EAST HANOVER, N.J., Dec. 2 Novartis announced today that new data, including a late-breaking presentation on Tasigna® (nilotinib) 200 mg capsules in a form of chronic myeloid leukemia, demonstrate the strength of the company's hematology portfolio in advancing the care of patients.
The new data, at the 51st American Society of Hematology (ASH) Annual Meeting and Exposition, highlight the company's current therapies and investigational agents in 195 studies including 39 oral presentations. Data will be presented on Tasigna, Afinitor® (everolimus) tablets, Exjade® (deferasirox) and pipeline agents including PKC412 (midostaurin), LBH589 (panobinostat), BHQ880 and INCB18424, an oral, selective Janus kinase (JAK) inhibitor that was recently added to the oncology pipeline through a licensing agreement.
"Data presented at ASH will demonstrate the vigorous research underway to explore the best treatment approaches for patients with rare blood cancers and conditions," said David Epstein, President and CEO, Novartis Oncology and Novartis Molecular Diagnostics. "We expect these data to lay the groundwork for regulatory submissions and provide a roadmap for the initiation of late-stage and pivotal trials."
The ASH Annual Meeting will feature results from a pivotal head-to-head study comparing the efficacy and safety of Tasigna versus Gleevec® (imatinib mesylate) tablets(*) in adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (Abstract #LBA-1; Tuesday, December 8, 2009 at 7:30 AM CST).
Data from this Phase III clinical trial, ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients), will show that Tasigna produced faster and deeper responses than Gleevec when used as first-line therapy.
Other key presentations at ASH include:
The Novartis Oncology pipeline features compounds in all phases of development, including six in late-stage development, and encompasses a broad array of therapeutic strategies for fighting cancer.
Tasigna has been approved in more than 80 countries for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including Gleevec. The effectiveness of Tasigna for this indication is based on confirmed hematologic and unconfirmed cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
Tasigna important safety information
WARNING: QT PROLONGATION AND SUDDEN DEATHS
Tasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.
Warnings and precautions
Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction.
Tasigna prolongs the QT interval. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically.
Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.
There were sudden deaths reported in the safety population and in the expanded access program. Ventricular repolarization abnormalities may have contributed to their occurrence.
Elevated serum lipase
Caution is recommended in patients with a history of pancreatitis. Check serum lipase levels monthly or as clinically indicated.
Serum bilirubin and hepatic transaminases
The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.
Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy.
Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment and QT interval should be monitored closely.
The concomitant use of QT prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of Tasigna.
Concomitant strong CYP3A4 inhibitors
The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval, and a dose reduction to 1/2 the daily dose is recommended (400 mg once daily). If the strong inhibitor is discontinued, a washout period should be allowed before Tasigna is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided.
Concomitant strong CYP3A4 inducers
The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St John's Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of Tasigna may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, the Tasigna dose should be reduced to the indicated Tasigna dose. Tasigna is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8, and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. Single-dose administration of Tasigna to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of Tasigna to induce metabolism has not been determined in vivo. Caution should be exercised when co-administering Tasigna with substrates for these enzymes that have a narrow therapeutic index. Tasigna inhibits human P-glycoprotein. If Tasigna is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised.
Food increases blood levels of Tasigna. Patients should avoid food 2 hours before and at least 1 hour after the dose is taken.
Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.
Use in pregnancy
There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna and should be advised of the potential hazard to the fetus if they do.
In chronic phase patients, the most commonly reported adverse reactions (>10%) were rash (33%), pruritus (29%), nausea (31%), fatigue (28%), headache (31%), constipation (21%), diarrhea (22%), and vomiting (21%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (28%), neutropenia (28%), elevated lipase (15%), and hyperglycemia (11%). In accelerated phase patients, the most commonly reported adverse reactions (>10%) were rash (28%), pruritus (20%), and constipation (18%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (37%), neutropenia (37%), anemia (23%), and elevated lipase (17%). Other serious adverse reactions included pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, and pyrexia (Grade 3/4: 2%).
Dose adjustments or modifications
Tasigna may need to be temporarily withheld and/or dose reduced for QT prolongation, hematological toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors. With concomitant use of strong CYP3A4 inducers, the dose of Tasigna may need to be increased, depending on patient tolerability.
