Capsule archive mid-Jan 04
- FDA approves Symbyax (Zyprexa-Prozac combination) as first bipolar depression medication
- Gene discovery sparks work on drug to counter multiple myeloma bone destruction
- France approves Exanta oral coagulant for prevention of VTE in hip/knee replacement surgery
- Iressa ZD1839 approved in Canada for advanced non-small cell lung cancer
- FDA Advisory Committees vote to allow OTC sale of Plan B emergency contraceptive
- Lexapro indication extended to include generalized anxiety disorder
- FDA approves labeling for use of Xenical (orlistat) in adolescents aged 12 to 16
- Gleevec converted to regular approval as second line treatment for refractory CML
- FDA approves Risperdal for treatment of bipolar mania
- FDA approves Serono's Zorbtive for use in patients with short bowel syndrome
- SAB-Pharma launches Regonol "shortage product" for reversing the effects of muscle relaxants
- Symbicort study sets new standards for treatment of COPD
FDA approves Symbyax (Zyprexa-Prozac combination) as first bipolar depression medication
INDIANAPOLIS, IND., December 29, 2003 -- Eli Lilly announced that the FDA has approved Symbyax (olanzapine and fluoxetine HCl) for the treatment of depressive episodes associated with bipolar disorder. Symbyax (pronounced SIMM-bee-ax), which is a combination of olanzapine, the active ingredient in Zyprexa, and fluoxetine, the active ingredient in Prozac, is the first FDA-approved medication for bipolar depression, a notoriously difficult-to-treat condition that afflicts millions of Americans.
"There is a desperate need for an effective treatment for bipolar depression, a devastating condition which often leads patients to take their own lives," said Terence A. Ketter, M.D., associate professor of psychiatry & behavioral sciences, and chief, Bipolar Disorders Clinic, Stanford University School of Medicine.
Bipolar disorder is a complex mental illness characterized by debilitating mood swings ranging from episodes of deep depression marked by feelings of extreme guilt, sadness, anxiety and, at times, suicidal thoughts to episodes of mania (abnormal euphoria, elation and irritability), interspersed with periods of normal mood.
Patients with bipolar disorder spend more than three times longer in the depressive phase than in the manic phase of the disorder and take longer to recover from it. Additionally, the depressive phase of bipolar disorder is associated with higher rates of morbidity and mortality. It is estimated that one in four people with bipolar disorder will attempt suicide at least once, and the relative risk of suicide among patients with bipolar depression has been shown to be nearly 35 times greater than for patients in the manic phase of bipolar disorder.
Robust symptom relief observed in clinical trials
According to a study (Tohen, et al.) published in the November 2003 issue of Archives of General Psychiatry, Symbyax helped to treat the symptoms of bipolar depression more effectively and at a significantly faster rate than placebo. In the pooled eight-week studies, patients in the Symbyax group experienced significantly greater improvement in depressive symptoms at weeks one, three, four, six and eight, compared with patients taking placebo. That robust symptom improvement was sustained throughout the entire eight weeks of the study. In addition, Symbyax patients had no statistically greater risk of treatment-emergent mania than patients taking placebo. In patients with bipolar depression, a manic episode is a potential consequence of treatment with a conventional antidepressant alone.
"Medications that clinicians have traditionally used to treat bipolar patients in a depressive phase can often take several weeks to work and have the additional risk of sending the patient into a manic episode," said Ketter. "Having a medication that can provide symptom relief quickly, while avoiding mania, will be so important to physicians in effectively treating patients with bipolar depression, particularly because these individuals are at a high risk of suicide."
Important information on Symbyax
Symbyax is indicated in the United States for the treatment of depressive episodes associated with bipolar disorder.
The most common adverse events reported in patients taking Symbyax in clinical trials was drowsiness. Other common events noticed in clinical trials were weight gain, increased appetite, feeling weak, swelling, tremor, sore throat and difficulty concentrating.
Hyperglycemia, in some cases associated with ketoacidosis, coma or death, has been reported in patients treated with atypical antipsychotics, including olanzapine, and concomitant olanzapine and fluoxetine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. The available data are insufficient to provide reliable estimates of differences in hyperglycemia-related adverse-event risk among the marketed atypical antipsychotics. All patients taking atypicals should be monitored for symptoms of hyperglycemia. Persons with diabetes who are started on atypicals should be monitored regularly for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood-glucose testing. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood-glucose testing.
