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Blueprint Medicines Announces European Medicines Agency Validation of Marketing Authorization Application for Avapritinib for the Treatment of PDGFRα D842V Mutant GIST and Fourth-Line GIST

On July 18, 2019 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported that the European Medicines Agency (EMA) has validated the company’s Marketing Authorization Application (MAA) for avapritinib for the treatment of adult patients with PDGFRα D842V mutant gastrointestinal stromal tumors (GIST), regardless of prior therapy, and fourth-line GIST (Press release, Blueprint Medicines, JUL 18, 2019, View Source [SID1234537608]). Validation of the MAA confirms that the application is sufficiently complete to begin the formal review process. Avapritinib is an investigational, potent and highly selective KIT and PDGFRA inhibitor for patients with advanced GIST. The European Commission has granted orphan medicinal product designation to avapritinib for the treatment of GIST.

"Prognoses are traditionally poor for patients with PDGFRα D842V mutant GIST and fourth-line GIST, and currently no effective therapy exists for either population," said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. "Avapritinib is specifically designed to inhibit the disease drivers of GIST, including mutant kinases associated with treatment resistance, representing a promising therapeutic approach. We look forward to working expeditiously with the EMA to bring this potential new treatment option to patients."

In June 2019, Blueprint Medicines announced the submission of a New Drug Application to the U.S. Food and Drug Administration (FDA) for avapritinib for the treatment of adult patients with PDGFRA Exon 18 mutant GIST, regardless of prior therapy, and fourth-line GIST.

About GIST

GIST is a sarcoma, or tumor of bone or connective tissue, of the gastrointestinal (GI) tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50 to 80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction.

Most GIST cases are caused by a spectrum of clinically relevant mutations that force the KIT or PDGFRA protein kinases into an increasingly active state. Because currently available therapies primarily bind to the inactive protein conformations, certain primary and secondary mutations typically lead to treatment resistance and disease progression.

In unresectable or metastatic GIST, clinical benefits from existing treatments can vary by mutation type. Mutational testing is critical to tailor therapy to the underlying disease driver and is recommended in expert guidelines. Currently, there are no approved therapies for patients with KIT-driven GIST whose disease progresses beyond imatinib, sunitinib and regorafenib. In patients with metastatic PDGFRα D842V-driven GIST, progression occurs in a median of approximately three to four months with available therapy.

About Avapritinib

Avapritinib is an investigational, oral precision therapy that selectively and potently inhibits KIT and PDGFRA mutant kinases. It is a type 1 inhibitor designed to target the active kinase conformation; all oncogenic kinases signal via this conformation. Avapritinib has demonstrated broad inhibition of KIT and PDGFRA mutations associated with GIST, including potent activity against activation loop mutations that are associated with resistance to currently approved therapies.

Blueprint Medicines is initially developing avapritinib for the treatment of advanced GIST, advanced systemic mastocytosis (SM), and indolent and smoldering SM. The FDA has granted Breakthrough Therapy Designation to avapritinib for two indications: one for the treatment of unresectable or metastatic GIST harboring the PDGFRα D842V mutation and one for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia. The European Commission has granted orphan medicinal product designation to avapritinib for the treatment of GIST and mastocytosis.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of avapritinib and certain other drug candidates in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for avapritinib in the rest of the world.

Select Medical Holdings Corporation Announces Estimate of Certain Results for Second Quarter Ended June 30, 2019 in connection with Refinancing Discussions

On July 18, 2019 Select Medical Holdings Corporation ("Select Medical") (NYSE: SEM) is reported currently in discussions with its lenders regarding a proposed refinancing of certain of its outstanding indebtedness (Press release, Select Medical, JUL 18, 2019, View Source [SID1234537607]). In connection with such discussions, Select Medical reported an estimate of certain results for its second quarter ended June 30, 2019 in advance of the announcement of actual results, which is expected to occur after market close on August 1, 2019.

Select Medical expects its net operating revenue for the second quarter of 2019 to be in the range of $1.360 billion to $1.362 billion. Select Medical expects earnings excluding interest, income taxes, depreciation and amortization, stock compensation expense, non-operating gain (loss), and equity in earnings (losses) of unconsolidated subsidiaries, or Adjusted EBITDA, for the second quarter of 2019 to be in the range of $185.5 million to $187.0 million. The above expectations regarding Select Medical’s results for the second quarter of 2019 are management estimates and projections based on currently available information, and are subject to change upon completion of Select Medical’s financial statement closing process.

The Company is not providing a reconciliation of estimated Adjusted EBITDA to Net Income for the second quarter of 2019. At this point in its financial statement closing process, the Company is unable to estimate, without unreasonable efforts, certain individual items required to reconcile estimated Adjusted EBITDA with the most directly comparable GAAP financial measure (Net Income). These items include income tax expense and equity in earnings of unconsolidated subsidiaries.

