Sandra Hanna, PharmD candidate

Entyvio (vedolizumab), manufactured by Takeda Pharmaceuticals, was approved in May 2014 for the treatment of adult patients with moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD) refractory to therapy with tumor necrosis factor (TNF)-blocking agents, immunomodulators, or corticosteroids. With a novel mechanism of action, this biologic agent provides a viable secondline option in the treatment of these gastrointestinal (GI) disorders.

The interaction of the alpha 4 beta 7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) contributes to the chronic inflammation implicated in UC and CD. Entyvio is a humanized monoclonal antibody and, as an integrin receptor antagonist, it specifically binds to the alpha 4 beta 7 integrin on certain memory T cells to block its interaction with MAdCAM-1, which is expressed on gut endothelial cells. This prevents these T cells from migrating across the endothelium into inflamed GI tissue. With the recommended dosing regimen, Entyvio exhibits a volume of distribution of 5 L, a linear clearance of 0.157 L/day, and a half-life of 25 days.

The recommended dose of Entyvio is 300 mg administered as a 30-minute intravenous (IV) infusion at 0, 2, and 6 weeks, and then every 8 weeks thereafter. If the patient does not show clinical improvement by week 14, therapy should be discontinued. Prior to administration, Entyvio must be reconstituted with 4.8 mL of sterile water for injection and diluted in 250 mL of normal saline; after the infusion, the line should be flushed with 30 mL of normal saline. Due to the risk of anaphylaxis or other hypersensitivity reactions that may occur, patients should be observed throughout the infusion with appropriate monitoring and support measures readily available.

The approval of Entyvio was obtained based on results of the GEMINI 1 study for UC and GEMINI 2 study for CD, both of which included patients who had not adequately responded to treatment with corticosteroids, immunomodulators, or TNF-blocking medications.

The GEMINI 1 study group conducted 2 integrated, double-blind, randomized, placebo-controlled trials for both induction and maintenance treatment of moderate to severe UC. For induction therapy, 374 patients (cohort 1) were randomized in a 3:2 ratio to IV treatment with Entyvio 300 mg or placebo at weeks 0 and 2 and 521 patients (cohort 2) received open-label Entyvio, also at weeks 0 and 2.

Patients receiving Entyvio from either cohort who had a clinical response at week 6 were randomized in a 1:1:1 ratio to be maintained on Entyvio every 4 or 8 weeks or switched to placebo for up to 52 weeks. At week 52, 44.8% of patients receiving Entyvio every 4 weeks, 41.8% of patients receiving Entyvio every 8 weeks, and 15.9% of patients receiving placebo went into clinical remission (P <.001 for each Entyvio group compared with placebo).

With a similar study design, the GEMINI 2 study group conducted 2 integrated, double-blind, randomized placebo-controlled trials for both induction and maintenance treatment of moderate to severe CD. For induction therapy, 368 patients (cohort 1) were randomized 3:2 to IV treatment with Entyvio 300 mg or placebo at weeks 0 and 2 and 747 patients (cohort 2) received open-label Entyvio, also at weeks 0 and 2.

Disease status, measured by CD Activity Index (CDAI), was assessed at week 6. Patients receiving Entyvio from either cohort who had a clinical response, deemed as a >70-point decrease in CDAI score, at week 6 were randomized in a 1:1:1 ratio to be maintained on Entyvio every 4 or 8 weeks or switched to placebo for up to 52 weeks. Among those patients who had a clinical response in the induction phase, 39.0% of those assigned to Entyvio every 8 weeks and 36.4% of those assigned to Entyvio every 4 weeks (P <.001 and P = .004, respectively) were in clinical remission at Week 52, compared with 21.6% of those assigned to placebo.

The most common (>10% incidence) adverse effects observed in both GEMINI trials were headache, arthralgia, and nasopharyngitis. Rare, serious adverse events have occurred with use of Entyvio, including hypersensitivity and infusion-related reactions, severe infections, and hepatic injury.

Entyvio is supplied as a 300-mg lyophilized cake in a sterile 20-mL single-dose vial. Entyvio has an acquisition cost of $5782 per vial.

Ashley L. Pappas, PharmD, BCPS, is a drug information specialist at University of North Carolina (UNC) Hospitals and an adjunct assistant professor at the UNC Eshelman School of Pharmacy.