Although Symbyax is not approved for elderly patients with dementia it is important to note the label for Symbyax includes a warning for patients in this population. The warning states that strokes or mini-strokes (also called transient ischemic attacks or TIAs), including fatalities were reported in elderly patients with dementia-related psychosis participating in clinical trials for olanzapine, an active ingredient in Symbyax. In fact, Symbyax has not been studied in elderly patients with dementia, nor do we expect Symbyax to be used to treat these patients.
Symbyax may induce orthostatic hypotension (a drop in blood pressure when standing up), associated with dizziness, speeding or slowing of heart rate, and in some patients, fainting, especially during initial therapy.
Symbyax prescribing should be consistent with the need to minimize the risk of neuroleptic malignant syndrome, tardive dyskinesia, and orthostatic hypotension.
Symbyax should not be administered until at least two weeks have passed since discontinuing an MAO inhibitor, and an MAO inhibitor is contraindicated for at least five weeks after discontinuation with Symbyax. Thioridazine should not be administered with Symbyax or within a minimum of five weeks after discontinuing Symbyax. Symbyax should be discontinued immediately if rash or other possibly allergic phenomena appear for which an alternative explanation cannot be identified.
Due to the cyclical nature of bipolar disorder, patients should be monitored for the signs of mania and hypomania during treatment with Symbyax. Patients should inform their physicians if they are taking Zyprexa, Prozac, Sarafem or fluoxetine.
Full prescribing information is accessible at www.symbyax.com. Symbyax will be available in pharmacies by mid-January, 2004.
Zyprexa is indicated in the United States for the treatment of schizophrenia and the short-term treatment of acute manic episodes associated with bipolar disorder and for the long-term therapy and maintenance of treatment response of schizophrenia. Additionally, Zyprexa is under review by the FDA for long-term maintenance of bipolar disorder.
Zyprexa is not indicated for the treatment of bipolar depression. Full prescribing information is available at www.zyprexa.com
Prozac was the first of a new class of drugs, called selective serotonin reuptake inhibitors (SSRIs), to be approved for use in the United States. This type of medication helps patients with depression by increasing the availability of serotonin in the brain. Scientists believe serotonin affects many types of activity in the brain, including the regulation of mood.
Prozac is not indicated for the treatment of bipolar depression. Full prescribing information is available at www.prozac.com
Source: Eli Lilly and Company www.lilly.com
Gene discovery sparks work on drug to counter multiple myeloma bone destruction
LITTLE ROCK, ARK., December 24, 2003 -- Scientists at the University of Arkansas for Medical Sciences (UAMS) have discovered the mechanism that destroys bone in the deadly cancer multiple myeloma and are developing a drug to stop or reverse the process.
John Shaughnessy, Jr., Ph.D., and his research team in the Myeloma Institute for Research and Therapy at UAMS report in the New England Journal of Medicine today that they have identified a gene, called DKK1, which causes bone lesions in multiple myeloma, leading to debilitating and intractable bone pain and a higher risk of bone fractures, spinal cord compression, and life- threatening levels of calcium in the blood.
Shaughnessy is developing a drug that will act like a sponge in the bloodstream to absorb DKK1, potentially arresting and reversing the bone destruction that is the primary effect of multiple myeloma. Almost always fatal, multiple myeloma strikes about 15,000 people in the United States each year.
"We can do it. We have the strategy. The soluble receptor should stop DKK1 from binding to bone cells," Shaughnessy said. The potential UAMS treatments include soluble receptor therapy or monoclonal antibody therapy. Pharmaceutical companies have developed similar approaches to treat leukemias and breast cancer.
Shaughnessy's team in the Donna D. & Donald M. Lambert Laboratory of Myeloma Genetics at UAMS found that DKK1 inactivates osteoblasts, the naturally occurring cells that cause bone growth, altering the natural balance of action between osteoblasts and bone-destroying cells called osteoclasts. "The paralysis of the bone-forming cells and the hyperactivation of osteoclasts result in a net loss of bone in patients with myeloma," Shaughnessy said.
