On March 2, 2022 Avenge Bio, Inc., ("Avenge" or the "Company") a biotechnology company developing the LOCOcyte immunotherapy platform for the precision administration of potent immune effector molecules to treat solid tumors, reported a publication in the peer-reviewed journal Science Advances describing the foundational, preclinical research establishing the LOCOcyte platform proof of concept in animal models (Press release, Avenge Bio, MAR 2, 2022, View Source [SID1234609409]). The manuscript, entitled "Clinically translatable cytokine delivery platform for eradication of intraperitoneal tumors," was published today and can be viewed on the Science Advances website.

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Ovarian cancer is one of the most difficult cancers to treat. It is typically not detected until later stages, and about 70 percent of patients will have recurrence after an initial treatment, which is often fatal. Furthermore, ovarian tumors produce fluid that makes it challenging to deliver drugs locally. To overcome this challenge, a research team at Rice University led by Omid Veiseh, Ph.D., has developed an innovative immunotherapy platform that enables engineered cells to produce immune-activating molecules, for a specified duration, within this fluid tumor microenvironment.

The Science Advances manuscript details the immunotherapy platform and its safety and efficacy in preclinical models. The human cells are engineered to produce murine immune cell signaling molecule interleukin-2 (IL2), a critical cytokine that initiates a robust localized immune response when administered into the intraperitoneal (IP) cavity of tumor-bearing mice that model advanced ovarian cancer. Notably, 100% of mice showed a significant tumor burden reduction after 30 days, compared to controls. The study also demonstrated that IL2 was localized to the IP cavity and that IL2 production was limited to a 30-day window, both of which suggest a minimal risk of systemic toxicities. Furthermore, the study features robust anti-tumor data in mice with colorectal cancer, demonstrating the broad potential of the immunotherapy platform. Studies in non-human primates demonstrated similar proof of concept of both efficacy and safety, setting the stage for clinical studies in humans.

"We are excited to share these data with the scientific community. Ovarian cancer remains a significant clinical challenge, which drove our team’s dedication to discover and develop an innovative treatment approach," said Dr. Veiseh, Assistant Professor of Bioengineering at Rice University and a Founder of Avenge Bio. "I am grateful to all of the researchers and collaborators involved with this project, including Amanda Nash who has worked on this project from inception. Amanda and I look forward to working with Avenge to bring this technology in the clinic to help patients in need."

Avenge Bio has an exclusive license from Rice University for this technology. Avenge has been engaged in discussions with the U.S. Food and Drug Administration (FDA) and expects to begin clinical studies in the second half of 2022.

"I would like to congratulate Omid and Amanda on this groundbreaking scientific work that resulted in this publication. These discoveries have the potential to dramatically change the treatment paradigm for certain solid tumors including metastatic peritoneal cancers." We have been working closely with Omid and his team to bring this technology into the clinic and look forward to its continued development," said Michael Heffernan, CEO of Avenge.

On March 2, 2022 AIkido Pharma Inc. (Nasdaq: AIKI) ("AIkido" or the "Company"), reported the closing of its previously announced registered direct offering with certain institutional investors of 11,000 shares of Series O redeemable convertible preferred stock and 11,000 shares of Series P redeemable convertible preferred stock (Press release, AIkido Pharma, MAR 2, 2022, View Source [SID1234609408]). Each share of Series O and Series P preferred stock has a purchase price of $952.38, representing an original issue discount of 5% of the $1,000 stated value of each share. Each share of Series O and Series P preferred stock is convertible into shares of AIkido’s common stock at an initial conversion price of $1.00 per share. Shares of the Series O and Series P preferred stock are convertible at the option of the holder at any time following the Company’s receipt of stockholder approval for a reverse stock split of the Company’s common stock. AIkido will be permitted to compel conversion of the Series O and Series P preferred stock after the fulfillment of certain conditions and subject to certain limitations. Total net proceeds from the offerings, before deducting the placement agent’s fees and other offering expenses, is approximately $20.9 million. To the extent Series O or P preferred stock is converted or otherwise not redeemed after 120 days from closing, the Company will use the net proceeds from this offering for working capital and general corporate purposes.

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H.C. Wainwright & Co. acted as the exclusive placement agent for the offering.