Sandra Hanna, PharmD candidate, is a fourth-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.

		Entyvio [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2014.

		Vedolizumab. DrugPoints Summary. Micromedex 2.0. Greenwood Village, CO: Truven Health Analytics, Inc. www.micromedexsolutions.com. Accessed April 21, 2015.

		Feagan BG, Rutgeerts P, Sands BE, et al; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. 

. 2013;369(8):699-710. doi: 10.1056/NEJMoa1215734.

		Sandborn WJ, Feagan BG, Rutgeerts P, et al; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. 

. 2013;369(8):711-721. doi: 10.1056/NEJMoa1215739.

		Briskin M, Winsor-Hines D, Shyjan A, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. 

		Pricing obtained from AmerisourceBergen.

Articles

Entyvio, manufactured by Takeda Pharmaceuticals, was approved in May 2014 for the treatment of adult patients with moderate to severe ulcerative colitis or Crohn's disease.

Entyvio by Takeda Pharmaceuticals

Keytruda (pembrolizumab), manufactured by Merck, is indicated for treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and a BRAF inhibitor (if the patient is 

 mutationpositive). Newly approved on an accelerated basis in September 2014, Keytruda is the first in its therapeutic class as a programmed death (PD)-1 inhibitor, blocking a cellular pathway that restricts the immune system from attacking melanoma cells. The FDA designated Keytruda as an orphan product, and it is the sixth new melanoma treatment that has emerged since 2011.

When the PD-1 ligands, PD-L1 and PD-L2 bind to the PD-1 receptor found on T-cells, T-cell proliferation and cytokine production are inhibited. Upregulation of these ligands occurs on the cell surface of some tumors, including melanoma, effectively decreasing active T-cell surveillance of these tumors. Keytruda, a humanized monoclonal antibody, binds to the PD-1 receptor with high selectivity, blocking its interaction with these ligands. The pharmacokinetics of Keytruda were studied in 479 patients who received doses of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. The peak concentration, trough concentration, and area under the plasma concentration versus time curve at a steady state increased dose-proportionally in the range of 2 to 10 mg/kg every 3 weeks. Keytruda has a mean clearance of 0.22 L/day and elimination half-life of 26 days.

Recommended dosing of Keytruda is 2 mg/kg administered as an intravenous (IV) infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity occurs. With its novel mechanism of action, Keytruda has the potential for severe immune-mediated adverse effects (AEs). Doses should be withheld if grade 2 pneumonitis or nephritis, grade 2 or 3 colitis, grade 3 hyperthyroidism, liver function test (LFT) elevations 3 to 5 times the upper limit of normal (ULN), or any other severe or grade 3 treatment-related adverse reactions occur. Keytruda should be permanently discontinued if LFTs increase greater than 5 times ULN, if persistent grade 2 or 3 adverse reactions do not recover to grade 0 to 1 within 12 weeks after last dose, or if grade 3 or 4 pneumonitis, nephritis, or infusion-related reactions occur.

Keytruda was approved based on a randomized, open-label, international expansion cohort of a phase 1 clinical trial in which 173 adult patients with advanced melanoma, whose disease had progressed after being given at least 2 doses of ipilimumab, were randomly assigned to IV pembrolizumab at a 1:1 ratio of either 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. Patients were treated until disease progression, intolerable toxicity, or consent withdrawal occurred. The primary end point was the overall response rate, assessed with Response Evaluation Criteria in Solid Tumors, and was found to be 26% at both doses (P = 0.96). Treatment was generally well tolerated with similar safety profiles in both dosing regimens: there were no drug-related deaths, and only 12% of patients overall experienced drug-related grade 3 or 4 AEs, few of which were potentially immune-mediated. Investigators concluded that Keytruda at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in ipilimumab-refractory advanced melanoma patients for whom there are few effective treatment options.

The most common AEs seen in clinical studies were fatigue, cough, nausea, diarrhea, constipation, anorexia, arthralgia, pruritus, and rash. Keytruda is a Pregnancy Category D medication solely based on its mechanism of action; no formal animal reproduction studies have yet been conducted. Previous animal models have demonstrated the role of the PD-1/ PDL-1 signaling pathway with pregnancy maintenance through induction of maternal immune tolerance to fetal tissue. Thus, potential risks of administering Keytruda during pregnancy may include increased rates of abortion or stillbirth. It is unknown whether Keytruda is excreted in breast milk.