The UAMS research group is one of the first to use gene expression profiling to discover how a disease process works. Other researchers have shown that mutations in the receptor for DKK1 cause two inherited bone syndromes, but the UAMS team is the first to trace elevated levels of DKK1 to multiple myeloma. Shaughnessy's team also is exploring whether DKK1 is elevated in women with postmenopausal osteoporosis -- a possibility that another UAMS scientist, Stavros Manologas, M.D., Ph.D., first suggested in the journal Science last year -- or in other cancers that cause bone loss.
Shaughnessy is an associate professor of medicine in the UAMS College of Medicine and a member of the Arkansas Cancer Research Center (ACRC) at UAMS. Myeloma Institute Director Bart Barlogie, M.D., Ph.D., and researchers Yupo Ma, Ronald Walker, Fenghuang Zhan, and Erming Tian, all of UAMS, and Erik Rasmussem of Cancer Research and Biostatistics in Seattle collaborated on the study that led to identification of DKK1. Shaughnessy and Barlogie have received research funding from the National Cancer Institute, part of the National Institutes of Health, and the Fund to Cure Myeloma and the Penninsula Community Foundation.
Shaughnessy linked DKK1 to bone disease using microarray technology, which measures the activity of all 35,000 human genes in each tumor sample in an experiment. In a related project, Shaughnessy is comparing variation in gene expression with variation in response to different drug treatments in patients with myeloma, using a technique he described in the journal Blood earlier this year. Now completing a larger, more definitive study of the technique, Shaughnessy anticipates establishing a method for "personalizing" treatment of multiple myeloma on the basis of individual patients' gene profiles in 2004.
UAMS has the largest myeloma treatment and research centers in the world. Led by Barlogie, the Myeloma Institute, located in the ACRC at UAMS, has achieved a median survival rate of six to seven years, even though the national median survival rate is roughly 2.5 to three years. Anti-DKK1 therapy may complement or even replace the current standard therapy, called autologous transplantation, which is to remove hematopoietic stem cells from the patient's bone marrow, treat the patient with high doses of chemotherapy, and then replace the stem cells.
Source: University of Arkansas for Medical Sciences www.uams.edu
France approves Exanta oral coagulant for prevention of VTE in hip/knee replacement surgery
LONDON, ENGLAND, December 23, 2003 -- AstraZeneca has received its first regulatory approval, in France, for Exanta (ximelagatran) for the prevention of venous thromboembolic events in major orthopaedic (hip or knee replacement) surgery. France is the Reference Member State for the European Union (EU) Mutual Recognition Procedure for Exanta.
Subject to approval, launches of Exanta in this first proof of principle' indication are expected to take place later in 2004.
Exanta is the first oral treatment in a new World Health Organisation class of direct thrombin inhibitors (DTIs) and is the first new oral anticoagulant approved since the introduction of warfarin almost 60 years ago. Exanta benefits from administration as a fixed oral dose, has a rapid onset and offset of action and shows low potential for food and drug interactions. Importantly, coagulation monitoring is also not necessary in treatment with Exanta.
The approval of Exanta for this first indication in France is based on the METHRO* study programme, involving an early postoperative start of Exanta treatment, with initial injectable dosing administered at least four hours after the completion of surgery, followed by oral Exanta 24mg twice daily for up to 11 days. This approval reflects clinical practice that is becoming increasingly common in Europe and allows use in conjunction with spinal anaesthesia with the oral dosing route enabling treatment to be easily continued following discharge from hospital. More than half of patients undergoing major orthopaedic surgery develop VTE in the absence of preventative anticoagulant treatment, and while effective treatments are available, no treatment regimen to date has successfully balanced efficacy and bleeding risk with oral dosing.
Regulatory submissions for prevention of stroke in atrial fibrillation and treatment of VTE, have already been filed in France as part of the EU Mutual Recognition Procedure. In the U.S., submissions have been filed with the FDA for use of Exanta in stroke prevention in patients with atrial fibrillation and long-term secondary prevention of VTE, alongside the orthopaedic surgery file for use of Exanta in prevention of VTE in total knee replacement.
