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P T. 2016;41(1): 26, 27, 59

Pharmaceutical Approval Update January 2016

Chris Fellner

Elotuzumab (Empliciti)

Manufacturers: Bristol-Myers Squibb, New York, New York, and AbbVie, North Chicago, Illinois

Date of Approval: November 30, 2015

Indication: Elotuzumab is indicated in combination with lenalidomide (Revlimid, Celgene Corporation) and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

Drug Class: Elotuzumab is a humanized, recombinant immunoglobulin G1 (IgG1) monoclonal antibody that specifically targets the cell-surface glycoprotein SLAMF7 (signaling lymphocytic activation molecule family member 7). It is produced in NSO cells by recombinant DNA technology.

Uniqueness of Drug: SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on natural killer cells, on plasma cells, and (at lower levels) on specific immune-cell subsets of differentiated cells within the hematopoietic lineage. Elotuzumab directly activates natural killer cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with natural killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity.

Warnings and Precautions:

Infusion reactions. Elotuzumab can cause infusion reactions. Clinicians should administer premedication consisting of dexamethasone, antihistamines (H1 and H2 blockers), and acetaminophen before elotuzumab infusion.

Infections. In a clinical trial involving 635 patients with multiple myeloma, infections were reported in 81% of those treated with elotuzumab combined with lenalidomide and dexamethasone.

Interference with determination of complete response. Elotuzumab is a humanized IgG kappa monoclonal antibody that can be detected on assays used for the clinical monitoring of endogenous myeloma protein. This interference can affect the determination of a complete response and possibly relapse from a complete response in patients with IgG kappa myeloma protein.

Pregnancy. There are no studies with elotuzumab in pregnant women, and no information on the presence of elotuzumab in human milk. There is a risk of fetal harm when elotuzumab is used with lenalidomide.

Pediatric use. The safety and efficacy of elotuzumab have not been established in pediatric patients.

Immunogenicity. As with all therapeutic proteins, there is a potential for immunogenicity to elotuzumab.

Dosage and Administration: The recommended dosage of elotuzumab is 10 mg/kg administered intravenously every week for the first two cycles and every two weeks thereafter in conjunction with the recommended dosing of lenalidomide and low-dose dexamethasone. Treatment is continued until disease progression or unacceptable toxicity occurs.

Commentary: Elotuzumab is the second monoclonal antibody approved to treat patients with multiple myeloma, following the approval of daratumumab (Darzalex) in November 2015. Despite being the second player on the scene, elotuzumab is expected to be preferred over daratumumab for use in combination with lenalidomide and dexamethasone because of its synergistic immunomodulatory effects when combined with lenalidomide. Consultant GlobalData predicts that the drug will reach blockbuster status by 2018 and will achieve peak sales of $4.2 billion in 2022. (A discussion of the drug pipeline for multiple myeloma medications appears on page 64.)

Sources: Food and Drug Administration (FDA), Empliciti prescribing information, GlobalData

Ixazomib (Ninlaro)

Manufacturer: Takeda Pharmaceuticals, Osaka, Japan

Date of Approval: November 20, 2015

Indication: Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Drug Class: Ixazomib is a reversible proteasome inhibitor with antineoplastic activity. It preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.

Uniqueness of Drug: Ixazomib is the only oral proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Unlike the newly approved injectable treatments elotuzumab (Empliciti) and daratumumab (Darzalex), ixazomib is an oral medication, supplied as gelatin capsules (2.3, 3.0, and 4.0 mg).

Warnings and Precautions:

Thrombocytopenia. In reports of thrombocytopenia with ixazomib, platelet nadirs typically occurred between days 14 and 21 of each 28-day cycle.

Peripheral neuropathy. Patients should be monitored for symptoms of neuropathy. In clinical studies, most peripheral neuropathy adverse reactions were grade 1 or grade 2 in severity.

Peripheral edema. In clinical studies, peripheral edema was reported in 25% of patients receiving the ixazomib regimen.

Hepatotoxicity. Events of liver impairment have been reported (6% of patients in the ixazomib regimen and 5% of those in the placebo regimen). Hepatic enzymes should be monitored regularly.

