Michelle Byrne, PharmD, MSPBA

On July 20, 2018, the FDA approved ivosidenib (Tibsovo) as a treatment option for adult patients with relapsed/refractory acute myeloid leukemia, specifically with a mutation in the 

 gene. The FDA granted the application both fast track and priority review designations, and ivosidenib also received orphan drug designation from the agency. The drug is the first wholly owned product from Agios to receive FDA approval and follows the manufacturer’s 2017 release of enasidenib (Idhifa), which was codeveloped and cocommercialized with Celgene for the treatment of AML with an 

 mutations are associated with increased age and occur in approximately 20% of adult patients with AML. IDH1 mutations are slightly less common than IDH2 mutations, occurring in approximately 7% to 14% of AML cases. Mutations in 

 together are the most common AML mutations, causing an oncometabolite, (R)-2-hydroxyglutarate (2-HG), to increase in concentration, seen both in vitro and in vivo. The result is direct inhibition of epigenetic regulators, such as chromatin-modifying histone and DNA demethylases, leading to a hypermethylation signature, in which gene expression is altered. Affected cells lose their ability to progress from immature progenitors to a fully differentiated state.

Eligible patients are identified by the presence of 

 mutations in the blood or the bone marrow. An FDA-approved test, the RealTime IDH1 Assay, sponsored by Abbott Laboratories, is available for 

 mutation detection. Patients with relapsed disease who had no 

 gene mutation at initial diagnosis should be retested because the mutation can emerge during treatment and at relapse.

Ivosidenib, a small molecule inhibitor, targets mutant 

 mutations are defined as those leading to increased levels of 2-HG in leukemia cells and where efficacy is predicted by clinically meaningful remissions with the recommended dose of ivosidenib and/or inhibition of mutant 

 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations are R132H and R132C substitutions.

Ivosidenib is available in 250-mg tablets. The recommended dose is 2 tablets (500 mg) taken orally at the same time each day with or without food. Administration with a high-fat meal should be avoided because of increased ivosidenib concentration. Unless patients encounter disease progression or unacceptable toxicity, treatment should continue for at least 6 months to allow for adequate clinical response time.

Nineteen percent of patients with relapsed/refractory AML treated with ivosidenib in clinical trials experienced differentiation syndrome (34 of 179 patients). Differentiation syndrome may be life-threatening or fatal if not treated and is associated with rapid proliferation and differentiation of myeloid cells.

Symptoms noted during clinical trials included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and increased creatinine clearance. Seventy-nine percent of patients who experienced differentiation syndrome recovered after treatment or after ivosidenib dose interruption.

Suspected differentiation syndrome should be treated with intravenous (IV) dexamethasone 10 mg every 12 hours, or an alternative oral or IV corticosteroid, along with hemodynamic monitoring until improvement. Treatment with hydroxyurea or leukapheresis should be initiated, when clinically indicated, for concomitant noninfectious leukocytosis. Corticosteroids and hydroxyurea should be tapered after symptom resolution, but corticosteroids should be continued for at least 3 days to avoid recurrence of differentiation syndrome symptoms associated with premature discontinuation. Additionally, if symptoms are severe despite 48 hours of corticosteroid treatment, ivosidenib treatment should be paused until signs and symptoms are no longer severe in nature.

Patients treated with ivosidenib can develop corrected QT (QTc) interval prolongation and ventricular arrhythmias. Nine percent of patients treated with ivosidenib had a QTc interval greater than 500 milliseconds, and 14% had an increase from baseline QTc greater than 60 milliseconds. Risk of QTc interval prolongation would be expected to increase with concomitant use of medications known to prolong QTc interval, such as antiarrhythmics, fluoroquinolones, triazole antifungals, 5-hydroxytryptamine-3 receptor antagonists, and cytochrome P450 (CYP) 3A4 inhibitors.

Certain patients may require more frequent monitoring, such as those with congenital long QTc syndrome, congestive heart failure, and electrolyte imbalances, as well as those taking medications in the categories noted above. Therapy adjustments should be evaluated against severity of QTc prolongation. Patients with QTc interval prolongation along with signs or symptoms of life-threatening arrhythmia should permanently discontinue ivosidenib. For QTc increases greater than 500 milliseconds, treatment should be interrupted and ivosidenib subsequently reduced. For QTc increases greater than 480 milliseconds but less than 500 milliseconds, treatment should be interrupted.

Although neuropathies are rare, patients should be monitored for their onset, such as that of unilateral/bilateral weakness, sensory alterations, paresthesia, and difficulty breathing. Patients with Guillain-Barré syndrome should permanently discontinue ivosidenib.