Thrombosis leads to the occlusion of blood vessels and prevents the circulation of blood to the heart (myocardial infarction) and brain (stroke). When blood clots break away, they can lead to thromboembolism in the lungs (pulmonary embolism), limbs (deep vein thrombosis) or within any blood vessels (venous thrombosis). Each year, nearly four million people experience thrombosis worldwide and those at greatest risk include people with atrial fibrillation, those who have experienced a previous cardiac event such as a myocardial infarction, and patients following orthopaedic surgery (OS: total hip or knee replacement surgery). Although existing treatments are effective, they have many limitations. Several require subcutaneous or intravenous administration, whilst current oral treatments are limited by risk of drug and food interactions, the need for regular coagulation monitoring and dose titration.
* METHRO: MElagatran for THRombin inhibition in Orthopaedic surgery study that compared injectable low molecular weight heparinsinitiated the evening before surgery, with preoperative (METHRO II) or post-operative (METHRO III) initiation of melagatran (active form) followed by oral ximelagatran in 4,688 patients undergoing total hip or knee replacement.
Iressa ZD1839 approved in Canada for advanced non-small cell lung cancer
LONDON, ENGLAND, December 19, 2003 -- AstraZeneca announced that Health Canada has granted approval of gefitinib (Iressa ZD1839) for the treatment of patients with advanced non-small cell lung cancer (NSCLC). Gefitinib is the first in a new class of biological, anti-cancer drugs known as 'Epidermal Growth Factor Receptor tyrosine kinase inhibitors' (EGFR TKIs).
Health Canada's Therapeutic Product Directorate granted conditional approval of gefitinib 250mg per day as monotherapy (third-line therapy) for the treatment of patients with locally advanced or metastatic NSCLC after the failure of prior platinum-based and docetaxel chemotherapy. NSCLC is a complex, severely symptomatic illness, which has a devastating impact on the patient and their family.
The approval in Canada is based on data from two large, randomised Phase II trials, IDEAL 1 and IDEAL 2 (Iressa Dose Evaluation in Advanced Lung Cancer). The trials demonstrated approximately 40% of patients -- for whom there were no other treatment options available -- gained life-enhancing benefit from gefitinib in terms of tumour shrinkage and stabilised disease, which were often associated with improvement in the debilitating symptoms associated with lung cancer.
Gefitinib has been approved for the treatment of advanced NSCLC in the US, Australia, Japan, Argentina, Singapore, Korea, Taiwan, Mexico, Malaysia and the Philippines and is currently undergoing review with several other regulatory authorities worldwide.
For further information on gefitinib and lung cancer, visit www.iressa.com
Source: AstraZeneca www.astrazeneca.com
FDA Advisory Committees vote to allow OTC sale of Plan B emergency contraceptive
WOODCLIFF LAKE, N.J., December 16, 2003 -- Barr Laboratories and Women's Capital Corporation (WCC) announced that two FDA Advisory Committees have recommended that Plan B, now available by prescription only as an emergency contraceptive, be permitted to be sold without a prescription.
The recommendation came following a joint meeting of the FDA's Nonprescription Drugs and Reproductive Health Drugs Advisory Committees. The FDA will now consider the recommendation. In presentations to the committees, Barr and WCC, among others, stated that increased education about the availability of the Plan B emergency contraceptive, and lowering of barriers that delay access, could eliminate more than 50% of unintended pregnancies.
If ultimately approved by the FDA, OTC access to Plan B will provide women who have had unprotected sexual intercourse and do not want to become pregnant with an additional contraceptive option, said Carole Ben-Maimon, M.D., President and Chief Operating Officer of Barr Research.
"Barr is committed to lowering the barriers that prevent women from being able to access this option in a timely manner. In many cases, being able to receive a prescription currently prevents the timely use of this method of contraception," Dr. Ben-Maimon added. "Making the product available without prescription would reduce these barriers and would represent a significant public health service to American women."
The company presented to the Advisory Committees an extensive education program for physicians and other healthcare professionals, as well as an array of educational materials that will be available for women who have questions about Plan B or its appropriate use. These include consumer-friendly labeling, a website, and a 24 hour hotline that will connect consumers directly with trained healthcare professionals to answer any questions.
Taken within 72 hours of unprotected intercourse, Plan B has been shown to reduce the risk of pregnancy by 89 percent after a single act of unprotected sex. Effectiveness declines as the interval between intercourse and the start of treatment increases. Taken in the first 24 hours after intercourse, Plan B can prevent 95 percent of expected pregnancies. The decline in efficacy from a delay in treatment is why a broad range of health professionals believe that barriers to more timely access to Plan B should be removed, including making the product broadly available without prescription.