For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. For Grade 3 to 4 bilirubin elevations, dosing should be withheld, and may be resumed at 400 mg once daily.
If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, a lower starting dose is recommended in patients with hepatic impairment and QT interval should be monitored. The following dose reduction should be considered:
For patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an initial dosing regimen of 400 mg in the morning and 200 mg in the evening (12 hours apart) per day followed by dose escalation to 400 mg twice daily based on patient tolerability should be considered. For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 400 mg in the morning and 200 mg in the evening (12 hours apart) per day and then to 400 mg twice daily based on patient tolerability should be considered.
Other patients in whom Tasigna should be used with caution
Tasigna should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast feed while taking Tasigna. The safety and effectiveness of Tasigna in pediatric patients have not been established.
Gleevec(®) (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP). Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in CP after failure of interferon-alpha therapy
Gleevec important safety information
Gleevec is often associated with edema and occasionally severe fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening.
Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).
Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse reactions, or hematologic adverse reactions.
In Ph+ CML trials,(**) severe (NCI Grades 3/4) lab abnormalities--including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (approx 5%)--and severe adverse reactions (NCI Grades 3/4), including hemorrhage (1.8%-19%), fluid retention (eg, pleural effusion, pulmonary edema, and ascites) (2.5%-11%) and superficial edema (1.5%-6%), and musculoskeletal pain (2%-9%) were reported among patients receiving Gleevec. Severe fluid retention appears to be dose-related, was more common in the advanced phase studies (where the dosage was 600 mg/day), and is more common in the elderly.
Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.
Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.
Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose, and future doses can be increased as tolerated. Doses greater than 600 mg/day are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg/day are not recommended. Gleevec should be used with caution in patients with severe renal impairment.
In the newly diagnosed CML trial, 2% of patients had (NCI Grades 3/4) hemorrhage.
There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and gastrointestinal (GI) perforation.
Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of Gleevec at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.
Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.
Consider potential toxicities--specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.
Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking Gleevec tablets and to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking Gleevec should use adequate contraception. If the patient does become pregnant while taking Gleevec, the patient should be advised of the potential hazard to the fetus.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec should increase by at least 50%, and clinical response should be carefully monitored, in patients receiving Gleevec with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions.)
For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.
Common side effects of Gleevec tablets
The majority of adult patients with Ph+ CML who received Gleevec in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all Grades) were superficial edema (60%-74%), nausea (50%-73%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), rash and related terms (36%-47%), muscle cramps (28%-62%), and vomiting (23%-58%).(**)((+))
Supportive care may help management of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with Gleevec may be necessary.
Gleevec tablets should be taken with food and a large glass of water to minimize GI irritation. Gleevec tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.
Patients should be informed to take Gleevec exactly as prescribed, not to change their dose or stop taking Gleevec unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose.
(**)Numbers indicate the range of percentages in 4 studies among adult patients with newly diagnosed Ph+ CML and patients in BC, AP, and CP after failure of interferon-alpha therapy.
(+)For more detailed study information, please see full Prescribing Information.
In the US, everolimus is approved under the trade name Afinitor for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. In the European Union (EU), Afinitor is approved for the treatment of patients with advanced RCC whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy. Further, in the EU, everolimus is available in different dosage strengths under the trade name Certican(®) for the prevention of organ rejection in heart and kidney transplant recipients. Everolimus is not approved in the US for this use.
With once-daily dosing, everolimus continuously targets mammalian target of rapamycin (mTOR) in cancer cells, a protein that acts as a central regulator of tumor cell division, blood vessel growth and cell metabolism. Everolimus is being studied in multiple tumor types, including breast cancer, neuroendocrine tumors, gastric cancer, hepatocellular carcinoma (HCC) and non-Hodgkin lymphoma (NHL), as well as tuberous sclerosis complex (TSC).
As an investigational compound, the safety and efficacy profile of everolimus has not yet been established in these cancer and tumor types. Access to everolimus for these cancer and tumor types is available through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the compound. For more information about everolimus clinical trials, healthcare professionals can visit www.theWIDEprogram.com. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will ever become commercially available for these cancer and tumor types anywhere in the world.