The most serious adverse reactions noted during clinical trials included differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolongation (7%). One case of progressive multifocal leukoencephalopathy was documented. Adverse reactions leading to dose interruption were electrocardiogram QT prolongation (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%). Three percent of patients (5 of 179) required a dose reduction after experiencing an adverse event (AE).

 These AEs were categorized as electrocardiogram QT prolongation (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%). Guillain-Barré syndrome, rash, stomatitis, and increased creatinine clearance (1% each) were cause for permanent discontinuation of therapy during clinical studies. Fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolongation, rash, pyrexia, cough, and constipation were the most common AEs (>20%) of any grade.

Plasma concentrations of ivosidenib can be increased when coadministered with CYP3A4 inhibitors, thus increasing the risk of QTc interval prolongation. Avoidance of moderate to strong CYP3A4 inhibitors is ideal, but if coadministration is unavoidable, reducing the ivosidenib dose to 250 mg once daily is advised. Alternatively, coadministration of strong CYP3A4 inducers can decrease ivosidenib plasma concentrations. CYP3A4 inducers should be avoided during treatment with ivosidenib.

The risk of QTc interval prolongation is heightened when QTc-prolonging drugs are coadministered with ivosidenib. Avoidance is also recommended, but if unavoidable, patients must be monitored closely for signs and symptoms of QTc interval prolongation.

Ivosidenib has been shown to induce CYP3A4 and may induce CYP2C9. Reduction of drug concentrations for sensitive substrates would be expected; therefore, alternative therapies should be considered. For example, ivosidenib should not be coadministered with itraconazole or ketoconazole (CYP3A4 substrates) because of a loss of antifungal efficacy. If coadministration is unavoidable, patients should be monitored for a reduction of clinical effect for affected medications.

The median time to maximum plasma concentration (C

) is approximately 3 hours. A high-fat meal increased ivosidenib C

 by 98% and area under the curve 0 to infinity by approximately 25%. The mean apparent volume of distribution of ivosidenib at steady state is 234 L, and protein binding ranges from 92% to 96% in vitro. The terminal half-life is 93 hours, and clearance is 4.3 L/hour. Ivosidenib is the predominant component (>92%) of total radioactivity in plasma and primarily metabolized by CYP3A4 with minor N-dealkylation and hydrolytic pathways. After a single oral administration, 77% of ivosidenib was eliminated in the feces (67% unchanged) and 17% in the urine (10% unchanged).

Pharmacokinetics evaluated in specific populations regarding age, sex, race, body weight, ECOG performance status, mild-to-moderate renal impairment, or mild hepatic impairment were not affected with any clinical significance. In patients with severe renal impairment, renal impairment requiring dialysis, or moderate-to-severe hepatic impairment, pharmacokinetic impacts are unknown.

The efficacy of ivosidenib was studied in a single-arm, open-label, multicenter clinical trial of 174 adult patients with relapsed/refractory AML with an 

 mutation. Patients were identified first by a local or central diagnostic test, which was confirmed retrospectively using the RealTime 

 Assay. Patients were started on a dose of 500 mg daily and continued untileither disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission [CR]), as well as patients with no evidence of disease and partial recovery of blood counts after treatment (complete remission with partial hematologic recovery [CRh]).

With a median follow-up of 8.3 months and median treatment duration of 4.1 months, approximately one-third of patients experienced a CR or a CRh that lasted a median 8.2 months. Of the 110 patients who required transfusions of blood or platelets because of AML at the start of the study, 41 (37%) did not require a transfusion for at least 56 days after treatment with ivosidenib.

		Isocitrate dehydrogenase mutations in myeloid malignancies. 

		List of cleared or approved companion diagnostic devices (in vitro and imaging tools).  FDA website. www.fda.gov/CompanionDiagnostics. Accessed August 2, 2018.

		Tibsovo [package insert]. Cambridge, MA: Agios Pharmaceuticals Inc.; 2018.

		FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation [news release]. Silver Spring, MD: FDA; July 20, 2018. 

www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm614115.htm

Articles

On July 20, 2018, the FDA approved ivosidenib (Tibsovo) as a treatment option for adult patients with relapsed/refractory acute myeloid leukemia, specifically with a mutation in the IDH1 gene. 

Ivosidenib for Relapsed/Refractory Acute Myeloid Leukemia

On July 20, 2018, Pfizer Inc announced the FDA approval of filgrastim-aafi (Nivestym), a biosimilar to Amgen’s biologic Neupogen (filgrastim). Pharmaceutical biologics are large molecular products created from live organisms that enable targeted therapy for chronic illnesses. Because of their complexity, biologics undergo a unique approval process through the FDA.