Emergency contraception is currently available in 100 countries, 33 of which do not require a prescription. Emergency contraception is currently available in a limited number of pharmacies in five U.S. states (Alaska, California, Hawaii, New Mexico and Washington) without an advance prescription from a physician or healthcare provider.
"If approved by FDA as an OTC product, Plan B would be sold in single use packages that would deter it from being used as a 'routine' form of birth control," said Dr. Ben-Maimon. "In addition, bleeding patterns associated with repeated use of Plan B make frequent use impractical."
Contraindications for Plan B
Progestin-only contraceptive pills (POPs) are used as a routine method of birth control over longer periods of time, and are contraindicated in some conditions. It is not known whether these same conditions apply to the Plan B regimen consisting of the emergency use of two progestin pills. POPs however, are not recommended for use in the following conditions: known or suspected pregnancy; hypersensitivity to any component of the product; and, undiagnosed abnormal genital bleeding.
Source: Barr Laboratories www.barrlabs.com
Lexapro indication extended to include generalized anxiety disorder
NEW YORK, N.Y., December 18, 2003 -- Forest Laboratories announced that the FDA has approved Lexapro (escitalopram oxalate), a selective serotonin reuptake inhibitor, for the treatment of generalized anxiety disorder (GAD).
The new indication is based on three studies, all of which were positive and support the efficacy and safety of Lexapro in the treatment of GAD. GAD is characterized by excessive anxiety and worry that significantly impacts an individual's daily functioning. Lexapro is also indicated for the initial treatment and maintenance of major depressive disorder.
"One of the biggest challenges in treating GAD patients is finding a treatment that is not only effective, but also one that patients will be able to tolerate for the long term," said Philip Ninan, M.D., professor of Psychiatry and Behavioral Sciences and director of the Mood and Anxiety Disorders Program at Emory University School of Medicine. "Lexapro is a first-line treatment option, which has proven to be effective with a favorable side effect profile."
All three studies that support the indication approval were randomized, double-blind, eight weeks in duration and placebo-controlled. The studies involved approximately 850 patients, 18 to 80 years of age, diagnosed with GAD. Patients in the Lexapro arm were administered a fixed dose of 10 mg per day for the first four weeks and then flexibly dosed to a maximum of 20 mg per day. The Hamilton Anxiety Scale (HAMA) total score was the primary efficacy variable, and secondary efficacy measures included changes in HAMA psychic anxiety subscale and Clinical Global Impressions (CGI) scores.
In each of the three studies, Lexapro 10 to 20 mg per day significantly improved GAD symptoms in patients compared to placebo as measured by change from baseline in HAMA score. By-visit analyses of data pooled across the three studies revealed significantly greater improvement in the Lexapro group beginning at week one or two and continuing through week eight for all primary and secondary efficacy variables.
Further analysis of one of the three placebo-controlled studies showed that Lexapro-treated patients experienced a significant improvement in quality of life compared to patients treated with placebo as measured by the Quality of Life (QOL) scale. Sixty-eight percent of Lexapro-treated patients in the study demonstrated a significant response rate as compared to 41 percent of placebo-treated patients. In addition, more than twice as many patients in the Lexapro 10 to 20 mg per day group were in remission at week eight than in the placebo group, 36 and 16 percent, respectively.
Lexapro was well tolerated in the pooled analysis of the three studies, with eight percent of patients discontinuing treatment due to adverse events compared to four percent of patients in the placebo group. The most commonly reported adverse events in the Lexapro group versus placebo were nausea (18.2% vs. 7.5 %), ejaculation disorder (14.3% vs. 1.5%), insomnia (11.9% vs. 5.6%), fatigue (7.7% vs. 2.1%), decreased libido (6.8% vs. 2.1%) and anorgasmia (5.7% vs. 0.4%).
FDA approves labeling for use of Xenical (orlistat) in adolescents aged 12 to 16
NUTLEY, N.J., December 15, 2003 -- Roche announced that the FDA has approved labeling for use of the prescription weight-loss medication Xenical (orlistat) in the management of obese adolescents ages 12 to 16 years. This is the first approval of its kind for a prescription weight-loss treatment.
