IMBRUVICA® U.S. Prescribing Information Updated to Include Long-Term Data for Waldenström's Macroglobulinemia

- ABBVie (NYSE: ABBV) announced today that the U.S. Food and Drug Administration (FDA) approved the update of the IMBRUVICA ® (ibrutinib) Prescribing Information to include efficacy and safety data for the combination of IMBRUVICA with rituximab for the treatment of Waldenström's macroglobulinemia (WM), based on the final analysis of the Phase 3 iNNOVATE study. First approved in 2013, IMBRUVICA is currently available to patients with several types of blood cancer, as well as chronic graft-versus-host disease. It was approved as a monotherapy for WM in 2015 and as a combination therapy with rituximab in 2018 based on the iNNOVATE primary analysis.

"We're encouraged by this latest recognition from the FDA as it underscores our commitment to supporting those impacted by Waldenström's macroglobulinemia, a rare and incurable form of non-Hodgkin's lymphoma," said Danelle James , M.D., M.A.S., IMBRUVICA Global Development Lead, Pharmacyclics LLC, an AbbVie company. "IMBRUVICA is the only FDA-approved treatment for these patients and now includes more than five years of safety and efficacy data to help provide better understanding of how to treat this rare blood cancer."

As of today, IMBRUVICA is the only Bruton's tyrosine kinase (BTK) inhibitor approved to treat WM. WM typically affects older adults and is primarily found in the bone marrow, although lymph nodes and the spleen may also be affected. In the U.S., there are approximately 2,800 new cases of WM each year. ¹ The National Comprehensive Cancer Network ^® (NCCN ^® ), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends IMBRUVICA, with or without rituximab, as the only Category 1 Preferred regimen for patients with previously untreated or previously treated WM. ²

"The long-term results from the Phase 3 iNNOVATE study provide clinicians even more evidence that patients with WM can benefit from treatment with an ibrutinib-based regimen and maintain prolonged progression-free survival," said Dr. Meletios A. Dimopoulos , Professor and Chairman of the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece , and principal investigator.

The IMBRUVICA Prescribing Information now includes final analysis data, with an overall follow-up of 63 months, from the Phase 3 iNNOVATE clinical trial. With additional follow-up since the primary analysis, the combination of IMBRUVICA plus rituximab continued to demonstrate prolonged progression-free survival (PFS) in WM patients compared to rituximab monotherapy. Patients treated in the IMBRUVICA arm experienced a 75 percent reduction in risk of disease progression or death compared to rituximab monotherapy (hazard ratio [HR] 0.25; 95% confidence interval [CI]: 0.15-0.42; p

In the iNNOVATE study primary analysis, the most common side effects (≥20%) in patients treated with IMBRUVICA plus rituximab were bruising, muscle pain, bleeding problems, diarrhea, rash, joint pain, nausea and high blood pressure.

About iNNOVATE  
iNNOVATE (PCYC-1127) is a Pharmacyclics-sponsored, randomized, placebo-controlled, double-blind, Phase 3 study, which enrolled 150 patients with relapsed/refractory and treatment-naïve Waldenström's macroglobulinemia. All patients received intravenous rituximab 375 mg/m ² once weekly for four consecutive weeks, followed by a second four-weekly rituximab course following a three-month interval. Patients were randomized to receive either ibrutinib 420 mg or placebo once daily continuously until criteria for treatment discontinuation were met. The primary endpoint was progression-free survival; secondary endpoints included overall response rate; hematological improvement measured by hemoglobin; time-to-next treatment; overall survival; and number of participants with adverse events as a measure of safety and tolerability within each treatment arm.

About IMBRUVICA
IMBRUVICA is a once-daily, first-in-class BTK inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics, LLC, an AbbVie Company, and Janssen Biotech, Inc. (Janssen). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread. ^3,4 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs. ⁵

Since its launch in 2013, IMBRUVICA has received 11 FDA approvals across six disease areas: chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; WM; previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy. ⁶

IMBRUVICA is now approved in 101 countries and has been used to treat more than 200,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

As of early 2019, the National Comprehensive Cancer Network ^® (NCCN ^® ), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and is a Category 1 treatment for treatment-naïve patients without deletion 17p. In January 2020 , the NCCN Guidelines ^® were updated to recommend IMBRUVICA, with or without rituximab, as a preferred regimen for the treatment of relapsed/refractory MCL, regardless of response duration to prior chemoimmunotherapy. In September 2020 , the NCCN guidelines for WM were updated and now recommends IMBRUVICA, with or without rituximab, as the only Category 1 Preferred regimen for patients with previously untreated or previously treated WM.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. For more information, visit www.IMBRUVICA.com .

*Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Side Effect Information

Before taking IMBRUVICA ^® , tell your healthcare provider about all of your medical conditions, including if you:

• have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA ^® for any planned medical, surgical, or dental procedure.
• have bleeding problems.
• have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes.
• have an infection.
• have liver problems.
• are pregnant or plan to become pregnant. IMBRUVICA ^® can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA ^® . Tell your healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA ^® .
• Females who are able to become pregnant should use effective birth control (contraception) during treatment with IMBRUVICA ^® and for 1 month after the last dose.
• Males with female partners who are able to become pregnant should use effective birth control, such as condoms, during treatment with IMBRUVICA ^® and for 1 month after the last dose.
• are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA ^® and for 1 week after the last dose.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA ^® with certain other medicines may affect how IMBRUVICA ^® works and can cause side effects.

How should I take IMBRUVICA ^® ?

• Take IMBRUVICA ^® exactly as your healthcare provider tells you to take it.
• Take IMBRUVICA ^® 1 time a day.
• Swallow IMBRUVICA ^® capsules or tablets whole with a glass of water.
• Do not open, break or chew IMBRUVICA ^® capsules.
• Do not cut, crush or chew IMBRUVICA ^® tablets.
• Take IMBRUVICA ^® at about the same time each day.
• If you miss a dose of IMBRUVICA ^® take it as soon as you remember on the same day. Take your next dose of IMBRUVICA ^® at your regular time on the next day. Do not take extra doses of IMBRUVICA ^® to make up for a missed dose.
• If you take too much IMBRUVICA ^® call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking IMBRUVICA ^® ?

• You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with IMBRUVICA ^® . These products may increase the amount of IMBRUVICA ^® in your blood.

What are the possible side effects of IMBRUVICA ^® ?

IMBRUVICA ^® may cause serious side effects, including:

• Bleeding problems (hemorrhage)   are common during treatment with IMBRUVICA ^® , and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding, or bleeding that is severe or that you cannot control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, dizziness, weakness, confusion, change in your speech, or a headache that lasts a long time or severe headache.
• Infections can happen during treatment with IMBRUVICA ^® .  These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA ^® .
• Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with IMBRUVICA ^® , but can also be severe.  Your healthcare provider should do monthly blood tests to check your blood counts.
• Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation, and atrial flutter), heart failure, and death have happened in people treated with IMBRUVICA ^® , especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past. Tell your healthcare provider if you get any symptoms of heart problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, swelling of the feet, ankles, or legs, chest discomfort, or you faint.  If you develop any of these symptoms, your healthcare provider may do a test to check your heart (ECG) and may change your IMBRUVICA ^® dose.
• High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with IMBRUVICA ^® . Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure.
• Second primary cancers. New cancers have happened during treatment with IMBRUVICA ^® , including cancers of the skin or other organs.
• Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.

The most common side effects of   IMBRUVICA ^® in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:

• diarrhea
• tiredness
• muscle and bone pain
• rash
• bruising

The most common side effects of IMBRUVICA ^® in adults with cGVHD include:

• tiredness
• bruising
• diarrhea
• mouth sores (stomatitis)
• muscle spasms
• nausea
• pneumonia

Diarrhea is a common side effect in people who take IMBRUVICA ^® . Drink plenty of fluids during treatment with IMBRUVICA ^® to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your healthcare provider if you have diarrhea that does not go away.

These are not all the possible side effects of IMBRUVICA ^® . Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of IMBRUVICA ^®

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA ^® for a condition for which it was not prescribed. Do not give IMBRUVICA ^® to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA ^® that is written for health professionals.

Please click here for    full    Prescribing    Information.

About AbbVie
AbbVie's mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women's health and gastroenterology, in addition to products and services across its Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com . Follow @abbvie on Twitter , Facebook , Instagram , YouTube and LinkedIn .

Forward-Looking Statements
Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, competition from other products, challenges to intellectual property, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2019 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

IMBRUVICA is a registered trademark of Pharmacyclics LLC.

¹ Lymphoma Research Foundation. Waldenström's Macroglobulinemia. https://lymphoma.org/aboutlymphoma/nhl/wm/ . Accessed October 2020 .
² National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Version 1.2021 Waldenström's Macroglobulinemia / Lymphoplasmacytic Lymphoma.
³ Genetics Home Reference. Isolated growth hormone deficiency. https://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency . Accessed June 2020.
⁴ Turetsky, et al. Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor. Scientific Reports. volume 4, Article number: 4782 (2014).
⁵ de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594.
⁶ IMBRUVICA U.S. Prescribing Information, December 2020 .

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SOURCE AbbVie