In This Issue
Ipilimumab for Pediatric Unresectable or Metastatic Melanoma ®®® From the Department of Pharmacy
Formulary Update September/October Issue 2017 Volume 5, Issue 5 Ipilimumab for Pediatric Unresectable or Metastatic Melanoma FDA Medication Safety Alert: Risk of VTE with Test osterone
By: Ashley Fan, Pharm.D. Marcia J. Wyman, Pharm.D., BCPS Background: Melanoma in pediatric CTLA-4 blocking its interaction with its Drug Information Pharmacist patients, de ined by the National ligands, CD80 and CD86. Editor Cancer Institute as patients less than Key Clinical Trial: A phase 2 study Mandy C. Leonard, Pharm.D., BCPS 20 years old, is a rare but serious health System Director, Drug Use Policy and concern. 1 Melanoma accounts for 7.1% examined the ef icacy and safety of ipili- Formulary Management of cancers in patients ages 15 to mumab at doses of either 3 mg/kg Editor 19 years, affecting 5 to 6 per million (n=4) or 10 mg/kg (n=8) in pediatric patients ages 12 to 18 years, with stage Meghan K. Lehmann, Pharm.D., BCPS under the age of 20. Unresectable stage III or IV malignant melanoma. 5 For the Coordinator, Drug Information Services III and IV metastatic melanoma in pedi- Drug Information Specialist atric patients are dif icult to treat 3- and 10-mg/kg groups, the median Editor and lack curative options. 2 Ipilimumab age was 13- and 15-years, respectively.
(Yervoy ®; Bristol-Meyers Squibb) is a After 1 year of treatment, three out of Marigel Constantiner, MSc, BCPS, CGP, CPh four patients on 3 mg/kg and ive out of Drug Information Specialist recombinant, fully human monoclonal Associate Editor antibody. 3 A study in adult patients eight patients on 10 mg/kg were alive. with metastatic melanoma demonstrat- Two patients on 10 mg/kg had partial Christopher Snyder, B.S., R.Ph. ed increased survival when treated responses and one patient from each Drug Information Pharmacist with ipilimumab, which led to its ap- group had stable disease. Treatment- Associate Editor related side effects were reported in proval by the Food and Drug Admin- Brian Hoffmaster, Pharm.D., BCPS istration (FDA) for adult patients in two of four and seven of eight patients Student Education Pharmacist 2011. 4 Since malignant melanoma tu- in the 3- and 10-mg/kg groups, respec- Associate Editor mors in children have similar immuno- tively. There was one grade 3-4 im- mune-related adverse event (irAE) with Maya Wai, Pharm.D. logic features as those in adults, Drug Information Pharmacist ipilimumab was studied in the pediatric 3 mg/kg dose and ive irAEs with the Associate Editor population and received FDA approval 10 mg/kg dose. The most common AEs for the treatment of unresectable or were hepatitis and pyrexia. Despite ear- Scott Knoer, MS, Pharm.D., FASHP ly termination due to low enrollment, Chief Pharmacy Of icer metastatic melanoma in patients aged 12 and older in July 2017. 2,3 the authors concluded that ipilimumab was an effective treatment for melano- Mechanism of Action: Ipilimumab is ma in patients aged 12 to 18 years of a irst-in-class monoclonal antibody age with a safety pro ile similar to that immune checkpoint inhibitor. 3 Cancer observed in adults. cells evade the immune system by using Safety: The most common AEs (>5%) checkpoint proteins, such as pro- associated with ipilimumab include fa- grammed death receptor 1 (PD1) or tigue, diarrhea, pruritus, rash, and coli- Cytotoxic T Lymphocyte Antigen 4 3 From the Department of Pharmacy tis. At higher doses of 10 mg/kg, AEs (CTLA-4) to “turn off” the immune sys- Drug Information Service include nausea, vomiting, headache, tem’s T cells preventing them from at- weight loss, pyrexia, decreased appe- (216) 444-6456, option #1 tacking carcinogenic tissue. Immune tite, and insomnia. It is important to checkpoint inhibitors prevent T cell de- note