Keytruda is supplied as 50-mg single-use vials that should be stored under refrigeration at 2°C to 8°C (36°F-46°F). Each vial should be reconstituted with 2.3 mL of sterile water for injection and then gently swirled and inspected for particulate matter. The required drug volume should then be withdrawn from the vial and transferred to an IV bag containing normal saline. After gently inverting for adequate mixing, this diluted solution should have a final concentration between 1 and 10 mg/mL. The acquisition cost of Keytruda is $5179 per vial. More information is available at www.keytruda.com.

Sandra Hanna, PharmD candidate, is a third-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.

		Keytruda [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; September 2014.

		FDA approves Keytruda for advanced melanoma [press release]. Silver Spring, MD: FDA; September 10, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412802.htm.

		Keytruda. Facts & Comparisons [online database]. St. Louis, MO: Wolters Kluwer Health, Inc; September 2014. Accessed January 28, 2015.

		Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial. 

		Pricing obtained from AmerisourceBergen wholesaler.

Keytruda, manufactured by Merck, is indicated for treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and a BRAF inhibitor.

Keytruda by Merck

Cyramza (ramucirumab), manufactured by Eli Lilly and Company, is an angiogenesis inhibitor indicated for the treatment of patients with advanced (unresectable) or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with disease progression on or after treatment with prior fluoropyrimidine- or platinum-containing chemotherapy. The FDA recently approved Cyramza under its priority review program, which is reserved for drugs that have the potential to be a “significant improvement in safety or effectiveness in the treatment of a serious condition.” In addition to an expedited review process, Cyramza was granted orphan product designation, as it is intended to treat a rare disease or condition. (It is the first and only approved second-line treatment for gastric cancer.)

Cyramza is a vascular endothelial growth factor (VEGF) receptor 2 antagonist that blocks binding of ligands VEGF-A, VEGF-C, and VEGF-D, resulting in inhibition of ligand-induced proliferation and migration of human endothelial cells. Pharmacokinetic data of Cyramza have not been fully characterized.

The recommended dose of Cyramza is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Once the required volume of drug is withdrawn from the vial, it should be further diluted with normal saline to a final volume of 250 mL. The container should then be gently inverted to ensure adequate mixing. Prior to each infusion, all patients should be premedicated with an IV H1 antagonist (eg, diphenhydramine). Patients who have experienced a grade 1 or 2 infusion reaction should also be premedicated with dexamethasone (or equivalent) and acetaminophen prior to each Cyramza dose. Continue Cyramza until disease progression or unacceptable toxicity occurs.

Cyramza obtained FDA approval based on the REGARD trial performed by Fuchs and colleagues. This multicenter, double-blind, phase III trial sought to assess the safety and efficacy of Cyramza in patients with advanced gastric or gastroesophageal junction adenocarcinoma. At a ratio of 2:1, 355 patients between the ages of 24 and 87 years, whose disease progressed after receiving first-line platinum-containing or fluoropyrimidine- containing chemotherapy, were assigned to receive either ramucirumab 8 mg/kg (n = 238) or placebo (n = 117) intravenously once every 2 weeks. All patients, regardless of assigned treatment, also received best supportive care. Median treatment duration was 8 weeks (4 doses) for the Cyramza group and 6 weeks (3 doses) for the placebo group. Radiological and symptomatic disease progression was the most common reason for treatment discontinuation, followed by adverse events (AEs).

In assessing overall survival (primary end point), investigators found that patients in the Cyramza group lived a median of 5.2 months (95% CI, 4.4-5.7) compared with 3.8 months (95% CI, 2.8-4.7) for patients in the placebo group, a statistically significant difference (P = .047). When assessing progression-free survival (secondary end point), investigators found that patients in the Cyramza group lived a median of 2.1 months (95% CI, 1.5-2.7) compared with 1.3 months (95% CI, 1.3-1.4) for patients in the placebo group, also a statistically significant difference (P <.001).