Biosimilars are designed to have similar properties as an existing biologic but are not, however, exact copies of their reference biologic product. FDA approval is assessed based on totality of evidence, comparing pharmacokinetic and efficiency data within the relevant patient population.

The following indications for filgrastim-aafi are approved by the FDA:

		To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever

		For reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML)

		To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation

		For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis

		For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia

Filgrastim-aafi is a granulocyte colony-stimulating factor (G-CSF) created through recombinant DNA technology. Colony-stimulating factors act on hematopoietic cells by binding to receptors and stimulating proliferation. G-CSFs affect the production of neutrophils within the bone marrow.

Filgrastim-aafi is available in the following strengths and dosage forms:

		Injection: 300 μg/mL in a single-dose vial

		Injection: 480.0 μg/1.6 mL in a single- dose vial

		Injection: 300.0 μg/0.5 mL in a single-dose prefilled syringe

		Injection: 480.0 μg/0.8 mL in a single- dose prefilled syringe

The recommended dosages are listed below.

		Patients with cancer receiving myelosuppressive chemotherapy or induction and/ or consolidation chemotherapy for AML: 5 μg/kg/day as a single daily subcutaneous injection, by short intravenous (IV) infusion over 15 to 30 minutes, or by continuous IV infusion. Therapy should begin at least 24 hours after chemotherapy and should not be administered within 24 hours prior to chemotherapy. Patients should be monitored twice a week during therapy. The dose can be increased by 5 μg/kg for each chemotherapy cycle if needed. Therapy should be continued for up to 2 weeks post chemotherapy or until the absolute neutrophil count increases to 10,000/mm

		Patients with cancer undergoing bone marrow transplantation: 10 μg/kg/day as an IV infusion no longer than 24 hours. The first dose should be administered at least 24 hours after chemotherapy and bone marrow infusion. Patient monitoring of complete blood counts (CBCs), including platelet counts, should be performed frequently post marrow transplantation. The dose should be titrated as follows:

	° Absolute neutrophil count (ANC) >1000/mm

 for 3 consecutive days: Reduce dose to 5 μg/kg/day.

 for 3 more consecutive days: Discontinue therapy.

		Patients undergoing autologous peripheral blood progenitor cell collection and therapy: 10 μg/kg/day as a subcutaneous injection for at least 4 days before the first leukapheresis procedure, continuing until the last leukapheresis. The optimal duration has not been established, but administration for 6 to 7 days with leukapheresis on days 5, 6, and 7 has been shown to be safe and effective. Neutrophil counts should be monitored after 4 days, and therapy should be discontinued if white blood cell count increases to 100,000/mm

		Patients with severe chronic neutropenia: Daily administration is required. Doses should be individualized based on clinical outcomes and ANC. CBCs with differential and platelet counts should be monitored monthly during the first year of treatment.

	° Congenital neutropenia: 6 μg/kg as a twice-daily subcutaneous injection

	° Idiopathic or cyclic neutropenia: 5 μg/kg as a single-daily subcutaneous injection

Adverse effects that have been reported in some patients following administration of filgrastim include:

Patients with cancer receiving myelosuppressive chemotherapy 

The safety and efficacy of filgrastim-aafi was established in a randomized, double-blind, placebo-controlled trial conducted in patients with small cell lung cancer. Patients received up to 6 cycles of IV chemotherapy given on days 1, 2, and 3 of a 21-day cycle, followed by filgrastim-aafi or placebo. Patients receiving filgrastim-aafi were dosed at 4 to 8 μg/kg/day and received a daily subcutaneous injection beginning on day 4 of each cycle for a maximum of 14 days. Of the patients treated with filgrastim-aafi, 40% experienced febrile neutropenia compared with 76% in the placebo group. This was a clinically significant result (P <.001). Additional significant reductions were noticed in the duration of infection, the severity of neutropenia, the incidence and duration of hospital admissions, and the number of reported days of antibiotic use.

Patients with AML receiving induction or consolidation chemotherapy

The safety and efficacy of filgrastim-aafi was established in a randomized, double-blind, placebo-controlled, multicenter trial in patients with newly diagnosed de novo AML. Patients received 5 μg/kg/day subcutaneously of filgrastim-aafi beginning 24 hours after their last chemotherapy dose and continuing until neutrophil recovery (ANC 31000/mm

 for 1 day) or for a maximum of 35 days. Patients treated with filgrastim-aafi experienced severe neutropenia for a median of 14 days versus 19 days in the placebo group, which was a clinically significant difference (P = .0001). There was also a reduction in median duration of IV antibiotic use (15.0 vs 18.5 days) and median duration of hospitalization (20 days vs 25 days). No statistically significant difference was noted for complete remission rate, median time to progression, or median overall survival.

