting the upper trunk • Pruritus • Vitiligo • Blistering, skin sloughing, and severe cutaneous irAEs (SJS, TENS) are treated more aggressively

• Typically presents during the first 2 treatment cycles • Ipilimumab is associated with higher rates of dermatologic irAEs compared with PD-1/PD-L1 inhibitors

• Continue ICPi for grades 1 and 2; hold with higher grades • Topical emollients, topical corticosteroids, and oral antihistamines • For more moderate symptoms, higher potency topical corticosteroids may be needed • Consider initiating oral corticosteroids for moderate symptoms (prednisone 0.5-1 mg/kg/day until back to grade 1, then taper over 4-6 wk)

• Watery diarrhea • Increase in stool count • Blood or mucus in stool • Abdominal pain, cramping

• Typically presents 6 to 8 weeks after starting treatment • Ipilimumab is associated with higher rates of gastrointestinal irAEs compared with PD-1/PD-L1 inhibitors

• Consider holding ICPi with grade 1; hold with higher grades • Oral hydration and dietary changes • Loperamide for 2-3 d • Consider initiating oral corticosteroids for grade 2 (prednisone 1-2 mg/kg/day until back to grade 1, then taper over 4-6 wk)

• Median time to onset is 2.5 months; earlier onset with combination therapy • PD-1/PD-L1 inhibitors are associated with higher rates of pulmonary irAEs compared with ipilimumab

• Hold ICPi with evidence of pneumonitis progression • For grade 2, oral corticosteroids (prednisone 1-2 mg/kg/day, then taper over 4-6 wk) • Consider empirical antibiotics

Pneumonitis • Dyspnea, cough • Chest pain • Difficulty with breathing (grade 1 – asymptomatic)

for corticosteroid AEs, gastrointestinal bleeding prophylaxis and Pneumocystis jirovecii prophylaxis should be considered.15 For CAR T-cell therapies, detailed information on the management of CRS can be found in the REMS programs for axicabtagene ciloleucel, brexucabtagene autoleucel, and tisagenlecleucel.22,23 Of note, hospitals that

Table 3. Key Education Points for Pharmacists Pearls on Use of Corticosteroids for irAEs • Prednisone is recommended if a patient can tolerate oral therapy; otherwise, IV methylprednisolone can be used. • Short-term use does not affect the antitumor efficacy of the checkpoint inhibitors. • Patients should expect some response within 48 to 72 hours of initiation; dose increases or additional immunosuppressive agents may be required if there is no initial response. • Once symptoms improve to a mild level (ie, grade 1), corticosteroids are tapered off over 4 to 6 weeks. • Consider prescribing a PPI for gastrointestinal prophylaxis during corticosteroid therapy. • For long-term immunosuppression (>30 mg prednisone for more than 3 weeks), consider PCP prophylaxis. • Monitor for AEs associated with corticosteroid therapy (eg, hyperglycemia, edema, anxiety, iatrogenic adrenal insufficiency). Pearls on Use of Tocilizumab for CRS • Tocilizumab is approved only for CAR T-cell–induced CRS, not CRS mediated by other factors. • Hospitals and clinics that prescribe CAR T-cell therapies must be certified through REMS programs and have immediate, on-site access to tocilizumab. • For CRS, tocilizumab should be administered as an IV infusion only. • Consider storing tocilizumab vials in a separate location from prefilled syringes that are intended for subcutaneous administration to reduce the risk for dispensing errors. • Through inhibition of IL-6, tocilizumab can induce cytochrome P450 activities, which can persist for several weeks after a dose; therefore, concomitant medications should be reviewed for potential monitoring or dose adjustments. • Patients with concomitant neurologic toxicity also will need corticosteroids, since tocilizumab has limited efficacy in treating neurologic symptoms.

ICPi, immune checkpoint inhibitor; irAEs, immune-related adverse events; PD-1/PD-L1, programmed death (ligand)-1; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis

AEs, adverse events; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; IL-6, interleukin-6; PCP, Pneumocystis jirovecii prophylaxis; PPI, proton pump inhibitor; REMS, risk evaluation and mitigation strategies

Based on references 13 and 18.

Based on references 1, 3, 4, 13, 15, 18, 25, and 30.

Guidance on grading and more specific management, including high-grade irAEs, can be found in the ASCO guideline.