Cyramza carries a black box warning concerning the increased risk of hemorrhage, which can sometimes be fatal, as demonstrated in the REGARD trial. The most common AEs observed in patients treated with Cyramza in clinical trials were hypertension and diarrhea at a rate of >10% and >2% higher than placebo, respectively. The most common serious adverse events seen were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of Cyramza-treated patients versus 8.7% of patients who received placebo. Approximately 2% of patients who received Cyramza in clinical trials experienced serious and sometimes fatal arterial thromboembolic events, such as myocardial infarction and stroke. Gastrointestinal perforation and infusion-related reactions occurred in less than 1% of patients. Proteinuria also occurred in 8% of Cyramza-treated patients compared with 3% of placebo-treated patients. No formal drug interaction studies between Cyramza and other drugs have been conducted. Cyramza is a pregnancy category C drug.

Cyramza is supplied in 100-mg/10- mL and 500-mg/50-mL (both at 10-mg/mL concentration) single-dose vials. Vials should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F), and should be kept in the outer carton to protect from light. Do not freeze or shake the vials. The wholesale acquisition cost of the 100-mg/10-mL vial is $1020, and the 500-mg/50-mL vial is $5100. More information is available at 

		Cyramza [package insert]. Indianapolis, IN: Eli Lilly and Company; April 2014.

		Cyramza. Micromedex [online database]. Greenwood Village, CO: Thomson Healthcare; May 2014.

		Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31-39.

		Pricing obtained from AmerisourceBergen database.

Cyramza, manufactured by Eli Lilly and Company, is an angiogenesis inhibitor indicated for the treatment of patients with advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with disease progression on or after treatment with prior fluoropyrimidine- or platinum-containing chemotherapy.

Cyramza by Eli Lilly and Company

Dalvance (dalbavancin), manufactured by Durata Therapeutics, is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible strains of Gram-positive bacteria. Dalvance is the first drug with the designation of Qualified Infectious Disease Product to receive FDA approval. Under the Generating Antibiotic Incentives Now title of the FDA Safety and Innovation Act, Dalvance was granted as such because it is an “antibacterial or antifungal human drug intended to treat serious or life-threatening infections.”

Dalvance is a semisynthetic lipoglycopeptide antibacterial agent that inhibits peptidoglycan crosslinking in bacterial cell walls by binding to the end of the D-alanyl-D-alanine pentapeptide chain in the nascent peptidoglycan. Dalvance is bactericidal against 

 (including methicillin-resistant strains), 

Dalvance time to peak is 0.5 to 1 hour. The volume of distribution is 9.75 to 15.7 L. Dalvance is not a substrate, inhibitor, or inducer of any cytochrome P450 enzyme. Elimination half-life of the drug is approximately 8.5 days, allowing for once-weekly dosing.

Adults with ABSSSI should be treated with a 2-dose regimen of 1000 mg followed 1 week later by 500 mg. Dalvance should be given over 30 minutes by intravenous (IV) infusion. In patients with renal impairment (creatinine clearance <30 mL/min) who are not receiving regular hemodialysis, the recommended 2-dose regimen is 750 mg followed 1 week later by 375 mg. Prior to use, Dalvance must be reconstituted under aseptic conditions using 25 mL of sterile water for injection for each 500-mg vial. After gently swirling to allow for dissolution, the required dose of reconstituted solution is then aseptically transferred from the vial to an IV bag or bottle containing 5% dextrose injection (D5W). The diluted solution must have a final concentration of 1 to 5 mg/ mL. The total time from reconstitution to dilution to administration should not exceed 48 hours.

Dalvance obtained FDA approval based on results from DISCOVER 1 and DISCOVER 2 trials of identical design performed by Boucher and colleagues. A total of 1312 adult patients with ABSSSI were enrolled in these Phase III, randomized, double-blind, doubledummy non-inferiority trials. Patients were treated for 2 weeks with either a 2-dose regimen of Dalvance (1000 mg followed by 500 mg one week later) or with IV vancomycin with the option to switch to oral linezolid after 3 days to complete 10 to 14 days of therapy. Eligible patients had cellulitis, major abscess, or wound infections, each associated with at least 75 cm

 of erythema. Patients were required to have at least 1 systemic sign of disease at baseline, defined as temperature at or greater than 38°C, white blood cell (WBC) count greater than 12,000 cells/mm

, or 10% or more band forms on the WBC differential, along with local infection signs and symptoms. The primary end point was defined as both the cessation of spread of infection- related erythema and the absence of fever (temperature consistently at or below 37.6°C for 3 consecutive readings performed 6 hours apart) at 48 to 72 hours after initiation of therapy.