Patients with cancer undergoing bone marrow transplantation 

The safety and efficacy of filgrastim-aafi in reducing the duration of neutropenia in patients undergoing autologous bone marrow transplantation was evaluated in 2 randomized controlled trials of statistically significant reduction in the median number of days of severe neutropenia (trial 1, P = .004; trial 2, P <.001). The number of days of febrile neutropenia was also significantly reduced in trial 2 (P <.0001). The safety and efficacy of filgrastim-aafi in patients undergoing allogenic bone marrow transplantation was evaluated in a randomized placebo-controlled trial. A statistically significant reduction in the median number of days of severe neutropenia was shown (P <.001). Additionally, time to recovery of ANC to 3500/mm

Patients undergoing autologous peripheral blood progenitor cell collection and therapy 

The safety and efficacy of filgrastim-aafi was supported through noncontrolled tri- als and a randomized trial. The randomized, unblinded study of patients with Hodgkin disease or non-Hodgkin lymphoma undergoing chemotherapy showed significantly fewer days of platelet transfusions in patients who received filgrastim-mobilized peripheral blood progenitor cells compared with autologous bone marrow (6 vs 10 days).

Patients with severe chronic neutropenia 

The safety and efficacy of filgrastim-aafi was established in a randomized controlled trial for patients with severe neutropenia. Subcutaneous filgrastim was administered in doses determined by the category of neutropenia (idiopathic, 3.6 μg/kg/day; cyclic, 6 μg/kg/day; congenital, 6 μg/kg/day divided 2 times per day). Doses were incrementally increased to 12 μg/kg/day divided into 2 doses if no response was shown. Patients who received filgrastim showed a lower incidence of infection and fever and duration of fever; decreased days of antibiotic use; and lower incidence, duration, and severity of oropharyngeal ulcers.

Nivestym (filgrastim-aafi) [prescribing information]. New York; NY: Pfizer Inc; 2018. https://bit.ly/2JMOq9Y. Accessed August 2, 2018.

On July 20, 2018, Pfizer Inc announced the FDA approval of filgrastim-aafi (Nivestym), a biosimilar to Amgenâ€™s biologic Neupogen (filgrastim).

Nivestym by Pizer, Inc

By now, you’ve heard that to be considered a player in specialty pharmacy, you must hold multiple pharmacy accreditations. In a competitive market in which so many pipeline drugs are being launched, it’s no wonder that pharmaceutical manufacturers are looking for a way to narrow the potential pharmacies to be included in their specialty network offering.

Accreditation becomes that key differentiator in many cases.

As a specialty pharmacy manager, you may be wondering where to start. After all, it seems as though there is a new accrediting body available every other day during this heat wave of pharmacy accreditations. If you find yourself in this situation, you may want to consider starting with what many consider to be the big three: URAC, The Joint Commission (TJC), and the Accreditation Commission for Health Care (ACHC). 

Originally incorporated under the name Utilization Review Accreditation Commission, URAC is an independent, nonprofit accreditation entity with a stated mission to “advance health care quality through leadership, accreditation, measurement and innovation.” The organization was founded in 1990 and is based in Washington, DC. Its original name was shortened to the acronym URAC in 1996 when the association began accrediting other types of organizations such as health plans, pharmacies, and provider organizations. 

The following outlines the basic beliefs held by the organization:

The patient is at the center of everything we do.

The best approach to care delivery is through physician-led teams.

Health care solutions must be local to be sustainable.

Continuous improvement is achieved through performance measurement.

The standards developed by URAC “promote industry best practices, encourage quality improvement, and protect and empower consumers.” Their programs and services follow continuous improvement aligning with the principles of Lean Six Sigma. 

The organization takes a learning approach to the accreditation process. They are not interested in “checking off a list of requirements,” but rather the promotion of continuous improvement and innovation for the client.

Accreditation through URAC usually takes approximately 10 to 12 months to complete and involves a 5-step process.

: Clients are assigned an account manager to aid in the application process. First, the organization is required to obtain approval from URAC as an applicant. The second part involves uploading required information to the URAC web portal. The timeline of the application process ranges from 6 to 9 months. 

: In this phase of the process, uploaded information is reviewed to ensure compliance with URAC standards. The organization will have an opportunity to address any deficiencies noted through a request for information. Completion of the desktop review takes somewhere between 30 to 45 days.

: The validation review involves a member of the URAC team visiting the organization. During the visit, leadership and staff members are interviewed and systems, work processes, and policies and procedures outlined in the desktop review are validated. The surveyor will provide information regarding any findings at the end of the review and a score will be generated outlining the organization’s compliance level.