Overweight and obesity has reached epidemic proportions in the United States. Currently, about 15% of adolescents in the U.S. are obese, and 30% are overweight. Poor dietary habits and physical inactivity have been clearly identified as contributors to this growing health problem. Adolescents who are obese are at greater risk of being obese as adults and of developing serious health problems, including type 2 diabetes and heart disease, and have an increased risk of mortality. According to the National Diabetes Education Program, some clinics are now reporting that one-third to one-half of all new cases of childhood diabetes are type 2 and that the overall number of new cases is increasing.
"If a parent is concerned that their child may be overweight, it's important to talk with their physician," said Dr. Jacobson. "Combining diet, exercise and changes in lifestyle habits with medication can help seriously overweight adolescents manage their weight and reduce their risk of serious health problems."
Clinical studies results
The safety and efficacy of Xenical in obese adolescents was assessed in a randomized, 54 week double-blind, placebo-controlled study that involved 539 patients aged 12 to 16 (120 mg of Xenical or matching placebo was administered three times a day with meals. This dose is consistent with the currently approved dose of Xenical for adults). Of this group, 357 were treated with Xenical and a reduced-calorie diet containing no more than 30% of calories from fat compared with 182 patients treated with placebo and diet. The average age of participants was 13 and-a-half years with an average weight of approximately 210 lbs., putting them in the 99th percentile for their age. Body mass index (BMI) was the primary efficacy parameter because it takes into account changes in height and body weight, which occur in growing children.
Study results showed that at the end of treatment:
- Patients treated with Xenical plus diet had a significantly reduced BMI compared with patients receivingplacebo plus diet.
- A greater than or equal to 5% reduction in BMI was achieved in 27% of patients receiving Xenical plus diet compared with 16% of patients receiving placebo plus diet.
- Tolerability was good and reported adverse events were generally similar to those seen in adults treated with Xenical such as fatty/oily stool, oily spotting and oily evacuation consistent with the drug's mechanism of action.
- The reduction in BMI was associated with greater loss of body fat in the Xenical plus diet-treated patients compared with the placebo plus diet patients (5.5 lbs. vs. 1.3 lbs.), while both groups experienced a similar increase in fat free mass and bone mineral content (as expected with normal growth).
A second study showed that the balance of calcium, magnesium, phosphorus, zinc or copper was not decreased and was similar in those receiving Xenical compared with those receiving placebo. The iron balance was decreased in both the Xenical treated patients and the placebo patients.
Xenical works locally in the gut to prevent dietary fat absorption by around 30%, to effectively promote weight loss. It is an effective therapy that not only helps patients lose weight, but also helps them maintain their weight loss. Xenical is well tolerated and unlike appetite suppressants which act on the central nervous system. Since it was first marketed in 1998, there have been more than 16.7 million patient treatments with Xenical worldwide. Xenical is approved for weight management in over 140 countries around the world.
The long-term effects of Xenical on morbidity and mortality associated with obesity have not been established. Because Xenical prevents about one-third of the fat in the food consumed from being absorbed, patients may experience gas with oily discharge, increased bowel movements, an urgent need to have them and an inability to control them, particularly after meals containing more fat than recommended. Xenical should not be taken if patients are pregnant, nursing, have food absorption problems or reduced bile flow. If taking cyclosporine, patients should speak to their doctors before taking Xenical. Xenical reduces the absorption of some vitamins. Therefore, a daily multivitamin is strongly recommended. For more information about Xenical visit the web site at www.xenical.com
Source: Roche www.rocheusa.com
Gleevec converted to regular approval as second line treatment for refractory CML
ROCKVILLE, MD., December 8, 2003 -- The FDA has granted Gleevec regular approval as a second line treatment for refractory chronic myeloid leukemia (CML), a rare life threatening form of cancer affecting about 40,000 people in the United States.
Regular approval means that the FDA has determined that Gleevec has demonstrated a long-term clinical benefit for refractory CML patients. When Gleevec was originally approved under the accelerated approval program in May of 2001, available evidence indicated that a long-term clinical benefit was highly likely but further studies were necessary to confirm it.