In the pooled analysis of DISCOVER 1 and 2, 525 of 659 patients (79.7%) in the Dalvance group and 521 of 653 (79.8%) in the vancomycin-linezolid group met the primary end point criteria (weighted difference, -0.1%; 95% confidence interval, -4.5 to 4.2). With these differences deemed nonsignificant at a non-inferiority margin of 10% and a 1-sided alpha level of 0.025, investigators concluded that the efficacy of Dalvance, administered once weekly, was not inferior to that of a conventional twice-daily antibiotic regimen for treatment of ABSSSI.

The most commonly observed adverse events of Dalvance in clinical trials were nausea, diarrhea, pruritus, and headache, lasting a median of 4 days in patients receiving Dalvance and 3 days in those receiving vancomycin-linezolid. Dalvance should not be coinfused with other medications or electrolytes. Saline-based infusion solutions may cause precipitation and, thus, should not be used. If a common IV line is being used to administer other drugs in addition to Dalvance, the line should be flushed with D5W before and after each diluted Dalvance infusion.

Dalvance is supplied as 500-mg vials for injection. The wholesale acquisition cost of Dalvance is $1490 for a 500-mg vial. More information is available at www .dalvance.com.

Sandra Hanna, PharmD candidate, is a thirdyear pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.

1.     Dalvance [package insert]. Chicago, IL: Durata Therapeutics, Inc; June 2014.

2.     FDA approves Dalvance to treat skin infections [press release]. FDA website. May 23, 2014. Accessed July 8, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm398724.htm.

3.     Dalvance. Micromedex [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated June 27, 2014.

4.     Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for skin infection. 

5.     Pricing obtained from AmerisourceBergen wholesaler.

Dalvance by Durata Therapeutics

Gazyva is a novel anti-CD20 monoclonal antibody approved, in combination with chlorambucil, for the treatment of previously untreated chronic lymphocytic leukemia patients.

Gazyva (obinutuzumab), manufactured by Genentech, is a novel anti-CD20 monoclonal antibody FDA approved, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

Approved November 1, 2013, Gazyva is the first drug with breakthrough therapy designation to receive FDA approval.

As a monoclonal antibody, Gazyva targets the CD20 antigen expressed on the surface of both mature and immature B-lymphocytes and, upon binding, mediates the lysis of these cells through 3 mechanisms: engaging immune effector cells to result in antibody-dependent cellular cytotoxicity and phagocytosis, directly activating apoptosis signaling pathways, and/or activating the complement protein cascade. Gazyva has a volume of distribution of approximately 3.8 L, a total body clearance of 0.09 L/day, and an elimination half-life of approximately 28.4 days.

Treatment with Gazyva is completed in 6 cycles, and premedication before each infusion during the 28-day cycle is strongly recommended to reduce the risk of potentially severe, life-threatening infusion reactions. Gazyva is administered only as an intravenous (IV) infusion via a dedicated line. On day 1 of cycle 1, a dose of 100 mg should be administered at 25 mg/h over 4 hours, and the infusion rate should not be increased. On day 2 of cycle 1, 900 mg should be administered at 50 mg/h, and the infusion rate may be increased in increments of 50 mg/h every 30 minutes to a maximum rate of 400 mg/h. This is followed by 1000 mg weekly for 2 doses on days 8 and 15 of cycle 1. Following completion of cycle 1, 1000 mg of Gazyva should be administered every 28 days with each dose designated as day 1 of 5 subsequent cycles. The 1000-mg doses should be infused at a rate of 100 mg/h and may be increased by 100 mg/h increments every 30 minutes to a maximum of 400 mg/h. Thus, for 1 course of treatment lasting approximately 6 months, a total of 9 doses of Gazyva would be administered to a patient.