: During this phase of the process, a formal assessment of the organization is completed by URAC’s Accreditation Committee. The committee is comprised of experts in health care fields relevant to the specialty pharmacy accreditation. Validation review findings and score will be considered to determine the application status. Notification of the results are normally received within a week of the committee decision.

Has policies and procedures in place to ensure consumers have access to appropriate drugs/medications.

Maintains methods to measure customer satisfaction.

Has policies and procedures that ensure adherence to drug safety protocols.

Follows a logical blueprint for quality management, maintenance, and reporting.

Meets rigorous performance measures for accuracy and turnaround time of dispensed prescriptions.

Has a patient-centered strategy for its patient management program that includes coordination of care, communication and education, patient rights and responsibilities.

Ensures the timeliness and performance of customer service center operations, including time to answer telephone inquiries.

Reports mandatory performance measures to URAC.

: Once accreditation is received, monitoring is required to ensure sustainability of the programs covered by the accreditation. Requirements may include collection and annual reporting of quality measures. A mid-cycle onsite review to confirm ongoing compliance may be conducted by URAC with 14 days-notice to your organization. Specialty pharmacy accreditation is awarded for a period of 3 years, at which time another visit to your organization will be completed by a member of the URAC team.

Founded in 1951, The Joint Commission on Accreditation of Healthcare Organizations (now known as TJC) is the nation’s oldest and largest standards-setting and accrediting body in health care. It is an independent, not-for-profit organization, evaluating more than 21,000 health care organizations and programs in the United States. 

Its accreditation is recognized as a symbol of quality that reflects an organization’s commitment to meeting performance standards. Their mission is “to continuously improve health care for the public, in collaboration with other stakeholders, by evaluating health care organizations and inspiring them to excel in providing safe and effective care of the highest quality and value.” 

Their vision statement outlines the goals of health care providers nationwide: “All people always experience the safest, highest quality, best-value health care across all settings.”

At this time, TJC does not have a separate accreditation for specialty pharmacy.  Specialty pharmacies wishing to obtain accreditation through TJC must comply with the standards that fall under the Home Care designation. Focus areas include:

ongoing monitoring — patient and drug interaction 

procedures for compounding and distribution of sterile infusion products 

performance improvement measures for quality, access and patient satisfaction 

The commission’s accreditation process primarily focuses on operational systems critical to the safety and quality of patient care. Pharmacies can expect an on-site survey during their initial accreditation and subsequent visits within 18 to 36 months.  The objectives of the on-site surveys are to:

Evaluate the organization using standards and elements of performance (for deemed organizations, many standards cross walk to the Centers for Medicare & Medicaid Services’ Conditions of Participation).

Provide education and “good practice” guidance that will help staff continually improve the organization’s performance.

The surveyors include professionals with at least 5 years of experience in home care, including registered nurses, pharmacists, respiratory therapists, rehabilitation technologists, orthotists, prosthetists, and medical equipment experts. Surveys are usually unannounced and have the following agenda:

opening conference and orientation to the organization

tracer methodology using actual patients, residents or individuals served to assess standards compliance

individual tracers following the experience of care for individuals through the health care process, including safety culture assessment

system tracers evaluating the integration of related processes and the coordination and communication among disciplines and departments 

medical staff credentialing and privileging (hospitals only) and optional medical staff session

environment of care session, including a building tour 

exit conference, including a written summary of the survey findings 

 After the survey, a report of ‘findings’ is posted on the Joint Commission extranet.  The accreditation decision becomes official at the time the summary report is available, effective the day after survey completion.  Accredited organizations receive TJC’s Gold Seal of Approval

.   If the organization received any requirements for improvement, the accreditation decision is made after submission of evidence of standards compliance. 

ACHC is a nonprofit accreditation organization known for value, integrity, and the industry’s best customer service. It has been a symbol of quality and excellence since 1986, with a mission “to deliver the best possible accreditation experience.”

ACHC outlines the benefits of receiving their accreditations with the following:

Dedicated account advisors who are committed to delivering quality customer service.

Service-specific standards that are relevant, realistic and easy to understand

Industry expert surveyors who take an educational approach.

Committed to education with program-specific resources available through Accreditation University, ACHC’s educational division.

CMS deeming authority for home health, hospice and Durable Medical Equipment, Prosthetics, Orthotics, and Supplies and national recognition from third-party payers.

Transition program that helps guide providers through the process of switching to ACHC.

The accreditation process can be outlined in 6 steps:

Accreditation helps pharmaceutical manufacturers narrow the potential pharmacies it may include in a specialty network offering.