Afinitor (everolimus) tablets important safety information
Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives or to any of the excipients. Potentially serious adverse reactions to Afinitor include non-infectious pneumonitis and infections, for which patients should be monitored carefully and treated as needed. In addition, non-infectious pneumonitis may require temporary dose reduction and/or interruption or discontinuation. Patients with systemic invasive fungal infections should not receive Afinitor. Oral ulceration is a common side effect of Afinitor. Renal function, blood glucose, lipids and hematological parameters should be evaluated prior to the start of therapy with Afinitor and periodically thereafter. Strong or moderate CYP3A4 or P-glycoprotein inhibitors should be avoided. An increase in the dose of Afinitor is recommended when co-administered with a strong CYP3A4 inducer. Live vaccinations and close contact with those who have received live vaccines should be avoided by patients taking Afinitor. Afinitor should not be used in patients with severe hepatic impairment. Afinitor may cause fetal harm in pregnant women.
The most common adverse reactions, irrespective of causality (incidence greater than or equal to 30%), were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%) and diarrhea (30%). The most common grade 3/4 adverse reactions, irrespective of causality (incidence greater than or equal to 3%), were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%) and asthenia (3%). The most common laboratory abnormalities (incidence greater than or equal to 50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%) and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence greater than or equal to 3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%) and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed in patients receiving Afinitor.
EXJADE is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. Further studies are being performed to determine the long-term benefits and risks of EXJADE.
Exjade important safety information
EXJADE is contraindicated in patients with hypersensitivity to deferasirox or to any other component of EXJADE.
Renal: Cases of acute renal failure, some with a fatal outcome, have been reported following the postmarketing use of EXJADE. Most of the fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematologic disorders. There have also been reports of renal tubulopathy in patients treated with EXJADE. Give particular attention to monitoring serum creatinine in patients who: are at increased risk of complications, have pre-existing renal conditions, are elderly, have comorbid conditions, or are receiving medicinal products that depress renal function.
Assess serum creatinine in duplicate before initiating therapy to establish a reliable pretreatment baseline, due to variations in measurements. Monitor serum creatinine monthly thereafter. In patients with additional renal risk factors (those who are at increased risk of complications, have pre-existing renal conditions, are elderly, have comorbid conditions, or are receiving medicinal products that depress renal function), monitor serum creatinine weekly during the first month after initiation or modification of therapy and monthly thereafter. Nonprogressive increases in serum creatinine have been noted in 38% of EXJADE-treated patients, compared to 14% of deferoxamine-treated patients in Study 1 and 36% vs 22%, respectively in Study 3, and appear to be dose related. These increases were within the normal range in 94% of patients. EXJADE dosages were adjusted when serum creatinine elevations were detected during the study.
Consider dose reduction, interruption, or discontinuation for elevations in serum creatinine. For adult patients, reduce the daily dose of EXJADE by 10 mg/kg if a rise in serum creatinine to >33% above the average of the pretreatment measurements is seen at 2 consecutive visits, and cannot be attributed to other causes. For pediatric patients, reduce the dose by 10 mg/kg if serum creatinine levels rise above the age-appropriate upper limit of normal at 2 consecutive visits. If there is a progressive increase in serum creatinine beyond the age-appropriate upper limit of normal, interrupt EXJADE use. Once the creatinine has returned to within the normal range, therapy with EXJADE may be reinitiated at a lower dose followed by gradual dose escalation, if the clinical benefit is expected to outweigh potential risks.
Intermittent proteinuria (urine protein/creatinine ratio >0.6 mg/mg) occurred in 18.6% of EXJADE-treated patients, compared to 7.2% of deferoxamine-treated patients in Study 1, and monthly monitoring is recommended.
Cytopenias: There have been postmarketing reports of cytopenias (including agranulocytosis, neutropenia and thrombocytopenia) in patients treated with EXJADE. Some of these patients died. The relationship of these episodes to treatment with EXJADE is uncertain. Most of these patients had pre-existing hematologic disorders that are frequently associated with bone marrow failure. In line with standard clinical management, monitor blood counts regularly. Consider interrupting treatment with EXJADE in patients who develop unexplained cytopenia. Reintroduction of therapy with EXJADE may be considered once the cause of the cytopenia has been elucidated.