For patients with high tumor burden and/or high circulating absolute lymphocyte counts (>25 × 10

/L), premedication with an antihyperuricemic, such as allopurinol, starting 12 to 24 hours prior to start of therapy, is advised. Adequate hydration should also be ensured to prevent tumor lysis syndrome in these patients. All patients on days 1 and 2 of cycle 1 should receive an IV glucocorticoid, such as 20 mg dexamethasone or 80 mg methylprednisolone, at least 1 hour prior to Gazyva, as well as 650 to 1000 mg acetaminophen and an antihistamine (eg, diphenhydramine 50 mg) at least 30 minutes before infusion as premedication therapy. The acetaminophen should be repeated for all patients on days 8 and 15 of cycle 1, as well as on the first day of subsequent cycles. The antihistamine may also be repeated on these days only for patients with an infusion-related reaction (IRR) of Grade 1 or higher from the previous infusion, and the IV glucocorticoid should only be repeated on those same days for patients with a Grade 3 IRR or with a lymphocyte count >25 × 10

Approval for Gazyva was based on a randomized, open-label multicenter phase III trial of 356 participants with previously untreated CLL comparing Gazyva in combination with chlorambucil against chorambucil alone. Gazyva was given according to the dosing protocol established above, and chlorambucil was given orally at 0.5 mg/kg on days 1 and 15 of all 6 treatment cycles. In the study, 95% of participants were Caucasian, 60% were male, and 76% had multiple coexisting medical conditions. The median age was 73 years, and the median estimated CrCL was 61 mL/min. At the conclusion of the study, 81% of patients treated with Gazyva and chlorambucil in combination received all 6 cycles of therapy compared with 67% of patients receiving chlorambucil alone. The median progression-free survival was 23.0 months in the arm receiving Gazyva and chlorambucil in combination and 11.1 months in the chlorambucil alone arm, deemed a significant difference (log-rank 

The most common adverse reactions seen during treatment with Gazyva are infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Black box warnings associa-ted with use of Gazyva include risk of hepatitis B virus reactivation that may result in fulminant hepatitis, liver failure, or death, as well as risk of progressive multifocal leukoencephalopathy, which may also be fatal. Because hypotension may occur during Gazyva infusions, providers should consider withholding antihypertensive treatments for 12 hours prior to and throughout each infusion, as well as for the first hour after administration. It is highly recommended that patients with neutropenia receive antimicrobial prophylaxis throughout the treatment period. Gazyva should not be administered to patients with an active infection, and patients with a history of chronic or recurring infections may also be at an increased risk of infection with Gazyva.

Gazyva is available as 1000 mg/40 mL (25 mg/mL) single-use vials containing preservative-free solution. The vials should be protected from light and refrigerated, as they are stable at 2°C to 8°C (36°F to 46°F). Cost of Gazyva is $41,300 for one 6-month course of treatment.

		Gazyva [package insert]. South San Francisco, CA: Genentech, Inc; November 2013.

		FDA approves Gazyva for chronic lymphocytic leukemia [press release]. November 1, 2013. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm373209.htm.

		Gazyva. Drug Facts & Comparisons [online database]. Wolters Kluwer Health, Inc; November 2013.

		Leuty R. Genentech scores FDA approval for new leukemia drug. 

. November 1, 2013. www.bizjournals.com/sanfrancisco/blog/biotech/2013/11/genentech-cll-leukemia-gadcyla-rituxan.html?page=all.

 is a drug information specialist at University of North Carolina (UNC) Hospitals and an adjunct assistant professor at the UNC Eshelman School of Pharmacy.

 is a second-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.

Gazyva is a novel anti-CD20 monoclonal antibody approved, in combination with chlorambucil, for the treatment of previously untreated chronic lymphocytic leukemia patients. 

Gazyva by Genentech

Obinutuzumab (Gazyva), manufactured by Genentech, is a novel anti-CD20 monoclonal antibody FDA approved, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

 Approved November 1, 2013, Gazyva is the first drug with breakthrough therapy designation to receive FDA approval. This designation, requested by a pharmaceutical company, is designed to expedite the development and review process of drugs that are intended to treat serious conditions when preliminary clinical evidence demonstrates that the drug clearly shows substantial improvement over current therapies on clinically significant end points.

As a monoclonal antibody, obinutuzumab targets the CD20 antigen expressed on the surface of both mature and immature B-lymphocytes and, upon binding, mediates the lysis of these cells through 3 mechanisms: engaging immune effector cells to result in antibody-dependent cellular cytotoxicity and phagocytosis, directly activating apoptosis signaling pathways, and/or activating the complement protein cascade. Obinutuzumab has a volume of distribution of approximately 3.8 L, a total body clearance of 0.09 L/day, and an elimination half-life of approximately 28.4 days.