Specialty Pharmacy Accreditations: The Big Three

Treatment options for multiple myeloma (MM) are divided into 2 categories: nonsymptomatic versus symptomatic. Nonsymptomatic treatment involves active surveillance of the diagnosis, and once a patient begins to experience symptoms, symptomatic treatment is initiated. Symptomatic treatment involves both treatment of the disease and supportive therapy to improve quality of life.

Disease-directed therapy includes targeted therapy and/or chemotherapy with or without steroids, stem cell transplantation, radiation, and surgery. Additionally, whether a patient just got their diagnosis or is experiencing a recurrence of MM is a factor in therapy decisions. Treatment plans for MM involve different stages:

		Induction therapy is used for rapid control of the cancer and to help relieve symptoms.

		Consolidation incorporates more chemotherapy or stem cell transplantation.

		Maintenance therapy occurs over a prolonged period to prevent recurrence.

		Targeted therapies focus on the cancer’s specific genes, proteins, or tissue environment that contributes to cancer growth and survival.

Targeted therapies block the growth and spread of cancerous cells, while limiting damage to noncancerous cells. This type of therapy has been shown to be successful for MM prognosis. Celgene Corporation’s lenalidomide (Revlimid) is a targeted therapy that stops the growth of myeloma cells in the bone marrow.

Approved by the FDA in 2005, lenalidomide is a prescription medication indicated to treat MM in combination with dexamethasone. It is the only MM therapy approved by the FDA for maintenance therapy after autohematopoietic stem cell transplantation.

Although the exact mechanism of action is unknown, lenalidomide acts as an immunomodulator, strengthening the immune cells to enable an attack on cancerous cells. It also possesses antiangiogenic properties, decreasing the cancer’s ability to create blood vessels.

Lenalidomide is available in a capsule formulation of the following strengths: 2.5, 5, 10, 15, 20, and 25 mg. It should be taken at about the same time each day, with or without food, and capsules should never be opened, broken, or chewed.

When used as combination therapy, the recommended starting dosage is 25 mg orally once daily on days 1 through 21 of a 28-day cycle in combination with dexamethasone. As maintenance therapy, the recommended starting dosage is 10 mg once daily continuously on days 1 through 28 of a 28-day cycle. Treatment should continue until disease progression or unac- ceptable toxicity. Starting doses may be adjusted for renal impairment, and doses may be modified based on clinical response.

Lenalidomide can cause fetal harm when administered during pregnancy. That its use resulted in limb abnormalities during an animal trial and its similarity to thalidomide, a known teratogen, led to its contraindication in pregnant females. Therefore, it is only available through the lenalidomide risk evaluation and mitigation strategy program.

Females of reproductive potential must avoid pregnancy for at least 4 weeks prior to initiating lenalidomide therapy, during therapy, and for at least 4 weeks after completing therapy. They must commit to abstinence from heterosexual intercourse or to use 2 methods of reliable birth control during this time. Two negative pregnancy tests, 1 performed within 10 to 14 days of therapy initiation and the other within 24 hours, must be obtained prior to beginning therapy. After therapy initiation, a weekly pregnancy test must be conducted during the first month, then monthly thereafter in females with regular menstrual cycles. Negative pregnancy tests are required every 2 weeks in females with irregular menstrual cycles.

Since lenalidomide is present in the semen of males on therapy, they must always use a latex or synthetic condom during sexual contact with females of reproductive potential while taking lenalidomide and for up to 4 weeks after completing therapy. Notably, this requirement still applies to males who have undergone a successful vasectomy. Additionally, males are not permitted to donate sperm during this timeframe.

Patients are not permitted to donate blood during treatment with lenalidomide and for 4 weeks after discontinuation of therapy to prevent the risk of donated blood being given to a pregnant female.

Lenalidomide may cause neutropenia and thrombocytopenia. Patients should therefore be monitored for signs of infection, bleeding, or bruising. Complete blood count assessments should be performed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, then every 28 days thereafter. In the MM maintenance therapy trials, grade 3 or 4 neutropenia was reported in up to 59% of lenalidomide-treated patients and grade 3 or 4 thrombocytopenia in up to 38%.

Risks for deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke increase in patients on lenalidomide. Patients with known risk factors may be at greater risk.

Clinical trial results have shown an increase of hematologic plus solid tumor second primary malignancies in patients with MM receiving lenalidomide.

The findings of 2 randomized clinical trials have shown an increase in mortality of patients with MM when pembrolizumab is added to a thalidomide analogue, such as lenalidomide, plus dexamethasone. As such, this combination is not recommended.