Specialty Pharmacy Continuum • September/October 2020

CLINICAL

treat patients with CAR T-cell therapies must have 2 vials of tocilizumab on hand as part of the REMS program. Table 3 contains some key educational pearls for pharmacists about the use of corticosteroids and tocilizumab for irAE management.1,3,4,13,15,18,25,30 In the setting of the COVID-19 pandemic, additional challenges have arisen in balancing the risks and benefits of starting or continuing immunotherapeutic agents in cancer patients.21,31 Delivery of these agents requires contact with the health care system, and it is not known whether receipt of these agents affects the risk for contracting COVID-19 or its clinical course. For example, with FDA approval, extended-interval dosing strategies for checkpoint inhibitors (eg, pembrolizumab every 6 week administration) may be considered to limit patient exposure to health care environments.32 For CAR T- cell therapies, it may be prudent to delay treatment if resources such as hospital and ICU capacity and tocilizumab availability are strained.31 However, delaying treatment may not be realistic for many patients who need these therapies.21,33 Treatment decisions should be Individualized and consider indications and therapy goals. It is important to keep patients who are starting or continuing treatment informed of potential risks and the need to promptly report any symptoms of cough, fever, or dyspnea. Use of telemedicine also may help minimize exposure.34 Regulations for telemedicine have been relaxed through federal packages, notably the Coronavirus Aid, Relief, and Economic Security (CARES) Act that expanded Medicare telehealth coverage. Several private payors also have expanded coverage of telemedicine as well. Given these expansions, pharmacists can contribute by encouraging telemedicine when appropriate and following up with patients to ensure that they have the knowledge and resources needed to navigate their health care during this pandemic.

Conclusion The use of immunotherapeutic agents has increased dramatically over the past few years with the approval of additional agents and expansion of indications.14 Thus, it is likely that more health care providers, including those in emergency medicine, will encounter patients with irAEs. Ultimately, timely recognition of irAEs and CRS is critical in managing the potential toxicities of immune checkpoint inhibitors and CAR T-cell therapies, respectively.35 Patients should be educated to promptly report any symptoms of cough, fever, and dyspnea during the COVID-19 pandemic in particular. Early

identification and prompt management reduce patient morbidity and mortality. The complexities of cancer treatment with immunotherapies make a multidisciplinary approach increasingly important, with pharmacists playing an integral role in optimizing the management of patients treated with these agents.

References 1.

Dushenkov A, Jungsuwadee P. Chimeric antigen receptor T-cell therapy: foundational science and clinical knowledge for pharmacy practice. J Oncol Pharm Pract. 2019;25(5):1217-1225.

2. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. 3. Yescarta [package insert]. El Segundo, CA: Kite Pharma Inc; 2020. 4. Kymriah [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 5. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2020. 6. Libtayo [package insert]. Regeneron Pharmaceuticals Inc; 2020. 7.

Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2020.

8. Keytruda [package insert]. Whitehouse Station, NJ: Merck Sharpe & Dohme Corp; 2020. 9. Tecentriq [package insert]. South San Francisco, CA: Genentech Inc; 2020. 10. Bavencio [package insert]. Rockland, MD: EMB Serono Inc; 2020. 11. Imfinzi [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2020. 12. Tecartus [package insert]. Santa Monica, CA: Kite Pharma Inc; 2020. 13. Management of immunotherapy-related toxicities. Version 2.2019. National Comprehensive Cancer Network website. www.nccn.org/professionals/physician_gls/ pdf/immunotherapy.pdf. Updated December 16, 2019. Accessed August 3, 2020. 14. Hryniewicki AT, Wang C, Shatsky RA, et al. Management of immune checkpoint inhibitor toxicities: a review and clinical guideline for emergency physicians. J Emerg Med. 2018;55(4):489-502. 15. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95. 16. Davies M, Duffield EA. Safety of checkpoint inhibitors for cancer treatment: strategies for patient monitoring and management of immune-mediated adverse events. Immunotargets Ther. 2017;6:51-71. 17. El Majzoub I, Qdaisat A, Thein KZ, et al. Adverse effects of immune checkpoint therapy in cancer patients visiting the emergency department of a comprehensive cancer center. Ann Emerg Med. 2019;73(1):79-87. 18. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768. 19. Russano M, Citarella F, Napolitano A, et al. COVID-19 pneumonia and immunerelated pneumonitis: critical issues on differential diagnosis, potential interactions, and management. Expert Opin Biol Ther. 2020;1-5. doi: 10.1080/14712598.2020.1789097 20. Burke RM, Killerby ME, Newton S, et al. Symptom profiles of a convenience sample of patients with COVID-19 — United States, January–April 2020. MMWR Morb Mortal Wkly Rep. 2020;69(28):904–908. 21. Rossi E, Schinzari G, Tortora G. Pneumonitis