The Series O and Series P preferred stock permit the holders thereof to vote together with the holders of the Company’s common stock and other voting preferred stock of the Company on a proposal to effectuate a reverse stock split of the Company’s common stock at an annual or special meeting of Company stockholders. The Series O preferred stock permits the holder to cast votes on such proposal on an as-converted to common stock basis. The Series P preferred stock permits the holder to cast votes equal to 30,000 votes per share of Series P preferred stock on such proposal. The Series O and Series P preferred stock will not be permitted to vote on any other matter. The holders of the Series O and P preferred stock agreed not to transfer their shares of preferred stock until after the meeting of Company stockholders. The holders of the Series P preferred stock have the right to vote their shares on such proposal in the same proportions as the shares of common stock, Series O preferred stock and other voting preferred stock of the Company are voted on that proposal. The holders of the Series O and Series P preferred stock have the right to require the Company to redeem their shares of preferred stock for cash at 105% of the stated value of such shares commencing after the earlier of the Company’s stockholders’ approval of the reverse stock split and 90 days after the closing and until 120 days after the closing.

Additional information regarding the securities described above and the terms of the offering are included in a Current Report on Form 8-K filed with the United States Securities and Exchange Commission ("SEC").

The Series O and Series P preferred stock and shares of common stock into which such preferred stock are convertible were offered pursuant to a registration statement on Form S-3 (333-238172), which was declared effective by the Securities and Exchange Commission on June 18, 2020. The offerings were made only by means of prospectus supplements and a prospectus that form a part of the registration statement. A final prospectus supplement and accompanying prospectus relating to the shares of preferred stock and underlying shares of common stock offered has been filed with the SEC. Electronic copies of the final prospectus supplement and accompanying prospectus may be obtained on the SEC’s website at View Source or by contacting H.C. Wainwright & Co., LLC at 430 Park Avenue, 3rd Floor, New York, NY 10022, by phone at (212) 856-5711 or e-mail at [email protected].

This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.

On March 2, 2022 Kashiv Biosciences, LLC ("Kashiv") reported the U.S. Food and Drug Administration (FDA) approval of its Biologics License Application (BLA) for filgrastim-ayow, a biosimilar referencing Neupogen (Press release, Kashiv BioSciences, MAR 2, 2022, View Source [SID1234609407]). The product will be marketed under the proprietary name RELEUKOTM.

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RELEUKOTM was developed in collaboration with Amneal Pharmaceuticals, Inc. and is expected to launch in the third quarter of 2022. It is used to treat neutropenia (low neutrophils which are a type of white blood cells that fight infection) which is commonly experienced by patients undergoing chemotherapy. Kashiv is planning for a pegfilgrastim biosimilar referencing Neulasta to also be approved in 2022.

"It is a proud moment for the Kashiv team and our partners at Amneal to have our first biosimilar, RELEUKO, approved by the U.S. FDA. Kashiv is one of a few domestic companies to manufacture and launch a biosimilar in the United States. Kashiv aims to continue bringing high quality biosimilars to the global markets over the coming years. I would like to extend a humble ‘thank you’ to our highly talented team, without whom this would not have been possible," said Dr. Chandramauli Rawal, Chief Operating Officer for Kashiv.

"The U.S. approval of our first biosimilar is a very significant milestone for Amneal. Biosimilars represent the next wave of providing access to affordable medicines in the U.S. Amneal is building a global biosimilars business by leveraging partner assets to start and then leveraging our own key capabilities over time. Our goal is to become a meaningful long-term player in biosimilars," said Chirag and Chintu Patel, Co-Chief Executive Officers for Amneal.

According to IQVIA, U.S. annual sales for filgrastim for the 12 months ended December 2021 were $407 million, of which $275 million represents biosimilar sales.

RELEUKOTM in the U.S. is indicated:

To decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti- cancer drugs associated with a significant incidence of severe neutropenia with fever.
To reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
To reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT).
To reduce the incidence and duration of sequelae of severe neutropenia‚ (e.g., fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.
RELEUKOTM IMPORTANT SAFETY INFORMATION

Patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim products or pegfilgrastim products.

Before you take RELEUKOTM, tell your healthcare provider if you are pregnant or plan to breast feed, and if you have sickle cell disorder, kidney problems or receiving radiation therapy.

