On May 27, 2016 TG Therapeutics, Inc. (Nasdaq:TGTX), reported that as part of a broader agreement with Jubilant Biosys ("Jubilant"), an Indian biotechnology company, TG Therapeutics entered into a sub-license agreement with Checkpoint Therapeutics, Inc. ("Checkpoint"), a Fortress Biotech company, to develop and commercialize Jubilant’s novel BET inhibitor program in the field of hematological malignancies (Press release, TG Therapeutics, MAY 27, 2016, View Source [SID:1234512830]).

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Checkpoint will develop and commercialize these small molecule inhibitors in solid tumors. The BET inhibitor program is the subject of an exclusive, worldwide license agreement pursuant to which Checkpoint in-licensed from Jubilant a family of patents covering compounds that inhibit BRD4, a member of the BET (Bromodomain and Extra Terminal) domain for cancer treatment.

Under the terms of the agreement, TG Therapeutics will pay an up-front licensing fee of $1 million and make additional payments contingent on certain preclinical, clinical, and regulatory milestones, including commercial milestones totaling up to approximately $177 million and a single-digit royalty on net sales. TG Therapeutics will also provide funding to support certain targeted research efforts at Jubilant Biosys.

Mr. Michael S. Weiss, Executive Chairman, Interim CEO and President stated, "We are very excited to add this BET inhibitor program to our growing portfolio of agents targeting hematological malignancies. BET inhibitors have shown early promise in the treatment of relapsed and refractory Non-Hodgkin lymphomas, which remains a significant area of unmet medical need. There is emerging preclinical data showing BET inhibitors may enhance the activity of immuno-oncology agents, such as anti-PD-1/PD-L1 antibodies, providing multiple opportunities for us to combine this novel mechanism within our portfolio. Epigenetic targeted agents, especially BET inhibitors, have been an area of great interest of ours for some time and are particularly attractive to us because of their effects on c-Myc driven tumors, like aggressive GCB-subtype DLBCL, an area we have seen early activity with TGR-1202 and our proprietary combination referred to as TG-1303. We want to thank our collaborators at Checkpoint for introducing us to this opportunity." Mr. Weiss continued, "As we prepare to launch our registration directed studies in DLBCL and Follicular Lymphoma, we continue to look toward next steps in the evolution of patient care and believe the best outcome will be achieved only through the combination of multiple novel agents."

On May 27, 2016 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a negative opinion, recommending against the authorization of NINLARO (ixazomib) capsules, an oral proteasome inhibitor for the treatment of patients with relapsed and/or refractory multiple myeloma (Press release, Takeda, MAY 27, 2016, View Source [SID:1234512829]). Takeda intends to appeal this opinion and request a re-examination by the CHMP.

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"We are disappointed by the CHMP’s opinion. With the support of European key medical experts, we will continue our efforts working closely with the CHMP to make NINLARO – the first oral proteasome inhibitor – available for patients in Europe," said Christophe Bianchi, M.D., President, Takeda Oncology. "Despite recent progress, myeloma remains an intractable disease, and patients suffering from multiple myeloma and their treating physicians need more options to improve outcomes. We stand behind the TOURMALINE-MM1 trial data, which were recently published in the New England Journal of Medicine and demonstrated a significant extension in progression-free survival for NINLARO + lenalidomide and dexamethasone vs. placebo + lenalidomide and dexamethasone and a favorable benefit-risk profile."

"After years of treating patients, I have yet to see two people whose diseases are exactly alike. The diversity of patients with multiple myeloma demands a wide range of innovative treatment options that offer efficacy, tolerable safety profiles and convenience, which are especially important benefits for elderly populations," said Philippe Moreau, M.D., University of Nantes, France. "In Europe, where no oral proteasome inhibitor is available, NINLARO would fill a noticeable void and enable the first all-oral triplet combination therapy for patients with relapsed or refractory multiple myeloma."

NINLARO was approved by the U.S. Food and Drug Administration (FDA) in November 2015 following a priority review. In the U.S., NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. The FDA approval of NINLARO marked the first global regulatory approval of ixazomib. Takeda also has submitted applications for approval of ixazomib to additional regulatory authorities around the world. In addition to the TOURMALINE-MM1 trial that is forming the basis of these global regulatory submissions in relapsed and refractory multiple myeloma, ixazomib is being investigated in a number of other multiple myeloma treatment settings.

There will be no significant impact to Takeda’s fiscal year 2016 financials due to the CHMP opinion.