Hepatic: There have been postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with EXJADE. Most of these events occurred in patients greater than 55 years of age. Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multi-organ failure. Serum transaminases and bilirubin should be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations. In Study 1, seventeen (5.7%) patients treated with EXJADE developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits versus five (1.7%) patients treated with deferoxamine.
Hypersensitivity: Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving EXJADE, with the onset of the reaction occurring in the majority of cases within the first month of treatment. If reactions are severe, discontinue EXJADE and institute appropriate medical intervention.
Skin rashes may occur during treatment with EXJADE. For rashes of mild to moderate severity, EXJADE may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, EXJADE may be interrupted. Reintroduction at a lower dose with escalation may be considered in combination with a short period of oral steroid administration.
Special senses: Auditory (high-frequency hearing loss, decreased hearing) and ocular (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) disturbances have been reported with EXJADE therapy in less than 1% of patients in clinical trials. Auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) are recommended before the start of EXJADE treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, consider dose reduction or interruption.
Gastrointestinal: Gastrointestinal (GI) irritation may occur during EXJADE treatment. Upper GI ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving EXJADE. Physicians and patients should remain alert for signs and symptoms of GI ulceration and hemorrhage and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. Use caution when administering EXJADE in combination with drugs that have ulcerogenic or hemorrhagic potential, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants.
Adverse reactions: The most frequently occurring adverse reactions with a suspected relationship to EXJADE were diarrhea, vomiting, nausea, abdominal pain, skin rash, and increases in serum creatinine. Maintenance of adequate hydration for patients experiencing diarrhea or vomiting is recommended. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related. These commonly reported adverse events were predominantly mild to moderate in severity with serious adverse events reported in 9.1% of patients in the EXJADE arm and 8.6% of patients in the deferoxamine arm.
For full prescribing information, please visit www.us.exjade.com
About midostaurin (PKC412)
Midostaurin is a multi-targeted kinase inhibitor that suppresses the FLT3 receptor tyrosine kinase, resulting in increased cell death and reduced cell division in tumors. The FLT3 gene is one of several cancer genes associated with the development of AML and approximately 30% of AML patients will have a mutation in their FLT3 gene. Patients who have this mutation have poor prognosis with reduced overall survival, and show higher relapse rates when compared to patients who do not have the mutation, often referred to as FLT3-wild-type.
There is an ongoing global randomized, placebo-controlled Phase III clinical trial called CALGB 10603-RATIFY (Randomized AML Trial In FLT3 in <60 Year Olds) to study midostaurin in combination with standard chemotherapy in newly diagnosed patients with FLT3-mutated AML. This is a multi-cooperative group global trial, sponsored by the Cancer and Leukemia Group B (CALGB) in North America and Novartis outside North America.
About panobinostat (LBH589)
Panobinostat is a potent pan-deacetylase (DAC) inhibitor. By interfering in the nucleus with gene expression and transcription, panobinostat decreases tumor cell division, causes tumor cell death and inhibits the formation of new blood vessels that feed tumors. Furthermore, in diseases that involve plasma cells such as multiple myeloma, panobinostat inhibits HDAC6 (a key enzyme in the elimination of pathologically hypersecreted monoclonal immunoglobulins) leading to cell death.
BHQ880 is a first-in-class, fully human, anti-dickkopf-1 (DKK-1) neutralizing antibody. By inhibiting the DDK-1 antibody, BHQ880 promotes activity of osteoblasts, cells that form bones.
INCB18424 (also known as INCB018424) is a Janus kinase (JAK) inhibitor. This oral targeted therapy is now in Phase III clinical trials for the treatment of myelofibrosis, a life-threatening neoplastic condition with no effective medical treatment that is characterized by varying degrees of bone marrow failure, splenomegaly (enlarged spleen) and debilitating symptoms. INCB18424 has the potential of becoming a first-in-class therapeutic agent for the treatment of this and other hematologic diseases.
ZOMETA is indicated for the treatment of hypercalcemia of malignancy (HCM) and patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Safe and efficacious use of ZOMETA has not been established for use in hyperparathyroidism or non-tumor-related hypercalcemia.