"Our experience with Gleevec demonstrates the value of making promising drugs available early to patients with life threatening diseases based upon valid surrogate endpoints, such as short term tumor response rate, that are reasonably likely to predict that the drug can improve their lives," said FDA Commissioner Mark B. McClellan. "Our experience also demonstrates the importance of follow-up studies after approval to confirm the drug provides a clinical benefit, just as the sponsor has done in this case."
The accelerated approval program helps make products for serious or life-threatening diseases available earlier in the development process by allowing approval to be based on a promising effect of the drug that can be observed in significantly sooner than a long-term clinical benefit. For Gleevec, these promising effects included a normalization of blood cell counts and a reduction in the percent of abnormal chromosomes in bone marrow white blood cells.
As part of the original approval, the sponsor, Novartis Pharmaceuticals, was required to continue to follow patients in the initial studies to confirm long-term benefit for this particular indication. Data presented to FDA showed that 95% of patients achieved normal blood cell counts. Further, favorable treatment responses were sustained. An estimated 88% of patients who achieved a reduction in the percent of abnormal chromosomes in bone marrow white blood cells maintained that response for at least two years. After two years of treatment, an estimated 85% of patients were free of disease worsening. The estimated overall survival was 91%. As a result of this additional data, FDA was presented with enough information to convert Gleevec, in this particular treatment setting, to regular approval.
Since May 2001, Gleevec has been approved for use in the first line treatment CML, for use in pediatric leukemia, and for a Gastrointestinal Stromal Cancer (GIST), a rare form of stomach/intestinal cancer.
The drug is manufactured by Novartis Pharma AG for Novartis Pharmaceuticals Corporation, East Hanover, N.J.
FDA approves Risperdal for treatment of bipolar mania
TITUSVILLE, N.J., December 5, 2003 -- The FDA has approved
Risperdal (risperidone) as monotherapy (alone) or in combination
with lithium or valproate for the short-term treatment of acute
manic or mixed episodes associated with bipolar I disorder, also
known as bipolar mania. In research studies, patients with bipolar
mania who took Risperdal showed significant improvement in manic
symptoms compared to placebo.
Bipolar disorder affects more than 2 million people in the United States and is characterized by dramatic mood swings, alternating between the highs of mania and the lows of depression. In mixed episodes, people with bipolar disorder experience symptoms of both mania and depression. Mania, a state of excessive excitement and hyperactivity, can lead to delusional thinking and dangerous risk-taking behavior. Nearly 40 percent of people with untreated bipolar illness abuse alcohol or drugs. Job loss, divorce and even suicide are not uncommon consequences of the illness.
"Bipolar mania is a serious, life-long illness with many hazardous consequences. We are desperately in need of new treatment options," said Robert Hirschfeld, M.D., chair of the department of psychiatry at the University of Texas Medical Branch in Galveston, TX. "Because Risperdal is effective and generally well tolerated, it offers an attractive choice for patients and physicians."
Clinical trial findings
The effectiveness of Risperdal in treating acute manic or mixed episodes of bipolar disorder was established in three studies -- two that analyzed the medication as monotherapy and one in which Risperdal was used in combination with lithium or valproate. In all studies, patients who received Risperdal, given in doses of 1 mg to 6 mg per day, experienced significantly greater symptom improvements than those in the control groups.
In all studies, efficacy was measured using the Young Mania Rating Scale (YMRS), which clinicians use to assess the degree of a patient's manic symptoms (such as irritability, disruptive/aggressive behavior, elevated mood, increased activity, language/thought disorder and other measures) from 0 (no manic features) to 60 (maximum score). The primary outcome in these studies was change from baseline in the YMRS total score. Clinical response also was defined as a 50 percent or greater reduction in the total YMRS score from baseline to endpoint.
Summary of study results
- In one, three-week, placebo-controlled study of 246 adult patients diagnosed with bipolar I disorder, who were in an acute manic episode, with or without psychotic symptoms, Risperdal was superior to placebo in reducing the YMRS total score. Participants taking Risperdal, on average, experienced an 11 point reduction on the YMRS compared to a five point reduction among placebo patients. Forty-three percent of the patients treated with Risperdal versus 24 percent of the patients given placebo had at least a 50 percent reduction in total manic symptom scores.