Conference Call

As previously announced, Select Medical will host a conference call regarding its second quarter results, as well as its business outlook, on Friday, August 2, 2019, at 9:00am ET. The domestic dial in number for the call is 1-866-440-2669. The international dial in number is 1-409-220-9844. The conference ID for the call is 5489707. The conference call will be webcast simultaneously and can be accessed at Select Medical Holdings Corporation’s website www.selectmedicalholdings.com.

For those unable to participate in the conference call, a replay will be available until 12:00pm ET, August 9, 2019. The replay number is 1-855-859-2056 (domestic) or 1-404-537-3406 (international). The conference ID for the replay will be 5489707. The replay can also be accessed at Select Medical Holdings Corporation’s website, www.selectmedicalholdings.com.

Diplomat to Release Second-Quarter 2019 Operating Results August 9

On July 18, 2019 Diplomat Pharmacy, Inc. (NYSE: DPLO), reported that it will release its second-quarter 2019 operating results before market open Friday, August 9. A conference call and live webcast will be held at 8:30 a.m. ET (Press release, Diplomat Speciality Pharmacy, JUL 18, 2019, View Source [SID1234537606]).

Shareholders and interested participants can listen to a live broadcast by calling 833.286.5805 (647.689.4450 for international callers) and entering participation code 7394702, starting about 15 minutes before the call. A live webcast of the conference call will be available on the investor relations section of Diplomat’s website at ir.diplomat.is. The site will host an audio recording and supplemental investor information for 90 days.

Amgen And Allergan’s MVASI™ (bevacizumab-awwb) And KANJINTI™ (trastuzumab-anns) Now Available In The United States

On July 18, 2019 Amgen (NASDAQ:AMGN) and Allergan plc (NYSE:AGN) reported that MVASI (bevacizumab-awwb), a biosimilar to Avastin (bevacizumab), and KANJINTITM (trastuzumab-anns), a biosimilar to Herceptin (trastuzumab), are now available in the United States (U.S.) (Press release, Amgen, JUL 18, 2019, View Source [SID1234537605]).

MVASI, the first oncology therapeutic biosimilar approved by the U.S. Food and Drug Administration (FDA), is approved for the treatment of five types of cancer: in combination with chemotherapy for metastatic colorectal cancer (mCRC); in combination with chemotherapy for non-squamous non-small cell lung cancer (NSCLC); recurrent glioblastoma; in combination with interferon-alfa for metastatic renal cell carcinoma; and in combination with chemotherapy for persistent, recurrent, or metastatic cervical cancer.

KANJINTI is FDA approved for all approved indications of Herceptin: for the treatment of HER2-overexpressing adjuvant and metastatic breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

"The introduction of biosimilars is an important step in increasing options for treating HER2-positive breast cancers, which account for about 25% of all breast cancers," said Paula Schneider, chief executive officer, Susan G. Komen Breast Cancer Foundation. "As patient advocates, we are working to ensure that patients are educated about biosimilars and understand that these FDA-approved treatments are just as effective as the original biologic drugs."

The Wholesale Acquisition Cost (WAC or "list price") of both MVASI and KANJINTI will be 15% lower than their reference products. MVASI is being made available at a WAC of $677.40 per 100 mg and $2,709.60 per 400 mg single-dose vial, 15% less than the WAC for Avastin. KANJINTI is being made available at a WAC of $3,697.26 per 420 mg multi-dose vial, 15% below the WAC of Herceptin. At launch, MVASI is priced 12% below the current Avastin Average Selling Price (ASP) and KANJINTI is priced 13% below the current Herceptin ASP. Both products will be available from both wholesalers and specialty distributors.

"Several years ago, Amgen made the strategic decision to invest in building a global biosimilars business, leveraging our nearly four decades of experience in developing and manufacturing best-in-class biologics," said Murdo Gordon, executive vice president of Global Commercial Operations at Amgen. "Following several recent launches in Europe, we are excited to be launching our first two biosimilars in the U.S., which will provide for immediate savings for Medicare patients and commercial payers. We have several more biosimilars advancing through our pipeline, even as we continue to drive innovation through novel therapies for cancer and other serious diseases."

The WAC price measure does not account for discounts and rebates and may be significantly higher than out-of-pocket cost for patients, which can vary depending on several factors. Medicare and commercial insurance, for example, will generally pay for MVASI and KANJINTI based on ASP rather than WAC. Out-of-pocket cost may also depend on and be reduced by additional factors, including eligibility for patient assistance.