from immune checkpoint inhibitors and COVID-19: current concern in cancer treatment. J Immunother Cancer. 2020;8(2):e000952. 22. FDA. Approved risk evaluation and mitigation strategies. Yescarta (axicabtagen ciloleucel) ) and Tecartus (brexucabtagene autoleucel). www.accessdata.fda.gov/Scripts/Cder/ Rems/index.cfm?event=IndvRemsDetails. page&REMS=375. Updated July 24, 2020. Accessed August 3, 2020. 23. Novartis. Kymriah (tisagenlecleucel) suspension for IV infusion. Risk evaluation and mitigation strategy (REMS): cytokine release syndrome and neurological toxicities. www. accessdata.fda.gov/drugsatfda_docs/rems/ Kymriah_2018_05_01_Live%20Trainng%20 Program%20Slides.pdf. April 2018. Accessed August 3, 2020. 24. Baymon DE, Boyer EW. Chimeric antigen receptor T-cell toxicity. Curr Opin Pediatr. 2019;31(2):251-255. 25. Actemra [package insert]. South San Francisco, CA: Genentech Inc; 2020. 26. Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943-947. 27. MacDougall K. The pharmacist’s role in educating the health-care team about adverse effects of immune checkpoint inhibitors. American Society of Clinical Oncology website. www.ascopost.com/ issues/may-25-2018/pharmacist-role-ineducating-the-health-care-team/. Published May 25, 2018. Accessed August 3, 2020. 28. Wood LS, Moldawer NP, Lewis C. Immune checkpoint inhibitor therapy: key principles when educating patients. Clin J Oncol Nurs. 2019;23(3):271-280. 29. Bosworth T. Tapering protocols needed to

manage checkpoint inhibitor AEs. www. clinicaloncology.com/Current-Practice/ Article/05-18/Tapering-ProtocolsNeeded-To-Manage-Checkpoint-InhibitorAEs-/48704. Published May 16, 2018. Accessed August 3, 2020. 30. Postow MA, Sidlow R, Hellmann MD. Immunerelated adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168. 31. Bachanova V, Bishop MR, Dahi P. Chimeric antigen receptor T cell therapy during the COVID-19 pandemic. Biol Blood Marrow Transplant. 2020;26(7):1239-1246. 32. Sehgal K, Costa DB, Rangachari D. Extendedinterval dosing strategy of immune checkpoint inhibitors in lung cancer: will it outlast the COVID-19 pandemic? Front Oncol. 2020;10:1193. 33. COVID-19 patient care information - cancer treatment & supportive care. American Society of Clinical Oncology website. www. asco.org/asco-coronavirus-resources/careindividuals-cancer-during-covid-19/cancertreatment-supportive-care. Updated July 23, 2020. Accessed August 3, 2020. 34. Royce TJ, Sanoff HK, Rewari A. Telemedicine for cancer care in the time of COVID-19 [published online ahead of print July 16, 2020]. JAMA Oncol. doi: 10.1001/ jamaoncol.2020.2684 35. Renna CE, Dow EN, Bergsbaken JJ, et al. Expansion of pharmacist clinical services to optimize the management of immune checkpoint inhibitor toxicities. J Oncol Pharm Pract. 2019;25(4):954-960.

Dr. Spencer reported no relevant financial relationships.

Specialty Pharmacy Continuum • September/October 2020

CLINICAL

Biosimilars Windfall continued from page 1

compromising outcomes, and it wouldn’t have been possible without the leadership of an advanced specialty pharmacy program and the insights that provides,” Dr. Pham said during the session, a one-day pre-conference workshop on health-system specialty pharmacy. “As more and more biosimilars come out, that represents a huge opportunity to decrease costs and an additional value point specialty pharmacy can bring to your institution,” said David Mitchell, PharmD, the pharmacist manager of specialty operations at UC Davis Health. He praised the BMC researchers for focusing not only on the cost containment aspect of the biosimilar switch, but also the outcomes that were achieved with new biosimilar products.

PBMs Finding Similar Benefits Major pharmacy benefit managers (PBMs) also have realized the value of biosimilar switches. In an initiative by Magellan Rx Specialty, biosimilar utilization significantly shifted from originator infliximab to a lower cost biosimilar formulation after implementation of a medical benefit drug management solution. Using the program, which leverages a comprehensive management solution to shift utilization to lower cost biosimilar

versions of infliximab for the treatment of autoimmune conditions such as rheumatoid arthritis and inflammatory bowel disease, health plans saw a shift in utilization of up to 86%. “This yielded a 34% cost savings, which is in line with what our expectations were given the cost difference between the brand and the biosimilars,” Steve Cutts, the senior vice president and general manager for Magellan Rx Specialty, told Specialty Pharmacy Continuum. When a “softer” approach was used, requiring only that new patients be started on biosimilar infliximab, biosimilar uptake was still as high as 75%. Although specific dollar savings were not available, recent data from Magellan Rx Management’s Medical Pharmacy Trend Report found that the originator infliximab is the most expensive drug on the medical benefit.