WARNINGS AND PRECAUTIONS

Fatal splenic rupture: Patients may experience enlarged spleen which can rupture and cause death.
Acute respiratory distress syndrome (ARDS): Patients may develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue RELEUKOTMin patients with ARDS.
Fatal sickle cell crises: Serious sickle cell crises have been reported in patients with sickle cell disorders receiving RELEUKOTM. Discontinue RELEUKOTMif sickle cell crisis occurs.
Serious allergic reactions, including anaphylaxis: Permanently discontinue RELEUKOTM in patients with serious allergic reactions.
Kidney injury (Glomerulonephritis): Kidney injury have been reported in patients on RELEUKOTM. Consider dose-reduction or interruption of RELEUKOTMin patients with kidney injury.
Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using RELEUKOTMin conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML.
Decreased platelet count (thrombocytopenia); increased white blood cell count (leukocytosis) and inflammation of your blood vessels (cutaneous vasculitis) have been reported. Monitor platelet counts and white blood cell count.
ADVERSE REACTIONS

Most common adverse reactions in patients:

With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs are pyrexia, pain, rash, cough, and dyspnea.
With AML are pain, epistaxis and rash.
With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by Bone Marrow Transplant is rash.
With severe chronic neutropenia are pain, anemia, epistaxis, diarrhea, hypoesthesia and alopecia

On March 2, 2022 A2 Biotherapeutics, Inc. ("A2 Bio”), a biotechnology company focused on the treatment of solid tumors, reported that key preclinical data related to its proprietary Tmod cell therapy platform have been published in Science Translational Medicine and Journal for ImmunoTherapy of Cancer (Press release, A2 Biotherapeutics, MAR 2, 2022, View Source [SID1234609406]). Tmod therapy is designed for cancer patients whose tumors harbor specific genetic deletions, and genetic testing enables early identification of patients that may benefit from such therapy. Tmod therapy exploits such deletions to selectively destroy tumors while sparing normal cells, potentially providing a radical new way to safely and effectively treat solid tumor cancers.

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"These two papers present a large body of preclinical in vitro and in vivo evidence that supports the robust, highly selective function of the Tmod system, a new approach to cancer therapy that addresses head-on the central problem of oncology – the ability of cancer medicines to distinguish between tumor and normal cells," said Dr. Alexander Kamb, Chief Scientific Officer at A2 Bio.

The paper published on March 2, 2022 in Science Translational Medicine (Sandberg et al., "A cell therapy designed to target the CEA antigen safely in selected patients with solid tumors") describes a clinical candidate directed at solid tumors of the colon and other organs which is currently advancing toward Phase 1. Dr. Han Xu, Vice President of Therapeutic Technology at A2 Bio and a senior author on the paper, said: "Our preclinical data suggest that this cell-based medicine will have the potency of a clinically active CEA-targeted therapeutic benchmark, but without the toxicity."

The paper published on January 28, 2022 in the Journal for ImmunoTherapy of Cancer (Tokatlian et al., "Mesothelin-specific CAR-T cell therapy that incorporates an HLA-gated safety mechanism selectively kills tumor cells") demonstrates the potential applications of Tmod T cells in lung cancer and other solid tumors. Dr. Agi Hamburger, Vice President of Drug Discovery and a senior author, commented: "Our publication not only describes the properties of an exciting new prospect for lung cancer patients but also highlights the impressive modularity of our Tmod platform, a platform that we hope can be extended to create therapies for many other cancer patients in the future."

Links to these and other A2 Bio publications can be accessed on the company’s website: www.a2bio.com/science/abstracts-and-publications.

On March 2, 2022 PharmaEssentia USA Corporation, the U.S. subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, reported that the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) has been updated to include BESREMi (ropeginterferon alfa-2b-njft) as a recommended therapeutic option for the treatment of adults with polycythemia vera (PV) (Press release, PharmaEssentia, MAR 2, 2022, View Source [SID1234609405]).

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The NCCN is a highly renowned and respected not-for-profit alliance of leading cancer centers in the United States. Its treatment practice guidelines are widely respected and followed by the U.S. physician community, and serve to inform and facilitate coverage decisions with payers for oncology therapies. Consistent with the broad indication for BESREMi upon its U.S. regulatory approval in November 2021, the guidelines provide consideration for use of the treatment among both high-risk and low-risk adult patients, regardless of their treatment history.

"Importantly, the NCCN Guidelines update includes mention of BESREMi in multiple settings, and in particular, as the only systemic option for low-risk patients with PV, which signals a shift toward more proactive treatment earlier in the disease journey," said Ruben Mesa, M.D., FACP, Executive Director of the UT Health San Antonio MD Anderson Cancer Center. "Now, treating physicians can leverage these expert guidelines to gain greater familiarity with BESREMi in the real world setting and understand its broad utility for patient care in a variety of treatment settings."