About NINLARO (ixazomib)
NINLARO (ixazomib) is an investigational oral proteasome inhibitor which is being studied in multiple myeloma and systemic light-chain (AL) amyloidosis. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval.

Ixazomib was granted orphan drug designation in multiple myeloma in both the U.S. and Europe in 2011 and for AL amyloidosis in both the U.S. and Europe in 2012. Ixazomib received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014.

The comprehensive ixazomib clinical development program, TOURMALINE, further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. TOURMALINE includes a total of five ongoing pivotal trials – four investigating every major multiple myeloma patient population and one in light-chain amyloidosis:

TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis
In addition to the TOURMALINE program, a large number of investigator initiated studies are evaluating ixazomib for patients globally.

About Multiple Myeloma

Multiple myeloma is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of monoclonal plasma cells, or myeloma cells, becomes cancerous and multiplies. These malignant plasma cells have the potential to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain. Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symptoms including bone pain and fatigue, a symptom of anemia. Multiple myeloma is a rare form of cancer, with approximately 39,000 new cases in the EU and 114,000 new cases globally per year.

Important Safety Information (U.S.)

WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications and platelet transfusions as per standard medical guidelines. Adjust dosing as needed. Platelet nadirs occurred between Days 14-21 of each 28-day cycle and recovered to baseline by the start of the next cycle.
Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting, were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea resulted in the discontinuation of one or more of the three drugs in 1% of patients in the NINLARO regimen and < 1% of patients in the placebo regimen. Adjust dosing for severe symptoms.
Peripheral Neuropathy (predominantly sensory) was reported with NINLARO. The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 1% of patients in both regimens. Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.
Peripheral Edema was reported with NINLARO. Monitor for fluid retention. Investigate for underlying causes when appropriate and provide supportive care as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms.
Cutaneous Reactions: Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Rash resulted in discontinuation of one or more of the three drugs in < 1% of patients in both regimens. Manage rash with supportive care or with dose modification.
Hepatotoxicity has been reported with NINLARO. Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in < 1% of patients treated with NINLARO. Events of liver impairment have been reported (6% in the NINLARO regimen and 5% in the placebo regimen). Monitor hepatic enzymes regularly during treatment and adjust dosing as needed.
Embryo-fetal Toxicity: NINLARO can cause fetal harm. Women should be advised of the potential risk to a fetus, to avoid becoming pregnant, and to use contraception during treatment and for an additional 90 days after the final dose of NINLARO.
ADVERSE REACTIONS

The most common adverse reactions (≥ 20%) in the NINLARO regimen and greater than the placebo regimen, respectively, were diarrhea (42%, 36%), constipation (34%, 25%), thrombocytopenia (78%, 54%; pooled from adverse events and laboratory data), peripheral neuropathy (28%, 21%), nausea (26%, 21%), peripheral edema (25%, 18%), vomiting (22%, 11%), and back pain (21%, 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%).

SPECIAL POPULATIONS

Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.
Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable.
Lactation: Advise women to discontinue nursing while on NINLARO.
DRUG INTERACTIONS: Avoid concomitant administration of NINLARO with strong CYP3A inducers.

Please see NINLARO full U.S. Prescribing Information: View Source

On May 27, 2016 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for the extension of the current conditional approval of ADCETRIS (brentuximab vedotin) and recommended its approval for the treatment of adult patients with CD30+ Hodgkin lymphoma at increased risk of relapse or progression following autologous stem cell transplantation (ASCT) (Press release, Takeda, MAY 27, 2016, View Source [SID:1234512828]).

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On average 50 percent of Hodgkin lymphoma patients relapse after ASCT and those patients with additional risk factors can be at even higher risk of relapse. ADCETRIS after ASCT is a new treatment paradigm based on the largest randomized study ever conducted in relapsed or refractory Hodgkin lymphoma. The AETHERA Phase 3 trial is the first completed study that has explored consolidation treatment immediately following ASCT as a way of extending the effect of transplant for prevention of relapse among people with Hodgkin lymphoma. The use of ADCETRIS in this setting may provide a meaningful treatment option where none currently exist for patients.

"While ASCT is the standard of care following failure of frontline chemotherapy in Hodgkin lymphoma, we know that many patients will unfortunately see their disease return. Early eradication of residual disease through treatment with ADCETRIS has the highest chance of preventing the disease from returning in these patients," said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. "This opinion, in addition to the recent five year overall survival data in relapsed or refractory Hodgkin lymphoma, further establishes the role of ADCETRIS in improving outcomes for patients. We look forward to the European Commission’s authorization of this new indication and bringing this medicine to physicians and patients in the European Union."