that ipilimumab carries a Boxed Comprehensive information about activation by interfering with these Warning for severe and fatal irAEs, medications, biologics, nutrients, checkpoint proteins. For example, ipili- which may involve any organ system. and drug therapy mumab helps to maintain T cell anti- Similar to adults, pediatric patients re- tumor immune response by binding to (Continued on page 2) (Continued from page 1) ceiving ipilimumab may develop drug-related entero- References: 1. Cambell LB, Kreicher KL, Gittleman HR, Strodtbeck K, Barn- colitis, hepatitis, dermatitis (including toxic epidermal holtz-Sloan J, Bordeaux JS. Melanoma incidence in children 2 necrolysis), neuropathy, and endocrinopathy. Pa- and adolescents: decreasing trends in the United States. J tients should be assessed for these disease states and Pedatr 2015;166(6):1505-13. be evaluated at baseline and before each dose. 3 If a 2. Mechant MS, Wright M, Baird K, Wexler LH, Rodriquez-Galindo severe irAE occurs, ipilimumab should be permanently C, Bernstein D et al. Phase I clinical trial of ipilimumab in pedi- atric patients with advanced solid tumors. Clin Cancer Res discontinued and systemic high-dose corticosteroid 2016;22(6):1364-70. therapy should be initiated. Additionally, ipilimumab 3. Yervoy ® [package insert]. Princeton NJ: Bristol-Myers Squibb can cause fetal harm; patients should be advised to use Company; July 2017. contraception. 4. Hodi FA, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. Improved survival with ipilimumab in pa- Dosing and Administration: The recommended tients with metastatic melanoma. N Engl J Med 2010;363: dose of ipilimumab for adult and pediatric patients 711-23. 5. Pappa AS, Bergeron C, Gore L, Sender LS, Dunke IJ, Herzog CE with unresectable or metastatic melanoma is 3 mg/kg et al. Phase II study of ipilimumab (IPI) in children and ado- given intravenously over 90 minutes every 3 weeks for lescents with unresectable stage III or IV malignant melanoma a maximum of four doses. 3 If toxicities occur, doses (MEL). J Clin Oncol 2017;Abstract e21006. may be delayed; however all treatment must be 6. Lexi-Comp Online. Lexi-Drugs Online, Hudson, Ohio: Lexi- Comp Inc; 2017: August 2017. administered within 16 weeks of the irst dose. 7. Melanoma: Treatment Options: American Society of Clinical Ipilimumab should be diluted in normal saline or Oncology. 2016 July. Available from: http://www.cancer.net/ dextrose 5% and water to a inal concentration be- cancer-types/melanoma/treatment-options Accessed: August tween 1 to 2 mg/mL and administered through a low- 8, 2017. protein-binding in-line ilter. 3
Availability and Cost: Ipilimumab is available as a 5 mg/mL intravenous solution in 10- or 40-mL vials.3 The suggested wholesale price of the 50 mg/10 mL vial is about $8,350 and the 200 mg/40 mL vial is about 6 $33,420. Therefore, the cost for a 70 kg patient to complete the therapy consisting of 3 mg/kg every 3 weeks for four cycles would be approximately $140,000.
Role in Therapy: Currently, ipilimumab is the only
FDA-approved treatment for unresectable or metastat- ic carcinoma in pediatric patients. Although its ap- proval was based on limited pediatric data from a very small clinical trial, it remains a viable therapy for a dis- ease state with very few effective treatment options. 7 Formulary Status: Ipilimumab is on the Pediatric CCHS Formulary restricted to the Department of He- matology and Oncology for outpatient use only in pa- tients ≥ 12 years of age with unresectable or metastat- ic melanoma using its FDA-approved dosing (3 mg/kg every 3 weeks for four doses). It is also on the Adult CCHS Formulary restricted to the Depart- ment of Hematology and Medical Oncology for adult outpatient use only using the FDA-approved dosing (3 mg/kg every 3 weeks for four doses).