Improving Imatinib Adherence BMC’s specialty pharmacy program also successfully improved adherence to imatinib (Gleevec, Novartis) among patients with chronic myeloid leukemia. Adherence is a key driver of treatment success for this agent, Dr. Pham explained. “Patients who are adherent have a 76.7% five-year event-free

survival rate, compared with just under 60% if you do not take the drug the right way,” he said, referring to results from a study in the American Journal of Hematology (2011;86[6]:471-474). BMC’s specialty pharmacy set an adherence goal for its patients receiving imatinib of a proportion of days covered (PDC) of 90% or higher. “Among the patients we observed at BMC specialty pharmacy, the average PDC was 93.5%,” Dr. Pham said. However, he added, when they included patients using outside pharmacies, they “saw PDCs of 75% to 80%, and sometimes far lower.” Patients who achieved 90% or better adherence as measured by PDC had significantly improved health care resource

utilization compared with those whose average PDC fell below 90%, as measured by annual average inpatient visits (0.4 vs. 4.1), total inpatient days (1.8 vs. 14.8), average length of stay in days (1.3 vs. 4.5), outpatient visits (30.2 vs 41.7), and total average cost per year ($58,000 vs. $107,000) (unpublished data). “Our specialty pharmacy is among the top five strategic initiatives at Boston Medical Center, because it brings so much value to the health system overall and is one of the few financial, operational and clinical drivers of our health system’s service lines,” Dr. Pham said. Underscoring the value of such initiatives, Dr. Mitchell told Specialty Pharmacy Continuum that “there are significant economic and outcomes opportunities associated with specialty pharmacy for an [integrated delivery network]. In 2010, when we were preparing to launch our specialty program, the University HealthSystem Consortium had valued the average academic medical center specialty pharmacy opportunity at about $200 million, and that was 10 years ago, so you can imagine what that’s grown to today.” —Gina Shaw Dr. Pham reported no relevant financial relationships. His co-authors Francis Farraye, MD, MSc, and Bhavesh Shah, RPh, reported financial relationships with companies including Janssen, Merck and Pfizer.

Health-system specialty pharmacies:

Lots of Data, but What Do Payors Want to Know?

lthough health-system specialty pharmacies have access to an abundance of clinical and dispensing data, according to one expert who spoke during a session at the 2020 NASP Annual Meeting & Expo Virtual Experience, some pharmacies in outcomes-based contracts continue to ask payors the same question: What outcomes do they want to know about? That’s the “million-dollar question,” Bryan Schuessler, PharmD, MS, the director of home infusion and specialty pharmacy at Saint Luke’s Health System in Kansas City, Mo., said during the session, a one-day pre-conference workshop on health-system specialty pharmacy. “What is it that people really want to see on that payor line? We’re not sure from payor to payor what’s valuable at this point.”

Many other health-system specialty pharmacies that are drawing up outcomes-based contracts are likely to be in the same boat, finding that payors do not always know what outcomes they want to have measured as part of a contract, Dr. Schuessler said. “Is a clinical outcome SVR [sustained virologic response] or is it days-to-therapy, or is it adherence?” he asked. Dr. Schuessler noted that his team draws on a large pool of data from the Saint Luke’s electronic medical record system as well as dispensing and clinical documentation data from their retail and specialty pharmacies. “We’re documenting all these things. We’re following patients. We’re making notes. We’re collecting all this data, but … we’re still struggling to understand what [payors] want to see,” he said.

At West Virginia University Hospitals, in Morgantown, a lack of payor clarity on the question of outcomes led Louis Sokos, BS Pharm, MBA, the director of allied health solutions, specialty pharmacy services, to formulate what he believes is a universally applicable equation. Specifically, he said, demonstrating the impact of specialty pharmacies on both clinical outcomes and total cost of care for the health system is “a value proposition that I think any payor can see.” He stressed that health-system specialty providers have “to make sure we manage our patients as efficiently as we can and drive down costs overall … to make sure we’re a player in this space.” For example, his specialty pharmacy looked at a group of the health system’s patients receiving antiviral medications and documented SVR rates that

were higher than those of most nearby pharmacies outside their system, showing “a better return on investment” for payors, he said. Other health-system specialty pharmacies should take similar initiative and articulate what they believe to be the value of their services, suggested session moderator Erin Hendrick, the senior vice president of hospital strategy at Shields Health Solutions, headquartered in Stoughton, Mass. “We seem to have, as a collective, been very reactive to the data that’s been requested of us,” she said. Instead, Ms. Hendrick said, “I think there’s an opportunity for health systems to better define what we believe good specialty outcomes really are.”

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