"Our goal with BESREMi has been to offer a compelling therapeutic alternative to conventional treatment options that can enable physicians to gain durable control over the disease beyond the symptoms and help more patients reach their long-term health goals," said Raymond Urbanski, M.D., Ph.D., U.S. Head of Clinical Development and Medical Affairs. "The NCCN Guidelines update just three months following our approval illustrates the community’s recognition of the strong potential of BESREMi in PV care."

About Polycythemia Vera

Polycythemia Vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.1

About BESREMi

BESREMi is an innovative monopegylated, long-acting interferon. With its unique pegylation technology, BESREMi has a long duration of activity in the body and is aimed to be administered once every two weeks (or every four weeks with hematological stability for at least one year), allowing flexible dosing that helps meet the individual needs of patients.

BESREMi has orphan drug designation for treatment of polycythemia vera (PV) in the United States. The product was approved by the European Medicines Agency (EMA) in 2019, in the United States in 2021, and has recently received approval in Taiwan and South Korea. The product was invented by PharmaEssentia and is manufactured in the company’s Taichung plant, which was cGMP certified by TFDA in 2017 and by EMA in January 2018. The company retains full global intellectual property rights for the product in all indications.

BESREMi was approved with a boxed warning for risk of serious disorders including aggravation of neuropsychiatric, autoimmune, ischemic and infectious disorders.

Important Safety Information

IMPORTANT SAFETY INFORMATION AND INDICATIONS

WARNING: RISK OF SERIOUS DISORDERS

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.

CONTRAINDICATIONS

Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt
Hypersensitivity to interferons including interferon alfa-2b or any of the inactive ingredients of BESREMi.
Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment
History or presence of active serious or untreated autoimmune disease
Immunosuppressed transplant recipients
WARNINGS AND PRECAUTIONS

Depression and Suicide: Life-threatening or fatal neuropsychiatric reactions have occurred in patients receiving interferon alfa-2b products, including BESREMi. These reactions may occur in patients with and without previous psychiatric illness.

Other central nervous system effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa products.

