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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.

May 15, 2019–Venetoclax (VENCLEXTA, AbbVie Inc. and Genentech Inc.) approved for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

June 8, 2018–Venetoclax (VENCLEXTA, AbbVie Inc. and Genentech Inc.) approved for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy (with Pharmacist's Applications to Practice.)

April 11, 2016–Venetoclax (VENCLEXTA™) approved for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion (with Pharmacists's Applications to Practice.)


May 15, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208573s013lbl.pdf .

On May 15, 2019, the Food and Drug Administration approved venetoclax (VENCLEXTA, AbbVie Inc. and Genentech Inc.) for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Approval was based on CLL14 (NCT02242942), a randomized (1:1), multicenter, open label, actively controlled trial of venetoclax in combination with obinutuzumab (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) in 432 patients with previously untreated CLL with coexisting medical conditions.

The major efficacy outcome was progression-free survival (PFS) assessed by an independent review committee. The trial demonstrated a statistically significant improvement in PFS for patients who received VEN+G compared with those who received GClb (HR 0.33; 95% CI: 0.22, 0.51; p<0.0001). Median PFS was not reached in either arm after a median follow-up duration of 28 months. The overall response rate was 85% in VEN+G arm compared to 71% in GClb arm, p=0.0007. The trial also demonstrated statistically significant improvements in rates of minimal residual disease negativity (less than one CLL cell per 104 leukocytes) in bone marrow and peripheral blood. Overall survival data were not mature at this analysis.

In CLL/SLL, the most common adverse reactions (≥ 20%) for venetoclax when administered with obinutuzumab, rituximab, or as monotherapy were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.

View full prescribing information for VENCLEXTA for recommended starting and ramp-up dosages.

FDA used the Real-Time Oncology Review and Assessment Aid Pilot Program for this application and granted priority review as well as orphan drug and breakthrough therapy designations. Approval was granted 3.7 months ahead of the PDUFA date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.


June 8, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208573s004s005lbl.pdf

On June 8, 2018, the Food and Drug Administration granted regular approval to venetoclax (VENCLEXTA, AbbVie Inc. and Genentech Inc.) for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.

Approval was based on MURANO (NCT02005471), a randomized (1:1), multicenter, open-label trial of venetoclax with rituximab (VEN+R) versus bendamustine with rituximab (B+R) in 389 patients with CLL who had received at least one prior line of therapy. Patients in the VEN+R arm completed a 5-week ramp-up venetoclax scheduleand then received venetoclax 400 mg once daily for 24 months measured from the rituximab start date. Rituximab was initiated after venetoclax ramp-up and given for 6 cycles (375 mg/m2 intravenously on cycle 1 day 1 and 500 mg/m2 intravenously on day 1 of cycles 2-6, with a 28-day cycle length). The comparator arm received 6 cycles of B+R (bendamustine 70 mg/m2 on days 1 and 2 of each 28-day cycle and rituximab at the above described dose and schedule).

Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee. After a median follow-up of 23 months, the median PFS was not reached in the VEN+R arm and was 18.1 months (95% CI: 15.8, 22.3) in the B+R arm (HR 0.19; 95% CI: 0.13, 0.28; p<0.0001). The overall response rate was 92% in the VEN+R arm compared to 72% for those treated with B+R.

In patients treated with VEN+R, the most common adverse reactions (incidence ≥20%) were neutropenia, diarrhea, upper respiratory tract infection, fatigue, cough, and nausea. Grade 3 or 4 neutropenia developed in 64% of these patients, and grade 4 neutropenia developed in 31%. Serious adverse reactions occurred in 46% of patients. Serious infections developed in 21% of patients, most commonly pneumonia (9%).

Due to rapid reduction in tumor volume, tumor lysis syndrome (TLS) is an important identified risk with venetoclax treatment. See the prescribing information for TLS risk stratification, prophylaxis, and monitoring.

All approved venetoclax regimens begin with a 5-week ramp-up. Full prescribing information is available at: Venclexta PI.