Zometa important safety information
ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast as they contain the same active ingredient.
Patients with HCM must be adequately rehydrated prior to use of ZOMETA and loop diuretics (if applicable). Loop diuretics should be used with caution in combination with ZOMETA to avoid hypocalcemia. ZOMETA should be used with caution with other nephrotoxic drugs. Carefully monitor serum calcium, phosphate, magnesium, and serum creatinine following initiation of ZOMETA. Short-term supplemental therapy may be necessary.
In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. Consider individual patient risk/benefit profile before starting ZOMETA therapy in HCM patients with severe renal impairment. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose.
Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible, as recovery may be prolonged. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
ZOMETA should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant or plans to breast-feed while taking this drug, the patient should be apprised of the potential harm to the fetus or baby.
In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including ZOMETA. Discontinue use if severe symptoms develop, and a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. There have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates.
Insufficient data exist on how to safely use ZOMETA in HCM patients with hepatic impairment.
Acute-phase reaction symptoms can occur in HCM patients, with fever most commonly reported (44% with ZOMETA vs. 33% with pamidronate). Patients may occasionally experience flu-like syndrome (fever, chills, flushing, bone pain and/or arthralgias and myalgias). The most common adverse events (greater than or equal to 10%) in HCM clinical trials, regardless of causality, with ZOMETA 4 mg (n=86) were as follows: fever (44%), nausea (29%), constipation (27%), anemia (22%), dyspnea (22%), diarrhea (17%), abdominal pain (16%), progression of cancer (16%), insomnia (15%), vomiting (14%), anxiety (14%), urinary tract infection (14%), hypophosphatemia (13%), confusion (13%), agitation (13%), moniliasis (12%), hypokalemia (12%), coughing (12%), skeletal pain (12%), hypotension (11%), and hypomagnesemia (11%). In controlled HCM clinical trials, adverse events (5-10% frequency) occurring in greater incidence with ZOMETA than pamidronate include: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, non-specific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Injection site reactions (redness, swelling) have been infrequently reported.
The most common adverse events (greater than or equal to 15%) in bone metastases clinical trials, regardless of causality, with ZOMETA 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lower-limb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%), and paresthesia (15%). Patients should also be made aware of the potential for abdominal pain.
Ocular adverse events may occur with bisphosphonates, including ZOMETA. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.
Caution is advised when bisphosphonates, including ZOMETA, are administered with aminoglycosides, loop diuretics, and potentially nephrotoxic drugs.
Patients with multiple myeloma and bone metastases due to solid tumors should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.
Please see full Prescribing Information.
The foregoing release contains forward-looking statements that can be identified by terminology such as "potential," "to present," "to show," "to demonstrate," "can," "will," "to explore," "pipeline," or similar expressions, or by express or implied discussions regarding potential new indications or labeling, or potential marketing approvals for the products described in this release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that any of the products or additional indications or labeling described in this release will be submitted for approval or approved for sale in any market. Nor can there be any guarantee that any of these products will achieve any particular levels of revenue in the future. In particular, management's expectations regarding these products could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, the Novartis Group offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. The Novartis Group is the only company with leading positions in each of these areas. In 2008, the Group's continuing operations achieved net sales of USD 41.5 billion and net income of USD 8.2 billion. Approximately USD 7.2 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 99,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.
* Known as Glivec® (imatinib) outside the US, Canada and Israel.
(1) Ghobrial, et al. A Phase II Trial of the Oral mTOR Inhibitor Everolimus (RAD001) in Relapsed or Refractory Waldenstrom's Macroglobulinemia. 51st American Society of Hematology Annual Meeting and Exposition, New Orleans, LA. December 5-8, 2009.
(2) Younes, et al. Efficacy of Panobinostat in Phase II Study in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL) After High-Dose Chemotherapy with Autologous Stem Cell Transplant. 51st American Society of Hematology Annual Meeting and Exposition, New Orleans, LA. December 5-8, 2009.