Embryo-fetal toxicity. Ixazomib may cause fetal harm when administered to a pregnant woman, based on the drug’s mechanism of action. No adequate and well-controlled studies have been conducted in pregnant women. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with ixazomib.

Dosage and Administration: The recommended starting dose of ixazomib is 4 mg administered orally once a week on days 1, 8, and 15 of a 28-day treatment cycle. The starting dose is reduced to 3 mg in patients with moderate-to-severe renal impairment or severe hepatic impairment. Ixazomib is administered in combination with lenalidomide and dexamethasone.

Commentary: The FDA approval of ixazomib was based on results from the phase 3 TOURMALINE-MM1 trial, the first double-blind, placebo-controlled study with a proteasome inhibitor. Study participants received either ixazomib in combination with lenalidomide and dexamethasone or placebo plus lenalidomide and dexamethasone. Those taking ixazomib lived longer without their disease worsening (average, 20.6 months) compared with participants taking the placebo regimen (average, 14.7 months).

Sources: FDA, Ninlaro prescribing information

Daratumumab (Darzalex)

Manufacturer: Janssen Biotech, Horsham, Pennsylvania

Date of Approval: November 16, 2015

Indication: Daratumumab is indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.

Drug Class: Daratumumab is an IgG1 kappa human monoclonal antibody directed against CD38 antigen, produced in a mammalian cell line (Chinese hamster ovary) using DNA technology. CD38 is a surface protein that is expressed by most, if not all, multiple myeloma cells.

Uniqueness of Drug: Daratumuab was the first monoclonal antibody approved for the treatment of patients with multiple myeloma.

Warnings and Precautions:

Infusion reactions. Daratumumab can cause severe infusion reactions, including bronchospasm, hypoxia, dyspnea, and hypertension. Approximately half of all patients in clinical trials experienced a reaction, most during the first infusion.

Interference with serological testing. Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (Coombs test). Daratumumab bound to RBCs masks the detection of antibodies to minor antigens in the patient’s serum.

Interference with the determination of a complete response. This can occur because daratumumab is a human IgG kappa monoclonal antibody that can be detected on assays used for the clinical monitoring of endogenous myeloma protein. This interference may affect the determination of a complete response and of disease progression in some patients with IgG kappa myeloma protein.

Immunogenicity. As with all therapeutic proteins, there is the potential for immunogenicity with daratumumab.

Use in specific populations. There is no information on the use of daratumumab during pregnancy or in pediatric patients. No dosage adjustments are necessary in patients with renal impairment or mild hepatic impairment. Daratumumab has not been studied in patients with moderate-to-severe hepatic impairment. No drug-interaction studies have been performed with daratumumab.

Dosage and Administration: The recommended dosage of daratumumab is 16 mg/kg administered as an intravenous infusion on weeks 1 to 8 (weekly schedule); on weeks 9 to 24 (biweekly schedule); and on week 52 onwards (monthly schedule) until disease progression occurs.

Commentary: The FDA’s approval of daratumumab came just two months after its biologics license application was accepted for priority review in September 2015. The product also received a breakthrough therapy designation in May 2013. It is expected to reach peak sales of $3.7 billion in 2023.

Sources: FDA, Janssen Biotech, Darzalax prescribing information, GlobalData

Osimertinib (Tagrisso)

Manufacturer: AstraZeneca, Wilmington, Delaware

Date of Approval: November 13, 2015

Indication: Osimertinib is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non–small-cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

Drug Class: Osimertinib is a TKI that binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion).

Uniqueness of Drug: Osimertinib is the only medication approved for the treatment of patients with EGFR T790M mutation-positive NSCLC.

Warnings and Precautions:

Interstitial lung disease/pneumonitis. This occurred in 3.3% of patients during clinical trials of osimertinib. Treatment should be permanently discontinued in these patients.

QTc interval prolongation. Osimertinib has the potential to cause this condition. Electrocardiograms and electrolytes should be monitored in patients with a history of or predisposition for QTc prolongation, or in those who are taking medications that are known to prolong the QTc interval. Osimertinib should be withheld and then restarted at a reduced dose or permanently discontinued in these patients.