FDA granted venetoclax in combination with rituximab Breakthrough Therapy Designation and granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.


Pharmacist's Applications to Practice

Venetoclax for Patients with CLL or SLL With or Without 17p Deletion, Who Have Received at Least One Prior Therapy

Author: Sara Gordon, PharmD
Clinical Pharmacy Specialist—Hematology/Oncology
VA Northeast Ohio Healthcare System
Cleveland, OH

What is the potential role for venetoclax in the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)?

  • The U.S. Food and Drug Administration granted regular approval for venetoclax on June 8, 2018, for the treatment of CLL/SLL, with or without 17p deletion, for patients who have received at least one prior therapy.1
  • Venetoclax is currently a National Comprehensive Cancer Network (NCCN) category-1 recommendation for relapsed or refractory CLL with or without 17p deletion.2
    • This recommendation includes patients less than 65 years of age without significant comorbidities, patients 65 years of age or older, younger patients with significant comorbidities, and frail patients with significant comorbidities.2
  • Other NCCN category-1 recommendations for this patient population include ibrutinib or idelalisib plus rituximab.2
  • No head-to-head trials have compared ibrutinib, idelalisib plus rituximab, or venetoclax plus rituximab for this indication.
  • Approval of venetoclax for this indication was based on a multicenter open-label randomized phase-3 trial. Patients who had previously received 1–3 treatments, including one chemotherapy-containing regimen, were randomized to receive venetoclax plus rituximab or bendamustine plus rituximab. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance score of 0–1.3
    • Median follow-up was 23.8 months. The median progression-free survival (PFS) was not reached with venetoclax plus rituximab versus 17 months with bendamustine plus rituximab (hazard ratio [HR] 0.17, 95% confidence interval [CI] 0.11–0.25).3
    • Overall survival (OS) at 24 months was 91.9% with venetoclax plus rituximab versus 86.6% with bendamustine plus rituximab (HR 0.48, 95% CI 0.25–0.9).3
    • Grade 3–4 adverse events (AEs) were reported in 82% of patients receiving venetoclax plus rituximab versus 70.2% for bendamustine plus rituximab. Grade 5 AEs occurred in 10 patients with venetoclax plus rituximab and in 11 patients with bendamustine plus rituximab. Four of these deaths were due to fatal infections or infestations in each group.3
  • Approval of ibrutinib was based on a multicenter open-label randomized phase-3 trial. Patients who had received at least one prior therapy and were considered inappropriate candidates for purine analog treatment were eligible. Patients were required to have an ECOG performance score of 0–2. Patients were randomized to receive ibrutinib or ofatumumab.4
    • Median follow-up was 9.4 months. The median PFS was not reached with ibrutinib versus 8.1 months with ofatumumab (HR 0.22, 95% CI 0.15–0.32).4
    • OS rate at 12 months was 90% for ibrutinib and 81% for ofatumumab (HR 0.43, 95% CI 0.24–0.79). Median OS was not reached in either group.4
    • Grade 3-4 AEs were reported in 51% of patients receiving ibrutinib and in 39% of patients receiving ofatumumab. Treatment discontinuation because of AEs was 4% in both groups.4
  • Approval for idelalisib plus rituximab was based on a multicenter double-blind randomized phase-3 trial. Patients whose disease had progressed within 24 months of the last treatment for CLL and who were not able to receive cytotoxic agents were randomized to receive idelalisib plus rituximab or placebo plus rituximab. Patients were required to have an ECOG performance score of 0–3.5
    • The trial was discontinued at the first interim analysis because of the benefit of combination therapy.5
    • Median PFS was not reached with idelalisib plus rituximab versus 5.5 months with placebo plus rituximab (HR 0.15, 95% CI 0.08–0.28).5
    • OS rate at 12 months was 92% for idelalisib plus rituximab versus 80% for placebo plus rituximab (HR 0.28, 95% CI 0.09–0.86). Median OS was not reached in either group.5
    • Grade 3-4 AEs were reported in 56% of patients who received idelalisib plus rituximab and in 48% of patients who received placebo plus rituximab. Treatment discontinuation because of AEs was 8% for idelalisib plus rituximab and 10% for placebo plus rituximab.5

What role can the pharmacist play in the management of patients on venetoclax?