The CHMP positive opinion for ADCETRIS will now be reviewed by the European Commission (EC). If the CHMP recommendation is formally adopted by the EC, which has the authority to approve medicines for the European Union (EU), ADCETRIS will be approved for marketing of this indication in the 28 member states of the EU, Norway Liechtenstein and Iceland.

This opinion is based on the results of the Phase 3 AETHERA study. The AETHERA trial met its primary endpoint with ADCETRIS (plus best supportive care) treatment resulting in a statistically significant improvement in progression-free survival (PFS) versus placebo (plus best supportive care) as assessed by an independent central review committee (hazard ratio=0.57; p-value=0.001), which equates to a 75 percent improvement in PFS. PFS was assessed after a minimum of two years post initiation of treatment for all study patients. An updated analysis conducted after three years of follow up showed sustained PFS improvement (per Independent Review Facility; HR=0.58; 95%CI (0.41,0.81). A pre-specified interim analysis of overall survival showed no statistically significant difference between the treatment arms. The safety profile of ADCETRIS in the AETHERA trial was generally consistent with the existing prescribing information.

About Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

About ADCETRIS
ADCETRIS (brentuximab vedotin) is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing proprietary technology by Seattle Genetics. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). In January 2016, the European Commission approved a Type II variation to include data on the retreatment of adult patients with Hodgkin lymphoma or sALCL who previously responded to ADCETRIS and who later relapse. ADCETRIS has received marketing authorization by regulatory authorities in more than 60 countries. See important safety information below.

ADCETRIS is being evaluated broadly in more than 45 ongoing clinical trials, including the Phase 3 ALCANZA trial in CD30+ cutaneous T cell lymphoma (CTCL) and two additional Phase 3 studies, one in frontline classical Hodgkin lymphoma (ECHELON-1) and one in frontline CD30+ mature T-cell lymphomas (ECHELON-2), as well as trials in many additional types of CD30-expressing malignancies.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On May 27, 2016 AstraZeneca reported positive results from the Phase III FALCON trial comparing Faslodex 500mg (fulvestrant) to Arimidex 1mg (anastrozole) for the treatment of locally-advanced or metastatic breast cancer, in post-menopausal women who have not had prior hormonal treatment for hormone-receptor-positive (HR+) breast cancer (Press release, AstraZeneca, MAY 27, 2016, View Source [SID:1234512823]).

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Faslodex 500mg demonstrated superiority compared with Arimidex 1mg in FALCON, and met its primary endpoint of extended progression-free survival. The trial showed an adverse event profile generally consistent with current knowledge of the safety profile of the medicines.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "The FALCON results bring us closer to offering more and earlier treatment options to postmenopausal women with HR+ locally-advanced or metastatic breast cancer; the potential to delay disease progression is important for these patients as there is currently no cure. Faslodex has over 10 years of clinical evidence and we are committed to exploring its potential along with the rest of our outstanding oncology portfolio."

A full evaluation of the data is ongoing and the results are expected to be presented at a medical meeting in 2016.

Aromatase inhibitors (such as Arimidex) are the current standard of care in first-line treatment for postmenopausal women with advanced HR+ breast cancer1.

Faslodex 500mg is approved for the treatment of postmenopausal women with oestrogen-receptor (ER)-positive locally-advanced or metastatic breast cancer whose cancer has progressed following anti-oestrogen therapy2. Most recently, on 2 March 2016, the US Food and Drug Administration approved Faslodex 500mg, in combination with palbociclib, for the treatment of women with hormone-receptor-positive, human-epidermal-growth-factor-receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC), whose cancer has progressed after endocrine therapy3.

About FALCON

The FALCON (Fulvestrant and AnastrozoLe COmpared in hormonal therapy Naïve advanced breast cancer) trial is a Phase III, randomised, double-blind, multicentre trial. The trial compared the anti-tumour effects and tolerability profile of a 500mg dose of Faslodex plus placebo with a 1mg dose of Arimidex plus placebo, in postmenopausal women with hormone-receptor-positive, locally-advanced or metastatic breast cancer who have not been treated previously with any hormonal therapy.

About Advanced breast cancer (ABC)

ABC is the most advanced stage of breast cancer (stage IV), and occurs when cancer cells have spread beyond the initial tumour site to other parts of the body outside of the breast. Since there is no cure for ABC, the goal of current treatment is to delay disease progression4.