(3) Stone, et al. A Phase 1b Study of Midostaurin (PKC412) in Combination with Daunorubicin and Cytarabine Induction and High-Dose Cytarabine Consolidation in Patients Under Age 61 with Newly Diagnosed De Novo Acute Myeloid Leukemia: Overall Survival of Patients Whose Blasts Have FLT3 Mutations is Similar to Those with Wild-Type FLT3. 51st American Society of Hematology Annual Meeting and Exposition, New Orleans, LA. December 5-8, 2009.
(4) Verstovsek, et al. Long-Term Follow Up and Optimized Dosing Regimen of INCB018424 in Patients with Myelofibrosis: Durable Clinical, Functional and Symptomatic Responses with Improved Hematological Safety. 51st American Society of Hematology Annual Meeting and Exposition, New Orleans, LA. December 5-8, 2009.
(5) Verstovsek, et al. A Phase 2 Study of INCB018424, An Oral, Selective JAK1/JAK2 Inhibitor, in Patients with Advanced Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory to Hydroxyurea. 51st American Society of Hematology Annual Meeting and Exposition, New Orleans, LA. December 5-8, 2009.
(6) Pennell, et al. Efficacy and Safety of Deferasirox (Exjade®) in b-Thalassemia Patients with Myocardial Siderosis: 2-Year Results From the EPIC Cardiac Sub-Study. 51st American Society of Hematology Annual Meeting and Exposition, New Orleans, LA. December 5-8, 2009.
(7) San-Miguel, et al. A Phase IB, Multi-Center, Open-Label Dose-Escalation Study of Oral Panobinostat (LBH589) and I.V. Bortezomib in Patients with Relapsed Multiple Myeloma. 51st American Society of Hematology Annual Meeting and Exposition, New Orleans, LA. December 5-8, 2009.
(8) Padmanabhan, et al. A Phase I/II Study of BHQ880, a Novel Osteoblat Activating, Anti-DKK1 Human Monoclonal Antibody, in Relapsed and Refractory Multiple Myeloma (MM) Patients Treated with Zoledronic Acid (Zol) and Anti-Myeloma Therapy (MM Tx). 51st American Society of Hematology Annual Meeting and Exposition, New Orleans, LA. December 5-8, 2009.
(9) Zometa Prescribing Information. March 2008.
(10) Tasigna (nilotinib) Prescribing Information. East Hanover, New Jersey, USA: Novartis Pharma. http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf.
(11) Gleevec (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2008.
-- Everolimus Phase II data to show efficacy and safety in patients with Waldenstrom's macroglobulinemia (WM) who had relapsed or become resistant to prior treatment (Abstract #587; Monday, December 7, 2009 at 3:45 PM CST)(1) -- Panobinostat data from two early phase studies to show efficacy in heavily pre-treated patients with multiple myeloma and Hodgkin lymphoma (Abstract #3852; Monday, December 7, 2009 at 6:00 PM CST; Abstract #923; Tuesday, December 8, 2009 at 8:30 AM CST)(2)(7) -- Midostaurin early stage data will demonstrate benefit in patients with FLT3-mutated acute myeloid leukemia when used in combination with chemotherapy (Abstract #634; Monday, December 7, 2009 at 5:15 PM CST)(3) -- INCB18424 data from a Phase II study in advanced polycythemia vera (PV) and essential thrombocythemia (ET) refractory to hydroxyurea (Abstract #311; Monday, December 7, 2009, 8:00 AM CST)(5)( ) -- INCB18424 long-term follow-up data to demonstrate durable clinical, functional and symptomatic responses with excellent hematological safety in patients with myelofibrosis (Abstract #756; Monday, December 7, 2009 at 5:45 PM CST)(4) -- Exjade two-year data from EPIC (Evaluation of Patients Iron Chelation with Exjade) trial to show benefit of Exjade for chronically transfused beta-thalassemia patients by continuing to significantly reduce toxic iron that can damage the heart (Abstract #4062; Monday, December 7, 2009 at 6:00 PM CST)(6) -- BHQ880 preliminary Phase I study data in combination with Zometa(®) (zoledronic acid) and an approved anti-myeloma therapy in patients with relapsed or refractory multiple myeloma who experienced a prior skeletal-related event (Abstract #750; Monday, December 7, 2009 at 5:45 PM CST)(8)(9)