Treatment with obinutuzumab is completed in 6 cycles, and premedication before each infusion during the 28-day cycle is strongly recommended to reduce the risk of potentially severe, life-threatening infusion reactions. Obinutuzumab is administered only as an intravenous (IV) infusion via a dedicated line. On day 1 of cycle 1, a dose of 100 mg should be administered at 25 mg/h over 4 hours, and the infusion rate should not be increased. On day 2 of cycle 1, 900 mg should be administered at 50 mg/h, and the infusion rate may be increased in increments of 50 mg/h every 30 minutes to a maximum rate of 400 mg/h. This is followed by 1000 mg weekly for 2 doses on days 8 and 15 of cycle 1. Following completion of cycle 1, 1000 mg of obinutuzumab should be administered every 28 days with each dose designated as day 1 of 5 subsequent cycles. The 1000-mg doses should be infused at a rate of 100 mg/h and may be increased by 100 mg/h increments every 30 minutes to a maximum of 400 mg/h. Thus, for 1 course of treatment lasting approximately 6 months, a total of 9 doses of obinutuzumab would be administered to a patient.

For patients with high tumor burden and/or high circulating absolute lymphocyte counts (>25 × 109/L), premedication with an antihyperuricemic, such as allopurinol, starting 12 to 24 hours prior to start of therapy is advised. Adequate hydration should also be ensured to prevent tumor lysis syndrome in these patients. All patients on days 1 and 2 of cycle 1 should receive an IV glucocorticoid, such as 20 mg dexamethasone or 80 mg methylprednisolone, at least 1 hour prior to obinutuzumab, as well as 650 to 1000 mg acetaminophen and an antihistamine (eg, diphenhydramine 50 mg) at least 30 minutes before infusion as premedication therapy. The acetaminophen should be repeated for all patients on days 8 and 15 of cycle 1, as well as on the first day of subsequent cycles. The antihistamine may also be repeated on these days only for patients with an infusion-related reaction (IRR) of Grade 1 or higher from the previous infusion, and the IV glucocorticoid should only be repeated on those same days for patients with a Grade 3 IRR or with a lymphocyte count >25 × 109/L prior to the next treatment.

Approval for Gazyva was based on a randomized, open-label multicenter phase III trial of 356 participants with previously untreated CLL comparing obinutuzumab in combination with chlorambucil to chorambucil alone. Obinutuzumab was given according to the dosing protocol established above, and chlorambucil was given orally at 0.5 mg/kg on day 1 and 15 of all 6 treatment cycles. In the study, 95% of participants were Caucasian, 60% were male, and 76% had multiple coexisting medical conditions. The median age was 73 years, and the median estimated CrCL was 61 mL/min. At the conclusion of the study, 81% of patients treated with obinutuzumab and chlorambucil in combination received all 6 cycles of therapy compared with 67% of patients receiving chlorambucil alone. The median progression-free survival was 23.0 months in the arm receiving obinutuzumab and chlorambucil in combination and 11.1 months in the chlorambucil alone arm, deemed a significant difference (log-rank 

The most common adverse reactions seen during treatment with obinutuzumab are infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Black box warnings associated with use of obinutuzumab include risk of hepatitis B virus reactivation that may result in fulminant hepatitis, liver failure, or death, as well as risk of progressive multifocal leukoencephalopathy, which may also be fatal. Because hypotension may occur during obinutuzumab infusions, providers should consider withholding antihypertensive treatments for 12 hours prior to and throughout each infusion, as well as for the first hour after administration. It is highly recommended that patients with neutropenia receive antimicrobial prophylaxis throughout the treatment period. Obinutuzumab should not be administered to patients with an active infection, and patients with a history of chronic or recurring infections may also be at an increased risk of infection with obinutuzumab. Patients should not be immunized with live virus vaccines during treatment. Platelet counts should be monitored in patients who develop grade 3 or 4 thrombocytopenia while being treated with obinutuzumab; transfusion of blood products may be necessary.

 Additional information can be found at www.gazyva.com.

Sandra Hanna, PharmD candidate, is a second-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.