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Additions to the Adult CCHS Formulary Pharmacologic Drug Formulary Use Restrictions/Comments Class Restricted to the Department of Hematology and Medical Oncology for outpatient use only in patients with AML Enasidenib Antineoplastic and identi ied IDH mutation AML (IDHIFA ®) Agent Note: Patients are instructed to bring home supply or ob- tain outpatient prescription if admitted to the hospital as an inpatient. Restricted to Staff Anesthesia in the setting of severe post- Fibrinogen postpartum hemorrhage in Blood Product Severe Post-Partum concentrate conjunction with the Massive Derivative Hemorrhage (RiaSTAP ®) Transfusion Protocol and to the Department of Hematolo- gy and Medical Oncology Restricted to the Department Inotuzumab Antineoplastic of Hematology and Medical ozogamicin ALL Agent Oncology for patients with (Besponsa ®) ALL Naltrexone Restricted to physicians certi- extended-release ied in Addiction Medicine for Opioid Management of Alcohol injectable use in outpatients for the Antagonist and Opioid Dependence suspension management of alcohol and (Vivitrol ®) opioid dependence
Rituximab and Restricted to the Department CLL hyaluronidase Antineoplastic of Hematology and Medical
subcutaneous injection Agent Oncology for outpatient use Lymphoma (Rituxan Hycela ™) only For use in liver lesions restricted to patients who:
1) Cannot have an MRI or CT Sulfur hexa luoride contrast (e.g., allergies or lipid-type A Cardiac Imaging Diagnostic poor renal function) microspheres for Agent 2) Cannot have an MRI due injectable suspension Hepatic Imaging to implanted device(s) (Lumason ®) 3) Need to avoid or
minimize ionizing radia- tion exposure Tranxemic acid Restricted to the Department Anti ibrinolytic Orthopedic (oral) of Orthopedic Surgery Agent Surgery (Lysteda ®) Note: Added to CCHS Formu- Neuromuscular Vecuronium Neuromuscular lary due to the inconsistent Blocker Blockade availability of rocuronium. Agent AML=Acute Myeloid Leukemia IDH=Isocitrate Dehydrogenase ALL=Acute Lymphoblastic Leukemia CLL=Chronic Lymphocytic Leukemia MRI=Magnetic Resonance Imaging CT=Computed Tomography
Changes to Restrictions of Medications on the Adult CCHS Formulary
Pharmacologic Drug Formulary Use Changes to Restrictions Class
Old restriction: Restricted to the Department of Hematology and Medical Oncology for outpatient use only Daratumumab Antineoplastic Relapsed/Refractory (Darzalex ®) Agent Multiple Myeloma Modi ied restriction: Restrict- ed to the Department Plasma Cell of Hematology and Medical Leukemia Oncology
Note: It may be used for inpa- tients who cannot be dis- charged due to disease bur- den, or for inpatients with plasma cell leukemia.
Old restriction: Oral gastro- gra in is restricted to Pulmonary and Critical Care Medicine
Diatrizoate meglumine Treatment of Modi ied restriction: diatrizoate sodium Iodinated Post -Operative Small 1) Restricted to Pulmonary (Gastrogra in ®) Contrast Media Bowel Obstruction and Critical Care Medicine and Ileus 2) Restricted to Colorectal Surgery and General Sur- gery for the treatment of post-operative small bow- el obstruction and ileus Added to various restrictions listed in Lexicomp: Modi ied restriction: Restrict- ed to General Neurology Staff Rituximab Antineoplastic Autoimmune Physicians and NeuroICU Staff (Rituxan ®) Agent Encephalitis Physicians for the manage- ment of autoimmune encepha- litis as second-line therapy (i.e., following steroids, IVIG, and PLEX) IVIG=Intravenous Immune Globulin PLEX=Plasma Exchange
Product Standardizations on the Adult CCHS Formulary Pharmacologic Drug Formulary Use Reason for Standarization Class Due to a signi icant cost in- crease for brand-name Lanoxin ®, CCHS pharmacies Atrial Fibrillation will be carrying generic digox- Generic digoxin Antiarrhythmic in. The same digoxin generic (Lanoxin ®) Agent Heart Failure manufacturer product will be
carried by all CC inpatient, ambulatory, and specialty pharmacies. In order to reduce cost and standardize products across CCHS, HyperRab ® was select- Rabies immune Post-Exposure Rabies ed as the rabies immune glob- globulin Immune Globulin Prophylaxis ulin product. Imogam® will (HyerRAB ®) be removed from the CCHS Formulary.
Removals from the Adult CCHS Formulary Pharmacologic Reason for Removal/ Drug Formulary Use Class Comments Reason for removal: There is a shortage of generic atenolol and the brand atenolol (Tenormin ®) has signi icantly increased in price. Beta Hypertension Atenolol Blocker A beta -blocker dose conver- sion chart should be utilized to assist prescribers in convert- ing from atenolol to another beta blocker. Reason for removal: Dyazide ® Hypertension Potassium-Sparing Maxzide ®-25 and Maxzide ® (Hydrochlorothiazide Diuretic tablets are more cost effective. and Triamterene) Edema
Reason for removal: Oxymorphone HCl ER Opioid Pain Reliever Removed from the market (Opana ® ER) Analgesic
Therapeutic Interchange on the Adult CCHS Formulary Pharmacologic Therapeutic Drug Formulary Use Class Interchange Pharmacists will automatically convert IV to PO orders for potassium chloride for select patients (i.e., those who re- ceived PO/enteral medications within the past 8 hours). Oral/enteral options are tab- lets, oral liquid, and efferves- cent packets.