Cardiomyopathy. During clinical trials of osimertinib, cardiomyopathy occurred in 1.4% of patients. Clinicians should assess the left ventricular ejection fraction before treatment and then every three months thereafter.

Embryo-fetal toxicity. Osimertinib can cause fetal harm. Female patients should be advised of the potential risk to the fetus, and they should be instructed to use effective contraception during treatment with osimertinib and for six weeks after the final dose. Male patients should be advised to use effective contraception for four months after the last dose of osimertinib.

Drug interactions. Concurrent administration with strong cytochrome P450-3A inhibitors or inducers should be avoided, if possible.

Dosage and Administration: The recommended dosage of osimertinib is one 80-mg tablet once a day until disease progression or unacceptable toxicity occurs. Osimertinib can be taken with or without food.

Commentary: Osimertinib was granted fast track, breakthrough therapy, priority review, and accelerated approval designations by the FDA. Its approval was based on data from two phase 2 studies (AURA extension and AURA2) that demonstrated efficacy in 411 patients with metastatic EGFR T790M mutation-positive NSCLC that had progressed on or after EGFR TKI therapy. In those studies, the overall objective response rate (ORR) was 59%. In a separate part of the AURA study (n = 63), the ORR was 51%, and the median duration of response was 12.4 months. Osimertinib is being studied in an open-label, randomized, phase 3 confirmatory trial designed to assess the drug’s efficacy and safety compared with that of platinum-based doublet chemotherapy in patients with EGFR T790M mutation-positive, locally advanced or metastatic NSCLC who have progressed after EGFR TKI therapy. Osimertinib is also being investigated in the adjuvant and metastatic first-line settings, including in patients with brain metastases, as well as in combination with other compounds.

Sources: FDA, AstraZeneca, Tagrisso prescribing information

Fluad (Influenza Vaccine, Adjuvanted)

Manufacturer: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts

Date of Approval: November 24, 2015

Indication: Fluad is indicated for active immunization against influenza disease caused by influenza virus subtypes A and B contained in the vaccine. It is approved for use in persons 65 years of age and older.

Drug Class: Fluad is a trivalent, inactivated influenza vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs inoculated with a specific type of influenza virus suspension.

Uniqueness of Drug: Fluad is the first seasonal influenza vaccine containing an adjuvant. It is formulated with the adjuvant MF59, an oil-in-water emulsion of squalene oil. Adjuvants are incorporated into some vaccine formulations to enhance or direct the immune response of vaccinated individuals.

Each 0.5 mL-dose of Fluad contains at least 15 mcg of hemagglutinin from each of the following three influenza strains recommended for the 2015/2016 influenza season: A/California/7/2009 NYMC X-181 (H1N1), an A/California/7/2009 pdm09-like virus; A/Switzerland/9715293/2013 NIB-88 (H3N2), an A/Switzerland/9715293/2013-like virus; and B/Brisbane/9/2014, a B/Phuket/3073/2013-like virus.

Warnings and Precautions:

Guillain–Barré syndrome (GBS). If GBS has occurred within six weeks of receipt of prior influenza vaccine, the decision to give Fluad should be based on careful consideration of the potential benefits and risks.

Allergic reactions. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of Fluad.

Altered immunocompetence. The immune response to Fluad in immunocompromised persons may be lower than in immunocompetent individuals.

Syncope. Fainting may occur in association with the administration of injectable vaccines, including Fluad.

Limitations of vaccine effectiveness. Vaccination with Fluad may not protect all vaccine recipients against influenza disease.

Dosage and Administration: Fluad is administered as a single 0.5-mL intramuscular injection in adults ages 65 years and older. The product is for intramuscular injection only.

Commentary: According to the FDA, immunizing individuals 65 years of age and older is especially important because this population bears the greatest burden of severe influenza disease and accounts for most influenza-related hospitalizations and deaths. In an international clinical study that included the U.S., Fluad induced antibody levels that were comparable with the levels induced by Agriflu (Novartis).

Sources: FDA, Fluad prescribing information

Author bio: 
Chris Fellner is a medical writer and the Editor of