Hepatic failure has been observed in patients treated with lenalidomide and dexamethasone. Serious hepatic events occurred in 2% of patients with MM. Lenalidomide should be discontinued in patients with elevated liver enzymes, but treatment may be re-initiated at a lower dose after return to baseline values.

Angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms have been reported in patients receiving lenalidomide. Therapy should be discontinued indefinitely in patients who experience these reactions. Patients with a prior history of grade 4 rash from thalidomide treatment should not receive lenalidomide, and therapy discontinuation should be considered for grade 2-3 skin rash.

Patients with a high tumor burden prior to treatment are at risk of tumor lysis syndrome. Close monitoring of these patients is recommended while taking lenalidomide.

A decrease in the number of CD34+ cells has been reported with lenalidomide treatment. Transplantation referral should occur early in treatment to optimize timing of cell collection.

Hypothyroidism and hyperthyroidism have been reported with the use of lenalidomide. Thyroid function should be evaluated prior to initiation of treatment and during therapy.

Digoxin levels can be increased by lenalidomide. Periodic monitoring of plasma lev- els is recommended during treatment. Erythropoietic agents, such as estrogen-containing therapies, should be used with caution.

Oral administration of lenalidomide results in rapid absorption. Maximum plasma concentrations occur 0.5 to 6 hours post administration. Maximum concentration (Cmax) and area under the curve (AUC) values increase proportional to the given dose. Administration with a high-fat meal resulted in a 20% reduction in Cmax and 50% reduction in AUC; however, lenalidomide may be taken with or without food.

Lenalidomide is not expected to affect CYP450 enzymes since it is not metabolized by the CYP450 pathway.

In patients with renal impairment, the half-life of lenalidomide increased 3-fold and clearance decreased 66% to 75% compared with healthy patients. Patients on hemodialysis had a 4.5-fold increase in half-life and an 80% decrease in renal clearance.

A randomized, multicenter, open-label trial of 1623 patients with newly diagnosed MM was conducted to compare the efficacy and safety of lenalidomide and dexamethasone with that of melphalan, prednisone, and thalidomide. Progression-free survival (PFS) was significantly longer with continuous lenalidomide and dexamethasone than with melphalan, prednisone, and thalidomide (P <.0001).

A lower percentage of patients in the lenalidomide arm had PFS events than the melphalan, prednisone, and thalidomide arm (52% vs 61%). The improved median PFS time in the lenalidomide arm was 4.3 months, and the response rate was higher compared with melphalan, prednisone, and thalidomide (75.1% vs 62.3%). Complete response was shown in 15.1% versus 9.3%, respectively, and the median times to first response were 1.8 compared with 2.8 months.

Maintenance Therapy Following Stem Cell Transplant

Two multicenter, randomized, double-blind, parallel group, placebo-controlled studies were conducted to evaluate safety and efficacy of lenalidomide maintenance therapy in patients with MM post stem cell transplantation. In both studies, 10 mg once daily continuously was used. This dose could be increased to 15 mg after 3 months if tolerated. In both studies, PFS was significantly longer with lenalidomide versus placebo (P <.001).

Celgene Corporationâ€™s lenalidomide (Revlimid) is a targeted therapy that stops the growth of myeloma cells in the bone marrow.

Revlimid for Multiple Myeloma

You are a specialty pharmacist verifying a prescription for one of your patients. Sometimes you receive faxed prescriptions or the rare verbal order, but this current prescription was received electronically. 

This is no surprise to you, since the majority of the prescriptions that you dispense are received electronically. After all, e-prescribing (eRx) is the primary mode for prescription submission these days, accounting for 1.7 billion prescriptions in 2017. 

As part of the verification process, you check the standard prescription components for accuracy, such as patient demographics, secondary identifiers, strength, dosage form, directions, quantity, and refills. The prescribed medication and dose seem to be correct based on the patient’s indication. 

As a specialty pharmacist, you are aware that the medication you are about to verify has additional safety requirements. You check the directions and comment fields on the eRx to see if the prescriber free-texted the information, but unfortunately there is nothing to be found. 

You pick up the phone and make an outbound call to the prescriber’s office and wait on hold until you are finally transferred to the right department. The receptionist asks if you would be willing to leave a message for the prescriber, so you leave your request and put the prescription aside for future follow-up. 

Hopefully the prescriber returns your call soon so that you can finish dispensing the medication to the patient. Otherwise, you send a follow-up message within a day or so requesting the information again. In the meantime, you contact the patient and explain that there is a delay in their order. They are frustrated and don’t fully understand what the holdup is since we have a valid prescription from the prescriber.