  • These patients are at high risk of tumor lysis syndrome (TLS), requiring weekly dose escalation to mitigate risk.6
    • Week 1: 20 mg once daily
    • Week 2: 50 mg once daily
    • Week 3: 100 mg once daily
    • Week 4: 200 mg once daily
    • Week 5: 400 mg once daily
  • Patients should also be premedicated with hydration and antihyperuricemic (allopurinol ± rasburicase) therapy to reduce TLS risk.6
    • All patients should be initiated on oral uric acid reducer (i.e., allopurinol) prior to venetoclax initiation.6
    • Clinicians may consider the addition of rasburicase if baseline uric acid is elevated.6
  • Rituximab is initiated after the patient has received venetoclax 400 mg daily for 7 days (week 6 of venetoclax therapy).6
    • Rituximab dosing3,7
      • Cycle 1, day 1: 375 mg/m2 IV
      • Cycles 2–6, day 1: 500 mg/m2 IV
    • Patients are maintained on venetoclax 400 mg once daily for 24 months from initiation of rituximab or until disease progression.6
  • No renal or hepatic dose adjustments are currently provided.6,7
  • Dose adjustments for toxicity during the dose escalation phase6
    • If patient is receiving 20 mg at time of therapy interruption, reinitiate at 10 mg.
    • If patient is receiving 50 mg at time of therapy interruption, reinitiate at 20 mg.
    • If patient is receiving 100 mg at time of therapy interruption, reinitiate at 50 mg.
    • If patient is receiving 200 mg at time of therapy interruption, reinitiate at 100 mg.
    • If patient is receiving 300 mg at time of therapy interruption, reinitiate at 200 mg.
    • Continue the reduced dose for 7 days prior to increasing the dose.6
  • Dose adjustments for toxicity during the maintenance phase: resume dose at 300 mg.7
  • Drug interactions: CYP3A4 inhibitors and P-glycoprotein (P-gp) inhibitors6
    • The use of strong CYP3A4 inhibitors is contraindicated at the initiation of venetoclax and during initial dose escalation. For patients receiving venetoclax maintenance dosing who require a strong CYP3A4 concurrently with venetoclax, reduce the venetoclax dose by at least 75%.6
    • If concurrent use of a moderate CYP3A4 or P-gp inhibitor is required, reduce the venetoclax dose by at least 50%.6
    • Following discontinuation of a CYP3A4 or P-gp inhibitor, the patient may resume the original venetoclax dose after 2–3 days.6
  • Administer with a meal and water, but avoid grapefruit products.6
  • Adverse events7
    • Nonhematologic (all grades): diarrhea (43%), nausea (42%), fatigue (32%), increased aspartate aminotransferase (53%), musculoskeletal pain (29%), upper respiratory tract infection (36%)7
    • Hematologic: leukopenia (89%), neutropenia (50%), lymphocytopenia (11%–37%), anemia (33%–71%), thrombocytopenia (29%–64%)7
    • Tumor lysis syndrome (2%–13%)7
      • Premedication for TLS prevention based on risk6
        • Low risk: All lymph nodes (LN) <5 cm and absolute lymphocyte count (ALC) <25 x 109/L
        • Medium risk: any LN 5 cm to <10 cm or ALC ≥25 x 109/L
        • High risk: any LN ≥10 cm or ALC ≥25 x 109/L and any LN ≥5 cm
      • Low to medium risk: hydrate with 1.5–2 L oral hydration and begin allopurinol 2–3 days prior to venetoclax initiation.6
      • High risk: hydrate with 1.5–2 L oral hydration and 150–200 ml/hr IV hydration as tolerated. Initiate allopurinol 2–3 days prior to venetoclax initiation; consider rasburicase if baseline uric acid is elevated.6
  • Patient assistance services: VENCLEXTA Access Solutions8
    • Available for eligible patients who have commercial insurance, public insurance, or no insurance8
      • Independent Co-pay Assistance Foundation: Patient Access Network Foundation (PANF)8
      • Genentech Access to Care Foundation (GATCF)8
    • Additional information: visit https://www.genentech-access.com/hcp/brands/venclexta.html or call 888.249.4918