Actual costs to patients and providers for MVASI and KANJINTI are anticipated to be lower than WAC as WAC does not reflect discounts or rebates. Out-of-pocket costs to patients will vary depending on insurance status and eligibility for patient assistance. MVASI and KANJINTI will be available from both wholesalers and specialty distributors.

"As the first products from our collaboration with Amgen to be launched in the U.S., MVASI and KANJINTI reinforce our ongoing dedication to providing patients with additional treatment options," said David Nicholson, chief research and development officer at Allergan. "We are excited about the progress we’ve made through this partnership and look forward to continued milestones together with our remaining biosimilar products."

Amgen and Allergan are committed to developing high-quality biosimilars supported by robust analytical and clinical packages. MVASI and KANJINTI were proven to be highly similar to, and to have no clinically meaningful differences in terms of safety and effectiveness from Avastin and Herceptin, respectively, based on a totality of evidence, which included comparative analytical, clinical safety and efficacy data. At the time of FDA approval, KANJINTI was the only trastuzumab biosimilar to incorporate the evaluation of a single transition in the clinical study, in which a portion of patients who began the study on Herceptin made a single transition to KANJINTI. This portion of the study demonstrated similar safety and immunogenicity in patients on KANJINTI who were previously on Herceptin.

Amgen has a total of 10 biosimilars in its portfolio, three of which have been approved in the U.S.

About MVASI (bevacizumab-awwb) in the U.S.
MVASI is a recombinant humanized monoclonal IgG1 antibody that binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

MVASI, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer (mCRC).

MVASI, in combination with fluoropyrimidine- irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab-containing regimen.

Limitations of Use: MVASI is not indicated for adjuvant treatment of colon cancer.

MVASI, in combination with carboplatin and paclitaxel, is indicated for the first line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC).

MVASI is indicated for the treatment of recurrent glioblastoma (GBM) in adults.

MVAS, in combination with interferon-alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC).

MVASI, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

MVASI (bevacizumab-awwb) Professional Important Safety Information
Gastrointestinal (GI) perforation

Serious and sometimes fatal GI perforation occurred at a higher incidence in bevacizumab-treated patients compared to patients treated with chemotherapy
The incidence of GI perforation ranged from 0.3% to 3% across clinical studies
Discontinue MVASITM in patients with GI perforation
Surgery and wound healing complications

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab-treated patients
Withhold MVASITM for at least 28 days prior to elective surgery. Do not administer MVASITM for at least 28 days after surgery and until the wound is fully healed
Discontinue in patients with wound healing complications requiring medical intervention
Hemorrhage

Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving bevacizumab. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4% to 7%
Do not administer MVASITM to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood)
Discontinue MVASITM in patients who develop grade 3-4 hemorrhage
Additional serious and sometimes fatal adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:

Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM)
Renal injury and proteinuria
Grade 3-4 proteinuria ranged from 0.7% to 7% in clinical studies
Nephrotic syndrome (<1%)
Additional serious adverse events with increased incidence in the bevacizumab-treated arm vs chemotherapy arm included:

Venous thromboembolism (grade ≥3, 11% seen in GOG-0240)
Hypertension (grade 3-4, 5%-18%)
Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
Congestive heart failure (CHF) (1%)
Infusion reactions with the first dose of bevacizumab occurred in <3% of patients, and severe reactions occurred in 0.2% of patients

Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction

Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with MVASITM

Pregnancy warning

Based on the mechanism of action and animal studies, MVASITM may cause fetal harm when administered to pregnant women
Advise female patients that MVASITM may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with MVASITM and for 6 months after the last dose
Advise nursing women that breastfeeding is not recommended during treatment with MVASITM and for 6 months following their last dose of treatment
MVASITM may impair fertility
Most Common Adverse Events

Across indications, the most common adverse reactions observed in bevacizumab -treated patients at a rate of >10% were: epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis
Across all studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions
Indication-Specific Adverse Events