Exceptions to the automatic interchange are patients with Intravenous Electrolyte these characteristics: Potassium Electrolyte Imbalance 1. Ventricular arrhythmias Chloride 2. Severe hypokalemia (KCl) (potassium <3 mmol/L or <3.5 mmol/L with symp- toms) 3. NPO 4. Dif iculty swallowing (e.g., dysphagia, mucositis) 5. Severe nausea/vomiting or received an antiemetic within the last 8 hours 6. Lost PO/enteral access (e.g., NG or Corpak pulled, re-intubated) IV=Intravenous PO=Oral NPO=Nothing by Mouth NG=Nasogastric
Additions to the Pediatric CCHS Formulary Pharmacologic Drug Formulary Use Restrictions/Comments Class Restricted to the Department of Pediatric Hematology/ Eculizumab Monoclonal Microangiopathic Oncology and Bone Marrow (Soliris ®) Antibody Hemolysis* Transplant for outpatient use only in patients with microan- giopathic hemolysis* Restricted to the Department of Pediatric Hematology/ Oncology for outpatient use only in patients at least Ipilimumab Antineoplastic Unresectable or 12 years of age with unresec- (Yervoy ®) Agent Metastatic Melanoma table or metastatic melanoma using its FDA-approved dosing (3 mg/kg every 3 weeks for four doses)
*Microangiopathic hemolysis includes thrombotic microangiopathy (TMA) and paroxysmal nocturnal hemoglobinuria (PNH) FDA=Food and Drug Administration
Removals from the Pediatric CCHS Formulary Pharmacologic Drug Formulary Use Comments Class Reason for removal: There is a shortage of generic atenolol
and the brand atenolol
(Tenormin ®) has signi icantly Atenolol Beta Hypertension increased in price. Blocker
This is a cost savings measure. Intranasal Allergic Patients may bring their own H Blockers Antihistamines 1 Rhinitis intranasal antihistamines from home.
Changes to Restrictions of Medications on the Pediatric CCHS Formulary Pharmacologic Drug Formulary Use Restrictions/Comments Class The Pediatric Neurology Service was added to the current restriction. Modi ied restriction: 1. Initiation of vigabatrin therapy is restricted to prescribers from the Pediatric Epilepsy Service and Pediatric Neurology. The pre- scriber MUST be registered (certi ied) with the Vigabatrin REMS Program. 2. Continuation of therapy is re- Infantile Spasms stricted to prescribers from the
Vigabatrin Pediatric Epilepsy Service Anticonvulsant (Sabril ®) Refractory Complex Vigabatrin REMS Program. How-
Seizures ever, the pharmacist is allowed to verify and dispense ONE dose ordered by a NON-certi ied pre- scriber for continuation of home therapy during OFF-HOURS. The primary service will need to con- sult with a certi ied inpatient pre- scriber from Pediatric Epilepsy Service or Pediatric Neurology the next day for approval of sub- sequent doses for continuation of therapy. REMS=Risk Evaluation Mitigation Strategy
Standardization of the Pediatric CCHS Formulary Pharmacologic Drug Formulary Use Comments Class Kidney, Liver, Heart Teva generic modi ied cyclosporine Neoral ®, Gengraf ® and Transplant capsules and oral liquid will be used other generic modi ied Immunosuppressive for both inpatient and ambulatory cyclosporine capsules Agent Rheumatoid Arthritis pharmacies. and oral liquids Psoriasis
Sandimmune ® Prophylaxis of Oral Capsules Immunosuppressive Organ Rejection Brand-name Sandimmune ® oral cap- (oral non-modi ied Agent sules will remain on Formulary. cyclosporine) Chronic Rejection
Generic Perrigo Injectable non- Sandimmune ® Prophylaxis of modi ied cyclosporine will be Injection Immunosuppressive Organ Rejection stocked. (Non-modi ied Agent cyclosporine) Chronic Rejection
FDA=Food and Drug Administration