Clinical Pearls

  • Venetoclax is available in a starting pack (first month with dose titration); maintenance venetoclax tablets are available in 10-mg, 50-mg, and 100-mg strengths.7
  • 17p deletion is no longer required for use in the relapsed or refractory setting.1-3
  • Venetoclax is not on the National Institute for Occupational Safety and Health 2016 list; however, it may meet the criteria for a hazardous drug. An update to the list is expected in fall 2018.7

References

  1. U.S. Food and Drug Administration. FDA approves venetoclax for CLL or SLL, with or without 17 p deletion, after one prior therapy. June 8, 2018. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610308.htm. Accessed August 31, 2018.
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2019. Updated November 2018. Accessed November 2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/cll_blocks.pdf.
  3. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107-1120.
  4. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphocytic leukemia. N Engl J Med. 2014;371:213-223.
  5. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007.
  6. Venclexta [package insert]: Chicago, IL: AbbVie Inc.; September 2018.
  7. Venetoclax. Lexi-Drugs Online [Internet]. Hudson, OH: Lexi-Comp, Inc. Updated August 31, 2018. Available at http://online.lexi.com.
  8. VENCLEXTA Access Solutions [Internet]. San Francisco, CA: Genentech USA, Inc.  Available at https://www.genentech-access.com/hcp/brands/venclexta.html.  

April 11, 2016 with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf

On April 11, 2016, the U. S. Food and Drug Administration approved venetoclax (VENCLEXTA™ tablets, marketed by AbbVie, Inc. and Genentech USA, Inc.) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.  

The approval was based on the results of a phase 2, single-arm trial of venetoclax for the treatment of patients with CLL harboring the 17p deletion who had received at least one prior therapy. The major efficacy outcome measure was overall response rate (ORR) according to the 2008 Modified IWCLL NCI-WG Guidelines for Tumor Response as evaluated by an independent review committee (IRC). Duration of response (DOR) was an additional outcome measure.

The trial enrolled 106 patients who had received at least one prior therapy with 17p deletion, as detected by an FDA-approved CLL fluorescence in situ hybridization (FISH) probe kit. Patients had a median of 2.5 prior treatments (range 1-10). The ORR by IRC was 80% (95% CI: 71%, 87%) with 8% complete remission (including 2% complete remission with incomplete marrow recovery). Minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with venetoclax. Three percent of the patients in the intent-to-treat population achieved a complete remission (CR or CRi) and were also negative for MRD in the bone marrow and peripheral blood. The median time to first response was 0.8 months (range: 0.1 to 8.1 months). Median duration of response (DOR) has not been reached with approximately 12 months median follow-up. The DOR ranged from 2.9 to more than 19.0 months.

Safety data were evaluated in 240 patients with previously-treated CLL who were treated with single-agent venetoclax at a target dose of 400 mg orally daily. The most common (greater than or equal to 20%) adverse reactions of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Serious adverse reactions were reported in 44% of patients, and the most common (greater than or equal to 2%) serious adverse reactions were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia, anemia, and tumor lysis syndrome (TLS).

Due to a rapid reduction in tumor volume, TLS is an important identified risk when initiating venetoclax. The risk of TLS is reduced with stratification by tumor burden, prophylaxis with hydration and anti-hyperuricemics, frequent blood chemistry monitoring and correction of electrolyte abnormalities. In patients with higher risk features, hospitalization for IV hydration, electrolyte monitoring, and aggressive correction of electrolyte abnormalities may be required. In 66 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a daily dose of 400 mg, the rate of TLS was 6% with no clinical events. All events were laboratory TLS and occurred in patients who had a lymph node(s) greater than or equal to 5 cm or ALC greater than or equal to 25 x 109/L.