Closely monitor patients for any symptoms of psychiatric disorders and consider psychiatric consultation and treatment if such symptoms emerge. If psychiatric symptoms worsen, it is recommended to discontinue BESREMi therapy.
Endocrine Toxicity: These toxicities may include worsening hypothyroidism and hyperthyroidism. Do not use BESREMi in patients with active serious or untreated endocrine disorders associated with autoimmune disease. Evaluate thyroid function in patients who develop symptoms suggestive of thyroid disease during BESREMi therapy. Discontinue BESREMi in patients who develop endocrine disorders that cannot be adequately managed during treatment with BESREMi.
Cardiovascular Toxicity: Toxicities may include cardiomyopathy, myocardial infarction, atrial fibrillation and coronary artery ischemia. Patients with a history of cardiovascular disorders should be closely monitored for cardiovascular toxicity during BESREMi therapy. Avoid use of BESREMi in patients with severe or unstable cardiovascular disease, (e.g., uncontrolled hypertension, congestive heart failure (≥ NYHA class 2), serious cardiac arrhythmia, significant coronary artery stenosis, unstable angina) or recent stroke or myocardial infarction.
Decreased Peripheral Blood Counts: These toxicities may include thrombocytopenia (increasing the risk of bleeding), anemia, and leukopenia (increasing the risk of infection). Monitor complete blood counts at baseline, during titration and every 3-6 months during the maintenance phase. Monitor patients for signs and symptoms of infection or bleeding.
Hypersensitivity Reactions: Toxicities may include serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis). If such reactions occur, discontinue BESREMi and institute appropriate medical therapy immediately. Transient rashes may not necessitate interruption of treatment.
Pancreatitis: Pancreatitis has occurred in 2.2% of patients receiving BESREMi. Symptoms may include nausea, vomiting, upper abdominal pain, bloating, and fever. Patients may experience elevated lipase, amylase, white blood cell count, or altered renal/hepatic function. Interrupt BESREMi treatment in patients with possible pancreatitis and evaluate promptly. Consider discontinuation of BESREMi in patients with confirmed pancreatitis.
Colitis: Fatal and serious ulcerative or hemorrhagic/ischemic colitis have occurred in patients receiving interferon alfa products, some cases starting as early as 12 weeks after start of treatment. Symptoms may include abdominal pain, bloody diarrhea, and fever. Discontinue BESREMi in patients who develop these signs or symptoms. Colitis may resolve within 1 to 3 weeks of stopping treatment.
Pulmonary Toxicity: Pulmonary toxicity may manifest as dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis. Some events have resulted in respiratory failure or death. Discontinue BESREMi in patients who develop pulmonary infiltrates or pulmonary function impairment.
Ophthalmologic Toxicity: These toxicities may include severe eye disorders such as retinopathy, retinal hemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion which may result in blindness. During BESREMi therapy, 23% of patients were identified with an eye disorder. Eyes disorders ≥5% included cataract (6%) and dry eye (5%). Advise patients to have eye examinations before and during BESREMi therapy, specifically in those patients with a retinopathy-associated disease such as diabetes mellitus or hypertension. Evaluate eye symptoms promptly. Discontinue BESREMi in patients who develop new or worsening eye disorders.
Hyperlipidemia: Elevated triglycerides may result in pancreatitis. Monitor serum triglycerides before BESREMi treatment and intermittently during therapy and manage when elevated. Consider discontinuation of BESREMi in patients with persistently, markedly elevated triglycerides.
Hepatotoxicity: These toxicities may include increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and bilirubin. Liver enzyme elevations have also been reported in patients after long-term BESREMi therapy. Monitor liver enzymes and hepatic function at baseline and during BESREMi treatment. Discontinue BESREMi in patients who develop evidence of hepatic decompensation (characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome or variceal hemorrhage) during treatment
Renal Toxicity: Monitor serum creatinine at baseline and during therapy. Avoid use of BESREMi in patients with eGFR <30 mL/min. Discontinue BESREMi if severe renal impairment develops during treatment.
Dental and Periodontal Toxicity: These toxicities may include dental and periodontal disorders, which may lead to loss of teeth. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with BESREMi. Patients should have good oral hygiene and regular dental examinations.
Dermatologic Toxicity: These toxicities have included skin rash, pruritus, alopecia, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, and hyperhidrosis. Consider discontinuation of BESREMi if clinically significant dermatologic toxicity occurs.
Driving and Operating Machinery: BESREMi may impact the ability to drive and use machinery. Patients should not drive or use heavy machinery until they know how BESREMi affects their abilities. Patients who experience dizziness, somnolence or hallucination during BESREMi therapy should avoid driving or using machinery.
Embryo-Fetal Toxicity: Based on the mechanism of action, BESREMi can cause fetal harm when administered to a pregnant woman. Pregnancy testing is recommended in females of reproductive potential prior to treatment with BESREMi. Advise females of reproductive potential to use an effective method of contraception during treatment with BESREMi and for at least 8 weeks after the final dose.
ADVERSE REACTIONS

The most common adverse reactions reported in > 40% of patients in the PEGINVERA study (n=51) were influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain. In the pooled safety population (n=178), the most common adverse reactions greater than 10%, were liver enzyme elevations (20%), leukopenia (20%), thrombocytopenia (19%), arthralgia (13%), fatigue (12%), myalgia (11%), and influenza-like illness (11%).

DRUG INTERACTIONS

Patients on BESREMi who are receiving concomitant drugs which are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification for these concomitant drugs. Avoid use with myelosuppressive agents and monitor patients receiving the combination for effects of excessive myelosuppression. Avoid use with narcotics, hypnotics or sedatives and monitor patients receiving the combination for effects of excessive CNS toxicity.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on mechanism of action and the role of interferon alfa in pregnancy and fetal development, BESREMi may cause fetal harm and should be assumed to have abortifacient potential when administered to a pregnant woman. There are adverse effects on maternal and fetal outcomes associated with polycythemia vera in pregnancy. Advise pregnant women of the potential risk to a fetus.
Lactation: There are no data on the presence of BESREMi in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children from BESREMi, advise women not to breastfeed during treatment and for 8 weeks after the final dose.
Females of Reproductive Potential: BESREMi may cause embryo-fetal harm when administered to a pregnant woman. Pregnancy testing prior to BESREMi treatment is recommended for females of reproductive potential. Advise female patients of reproductive potential to use effective contraception during treatment with BESREMi and for at least 8 weeks after the final dose.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.