In CC, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (≥2%) in 218 patients receiving bevacizumab plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), diarrhea (6% vs 3%), anal fistula (4% vs 0%), proctalgia (3% vs 0%), urinary tract infection (8% vs 6%), cellulitis (3% vs 0.5%), fatigue (14% vs 10%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), hypokalemia (7% vs 4%), hyponatremia (4% vs 1%), dehydration (4% vs 0.5%), neutropenia (8% vs 4%), lymphopenia (6% vs 3%), back pain (6% vs 3%), and pelvic pain (6% vs 1%)
In mRCC, the most common grade 3-5 adverse events in AVOREN, occurring at a >2% higher incidence in bevacizumab-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%, including hypertension and hypertensive crisis), and hemorrhage (3% vs 0.3%;, including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)
In rGBM Study EORTC 26101, 22% of patients discontinued treatment in the bevacizumab with lomustine arm due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adverse reaction profile was similar to that observed in other approved indications
In NSCLC, grade 3-5 (nonhematologic) and grade 4-5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in bevacizumab-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thromboembolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
In first-line mCRC, the most common grade 3-4 events in Study 2107, which occurred at a ≥2% higher incidence in the bevacizumab plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
In second-line mCRC, the most common grade 3-5 (nonhematologic) and 4-5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the bevacizumab plus FOLFOX4 vs FOLFOX4 groups, were fatigue (19% vs 13%), diarrhea (18% vs 13%), sensory neuropathy (17% vs 9%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), hypertension (9% vs 2%), abdominal pain (8% vs 5%), hemorrhage (5% vs 1%), other neurological (5% vs 3%), ileus (4% vs 1%), and headache (3% vs 0%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Amgen at 1-800-772-6436.

Please see full Prescribing Information at www.Amgen.com.

About KANJINTITM (trastuzumab-anns) in the U.S.
KANJINTI is a biosimilar to Herceptin, a recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody. The active ingredient of KANJINTI is a humanized monoclonal antibody that has the same amino acid sequence, structure and function as Herceptin. KANJINTI has the same pharmaceutical dosage form and same strength after reconstitution as Herceptin.

In the U.S., KANJINTI is approved for:

Adjuvant Breast Cancer
KANJINTI is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer:

As part of a treatment regimen containing doxorubicin, cyclophosphamide and either paclitaxel or docetaxel
As part of treatment with docetaxel and carboplatin
As a single agent following multi-modality anthracycline-based therapy
Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product.

* High-risk is defined as ER/PR positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.

Metastatic Breast Cancer
KANJINTI is indicated:

In combination with paclitaxel for the first line treatment of HER2-overexpressing metastatic breast cancer
As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease
Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product.

Metastatic Gastric Cancer
KANJINTI is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease.

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product.

KANJINTI U.S. Boxed WARNINGS and Important Safety Information

Boxed WARNINGS and Additional Important Safety Information

Cardiomyopathy

Trastuzumab products administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens
Evaluate left ventricular function in all patients prior to and during treatment with KANJINTITM. Discontinue KANJINTITM treatment in patients receiving adjuvant therapy and withhold KANJINTITM in patients with metastatic disease for clinically significant decrease in left ventricular function
Infusion Reactions; Pulmonary Toxicity

Trastuzumab products administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration. Interrupt KANJINTITM infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue KANJINTITM for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome
Embryo-Fetal Toxicity

Administration of trastuzumab products can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy
Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death
Trastuzumab products can also cause asymptomatic decline in left ventricular ejection fraction (LVEF)
Discontinue KANJINTITM treatment in patients receiving adjuvant breast cancer therapy and withhold KANJINTITM in patients with metastatic disease for clinically significant decrease in left ventricular function
Cardiac Monitoring

Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of KANJINTITM
Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan
Monitor frequently for decreased left ventricular function during and after KANJINTITM treatment
Monitor more frequently if KANJINTITM is withheld for significant left ventricular cardiac dysfunction
Infusion Reactions

KANJINTITM administration can result in serious and fatal infusion reactions
Symptoms usually occur during or within 24 hours of KANJINTITM administration
Interrupt KANJINTITM infusion for dyspnea or clinically significant hypotension
Monitor patients until symptoms completely resolve
Discontinue KANJINTITM for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Strongly consider permanent discontinuation in all patients with severe infusion reactions
Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion include nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia
Embryo-Fetal Toxicity

Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception
Verify the pregnancy status of females of reproductive potential prior to the initiation of KANJINTITM
Advise pregnant women and females of reproductive potential that exposure to KANJINTITM during pregnancy or within 7 months prior to conception can result in fetal harm
Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of KANJINTITM. Advise female patients to contact their healthcare provider with a known or suspected pregnancy
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for KANJINTITM treatment and any potential adverse effects on the breastfed child from KANJINTITM or from the underlying maternal condition
Pulmonary Toxicity

Trastuzumab products can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions
Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity
Discontinue KANJINTITM in patients experiencing pulmonary toxicity
Exacerbation of Chemotherapy-Induced Neutropenia

In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3-4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not
Most Common Adverse Reactions

The most common adverse reactions associated with trastuzumab products in breast cancer were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia
The most common adverse reactions associated with trastuzumab products in metastatic gastric cancer were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia
You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Amgen at 1-800-772-6436.

Please see full Prescribing Information, including Boxed WARNINGS, at www.Amgen.com.