The recommended dose and schedule for venetoclax for the approved indication is a ramp-up schedule over 5 weeks. Dosing is initiated at 20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg, then the recommended daily dose of 400 mg until disease progression or unacceptable toxicity.

This application was approved before the Prescription Drug User Fee Act (PDUFA) goal date of June 29, 2016. Venetoclax received Orphan drug status for the treatment of CLL and was granted Breakthrough Therapy Designation for the 17p deletion CLL development program. The application was granted Priority Review, and the current indication was approved under FDA’s Accelerated Approval Program. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information for venetoclax tablets is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 


Pharmacist's Application to Practice

Venetoclax for Previously Treated Chronic Lymphocytic Leukemia (CLL) with 17p Deletion

Author: Morgan Culver, PharmD, BCOP
Clinical Pharmacy Specialist, Hematology/Oncology
Virginia Commonwealth University Health System, Richmond, VA

What is the potential role for venetoclax in the treatment of relapsed / refractory CLL?,6

  • Venetoclax is a promising agent for patients with relapsed or refractory CLL with del(17p) who have failed at least one prior therapy.  Based on overall response rates, a rapid reduction in absolute lymphocyte count, and a favorable toxicity profile compared to other agents used to treat CLL, venetoclax should be considered after first line therapy has failed.
  • NCCN has added venetoclax to their recommendations for the treatment of patients with CLL and del(17p) in the relapsed or refractory setting.
  • While not yet compared head-to-head with other therapies for relapsed or refractory CLL, current evidence suggests venetoclax may have superior overall and complete response rates, specifically in the del(17p) population, when compared to agents such as ibrutinib or idelalisib given with rituximab.

What role can the pharmacist play in the management of patients on venetoclax?2

  • Drug-drug interactions can be significant and may necessitate venetoclax dose reductions.  Strong CYP3A4 inhibitors are contraindicated during the ramp-up period, but may be used once the patient is on a consistent daily dose if venetoclax is dose reduced 75%.  A 50% dose reduction is recommended for concomitant moderate CYP3A4 inhibitors and P-gp inhibitors.
  • Patients must be assessed for the risk of tumor lysis syndrome.  While the risk of tumor lysis may not be as significant as initially reported (prior to utilization of ramp-up dosing), patients should be stratified based on risk and receive appropriate prophylaxis (Table 2). 

Clinical Pearls2, 4-6

  • A recent study demonstrated increased rituximab clearance (1.2-fold) with co-administration of venetoclax.  While approved as monotherapy, it is likely that venetoclax will be used as part of combination therapy in the future and current studies are evaluating the extent of this interaction.
  • VENCOMPASS patient support services (1-844-926-6727) and co-pay assistance programs (1-855-692-6729) are both available.  The anticipated wholesale acquisition price for the first year of therapy is $109,500.
  • A starter pack is provided for week 1 through week 4; subsequent doses are provided using 100 mg tablets.
  • Utilized in conjunction with FDA approved test for 17p deletion

References:

  1. Venetoclax. U.S. Food and Drug Administration: Approved Drugs. April 11, 2016. Available at: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm495351.htm. Accessed June 30, 2016.
  2. Venclexta™ (venetoclax) [package insert]. North Chicago, IL and South San Francisco, CA: AbbVie Inc. and Genentech USA, Inc.; April 2016.
  3. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 2016;17:768-78.
  4. Sandburg B. FDA Accentuates Venclexta Superiority To Imbruciva. Pink Sheet 2016.
  5. Jones AK, Freise KJ, Agarwal SK, et al. Clinical predictors of venetoclax pharmacokinetics in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma patients: a pooled population pharmacokinetic analysis.  AAPS J 2016 [Epub ahead of print].
  6. Non-Hodgkin’s Lymphomas. Version 3.2016. National Comprehensive Cancer Network. Available at https://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed June 29, 2016.
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