This scenario might sound a bit exhausting to you, but it is a common occurrence in pharmacy practice these days—especially when it comes to Elements to Assure Safe Use (ETASU) and risk evaluation and mitigation strategies (REMS). ETASU and REMS requirements were derived from the FDA Amendments Act of 2007.  

These requirements were a means to ensure that the benefits of a medication outweighed its risks for the patient. The goal of REMS is to inform patients and prescribers of these serious risks and to provide mitigation strategies for these risks. 

It is the pharmacist’s responsibility to ensure that ETASU and REMS data are present and documented accordingly prior to dispensing of a patient’s prescription. If this information is missing or incomplete, a pharmacist is not authorized to dispense the prescription to the patient. The FDA describes ETASU as including 1 or more of the following:

Health care providers who prescribe the drug have particular training or experience or are specially certified.

Pharmacies, practitioners, or health care settings that dispense the drug are specially certified.

The drug may be dispensed only to patients in certain health care settings, such as in hospitals or infusion centers.

The drug is dispensed to patients with evidence or other documentation of safe-use conditions (for example, liver enzyme tests or pregnancy tests).

Each patient using the drug may be subject to certain monitoring or each patient using the drug must be enrolled in a registry.

As you can imagine, it may be difficult for a specialty pharmacist to keep track of the different requirements for each drug product. However, compliance to these requirements is critical both for patient safety and for the pharmacy’s ability to continue to dispense the medication. 

To aid with compliance, some pharmacy management systems have been technologically enhanced to ensure appropriate documentation of applicable requirements prior to dispense. Although this can help to standardize the documentation of ETASU and REMS requirements internally, the missing piece still lies within the lack of standardization across health care entities and the ability to communicate within a multi-dimensional system. 

As the specialty pharmacy industry continues to quickly grow, more medications are being released with REMS requirements. At the time of writing, there are 74 products containing these requirements. 

There has been an increased focus on the standardization of these requirements, beginning in 2011 with the creation of the FDA’s REMS Integration Initiative. The goals of the initiative are to “develop guidance on how to apply statutory criteria to determine when a REMS is required, improve standardization and assessment of REMS, and improve the integration of REMS into the existing and evolving health care system.” 

The initiative focuses on the following 4 projects: 

1) Benefit Risk Information—establishing best practices for counseling patients.

2) Prescriber Education—incorporation of continuing education into REMS programs.

3) Pharmacy Systems—Structured product labeling.

4) Practice Settings—Enhancement of REMS information repository. 

Although the pharmacy systems project will aid in the formatting of REMS requirements, it does not solve for the lack of an integrated communication platform between health care providers. The ability to capture and transmit ETASU and REMS between prescribers, pharmacists, and manufacturer hubs would be a groundbreaking achievement for the pharmacy industry.  

This functionality could greatly enhance the efficiency, organization, and compliance across the health care organization. I believe this topic will continue to be a focal point for the health care industry over the next several years. 

Currently, some vendors offer REMS data collection services, such as Cardinal Health and Pharmaceutical Product Development. Although an integrated system capable of multidimensional communication between providers has yet to emerge.

Some ideas are promising, such as transmission of REMS data through electronic prescribing or claim submission through the REMS administrator, similar to completing an online claim adjudication. But again, this functionality will not support the communication needs previously outlined.  

A foreseeable challenge to implementation of such a program would be the lack of standardization and uniformity surrounding the current REMS programs for today’s drug products. The range of requirements is wide, and the mode for collecting the requirements also differ. For example, some manufacturers require information to be obtained via phone while others offer a web portal. 

The information documented also ranges from prescriber and patient identification numbers to dispense authorization numbers. Depending on the program, some identification numbers remain the same for each prescriber and patient, while others change with each dispense. If the desired technology is developed, it will need to account for these varying requirements.

Successful creation of this technology would be beneficial to specialty pharmacies in many ways. First, it will offer a standardized formatting for viewing and collecting REMS data. Second, it will aid in systematic efforts to prevent the dispensing of products prior to ensuring that all requirements have been fulfilled. 

Most specific to the technology I have described, it will allow for communication between the pharmacy, prescriber, and manufacturer hub. Let’s revisit our earlier scenario. If this type of communication was available, there are a variety of ways in which the situation may have played out.

 The prescriber attempts to send the electronic prescription to the pharmacy without the required REMS information. An alert is received communicating the missing information to the prescriber. The prescriber gathers the required information, enters it into the e-prescribing software, and successfully submits the prescription to the pharmacy.

With this technology interface, the health care system could experience enhanced communication, efficiency, and regulatory compliance, which makes patient safety the ultimate benefit. 