About Faslodex 500mg (fulvestrant)

Faslodex 500mg is indicated for the treatment of postmenopausal women with ER+, locally-advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on therapy with an anti-oestrogen.2

In the US, Faslodex 500mg is also approved, in combination with palbociclib, for the treatment of US women with HR+, human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC), whose cancer has progressed after endocrine therapy. Faslodex 500mg represents a hormonal therapy approach that helps to slow tumour growth by blocking and degrading the oestrogen receptor – a key driver of disease progression5.

On May 27, 2016 Amgen (NASDAQ:AMGN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion to extend the current indication for Kyprolis (carfilzomib) to include treatment in combination with dexamethasone alone for adult patients with multiple myeloma who have received at least one prior therapy (Press release, Amgen, MAY 27, 2016, View Source [SID:1234512821]).

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"In the first ever comparative Phase 3 head-to-head study of two proteasome inhibitors in relapsed multiple myeloma, Kyprolis in combination with dexamethasone nearly doubled progression-free survival compared to a current standard of care regimen," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We are pleased that the CHMP has recognized these robust data with a positive opinion, and we look forward to ensuring approval of this extended indication of Kyprolis."

The CHMP positive opinion is based on data from the Phase 3 head-to-head ENDEAVOR study in which patients with multiple myeloma treated with Kyprolis plus dexamethasone achieved superior progression-free survival (PFS) of 18.7 months compared to 9.4 months in those receiving Velcade (bortezomib) plus dexamethasone, (HR=0.53; 95 percent CI: 0.44,0.65 p<0.0001). The most common adverse reactions that occurred in greater than 20 percent of patients in the Kyprolis arm were anemia, fatigue, diarrhea, thrombocytopenia, nausea, pyrexia, dyspnea, respiratory tract infection, cough and peripheral edema.

The CHMP positive opinion will now be reviewed by the European Commission (EC) and if granted, the marketing authorization will be extended to include Kyprolis in combination with dexamethasone in the 28 member countries of the European Union, as well as Iceland, Lichtenstein and Norway. The extended indication adopted by the CHMP is: Kyprolis in combination with either lenalidomide and dexamethasone or dexamethasone alone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

The EC previously granted marketing authorization for Kyprolis in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy based on results of the ASPIRE study in November 2015. Today’s CHMP positive opinion follows the U.S. Food and Drug Administration’s approval of a supplemental New Drug Application based on the ENDEAVOR results in January 2016.

About Multiple Myeloma

Multiple myeloma is characterized by a recurring pattern of remission and relapse.1 It is a rare and very aggressive orphan disease that accounts for approximately one percent of all cancers worldwide.2-4 In Europe, approximately 39,000 patients are diagnosed with multiple myeloma each year and 24,000 patient deaths are reported on an annual basis.5

About ENDEAVOR

The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated Kyprolis in combination with low-dose dexamethasone, versus bortezomib with low-dose dexamethasone in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. In a clinical trial, measuring the PFS is one way to demonstrate how well a treatment works.6

This study was conducted at 235 sites worldwide. For information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT01568866.

About Kyprolis (carfilzomib)

Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.7 Kyprolis has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.7 In some cells, Kyprolis can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.7,8

Kyprolis is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
Kyprolis is also approved in Argentina, Israel, Kuwait, Mexico, Thailand, Colombia, Korea, Canada, Switzerland, Russia and the European Union. Additional regulatory applications for Kyprolis are underway and have been submitted to health authorities worldwide.

For more information, please visit www.kyprolis.com.

Important EU Product Safety Information

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy. The most serious side effects that may occur during Kyprolis treatment include: Cardiac toxicity, pulmonary toxicities, pulmonary hypertension, dyspnea, hypertension including hypertensive crises, acute renal failure, tumor lysis syndrome, infusion reactions, thrombocytopenia, hepatic toxicity, posterior reversible encephalopathy syndrome (PRES) and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). The most common side effects are anemia, fatigue, diarrhea, thrombocytopenia, nausea, pyrexia, dyspnea, respiratory tract infection, cough and peripheral edema.

Please refer to the Summary of Product Characteristics for full European prescribing information.

Important U.S. Product Safety Information

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.
Acute Renal Failure

Cases of acute renal failure and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug‐induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions

Infusion reactions, including life‐threatening reactions, have occurred in patients receiving KYPROLIS. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro‐radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

Full prescribing information for the U.S. is available at www.kyprolis.com.