- The second, similarly designed, monotherapy trial studied 286 bipolar I patients with manic or mixed episodes. Again, Risperdal monotherapy was superior to placebo. On average, Risperdal patients had a total reduction of 22.7 points on the YMRS, versus a 10.5 point reduction in the placebo patients. At endpoint, 73 percent of patients receiving Risperdal compared to 36 percent of patients given placebo achieved clinical response.
- The combination therapy study was a three-week, placebo-controlled trial in 148 adults diagnosed with bipolar I disorder experiencing a manic or mixed episode, with or without psychotic features, and with or without rapid cycling between moods. At the conclusion of the study, participants taking Risperdal had experienced, on average, a 14.3 total YMRS point reduction versus an 8.2 point reduction among placebo patients. Fifty-seven percent of patients treated with Risperdal versus 38 percent of patients who received placebo had at least a 50 percent improvement in manic symptoms.
In these studies, all doses of Risperdal were generally well tolerated, with the percentage of patients who discontinued the study due to side effects comparable to the dropout rate among those who received placebo. In one of the monotherapy studies, 3.9 percent of patients experienced a 7 percent or greater increase in body weight. In the other monotherapy trial, 2.8 percent of patients had a weight increase of 7 percent or greater. In the combination therapy study, 10.5 percent of patients had a weight increase of 7 percent or greater.
The most common side effects experienced in the Risperdal monotherapy studies included extrapyramidal symptoms (reversible movement disorders or muscle disturbances such as restlessness, tremors and muscle stiffness), sleepiness, dyspepsia, nausea, abnormal vision and increased saliva. In the combination therapy study, the most common side effects included sleepiness, dizziness, Parkinsonism (abnormal muscle movements), increased saliva, akathisia (restlessness), abdominal pain and urinary incontinence.
Drug interactions with some anticonvulsants and Risperdal have been noted. Co-administration of carbamazepine and Risperdal led to a 50 percent reduction in plasma concentrations of Risperdal. Risperdal had no effect on the average plasma concentration of valproate, however a 20 percent increase in peak plasma concentrations was seen. In addition, Risperdal had no affect on the plasma concentrations of lithium.
When in a manic state, a person's behavior becomes unpredictable and his or her judgment is impaired. People often make reckless decisions during periods of mania, and they become oblivious to the negative consequences of their extreme actions. Spending sprees, alcohol and drug abuse, and hypersexuality are common. In patients with mixed mania, both symptoms of mania and depression occur within the same episode. For example, a person experiencing a mixed episode may have a very sad, hopeless mood while at the same time feel extremely energized.
Nearly 80 percent of those suffering from bipolar disorder are either misdiagnosed or undiagnosed altogether. One reason for misdiagnosis is that the symptoms of the disease are common to other conditions, such as depression and substance abuse. In some cases, patients don't seek treatment because the feelings associated with acute mania can be exhilarating. Often they deny that they have any sort of problem or illness. Once patients are diagnosed, there are a variety of treatments available that can help manage the symptoms of bipolar disorder.
Risperdal was discovered and developed at the Janssen Research Foundation, now part of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD). Researchers at J&JPRD led the development of Risperdal as a treatment for acute manic or mixed episodes associated with bipolar I disorder.
Risperdal has been marketed in tablet form in the United States by Janssen Pharmaceutica Products, L.P., since 1994, and also is available in oral solution and quick dissolving tablet forms. Approved for marketing in more than 100 countries, Risperdal is the most widely prescribed atypical antipsychotic in the world. In a study published in the January 2002 issue of The New England Journal of Medicine, Risperdal was found to be significantly more effective in reducing the risk of relapse in patients with schizophrenia than haloperidol, a conventional antipsychotic.
Risperdal is available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg doses. Risperdal currently is available as a standard, oral tablet; a quick-dissolving tablet (Risperdal (R) M-Tab) in 0.5 mg, 1 mg, and 2 mg doses; and an oral solution in a 1.0 mg/mL dose. Risperdal M-Tab contains phenylalanine. Risperdal is indicated for the treatment of acute manic or mixed episodes associated with bipolar I disorder and schizophrenia. In clinical trials, Risperdal was generally well tolerated. However, as with all other psychotropic medications, Risperdal was associated with adverse events. For more information, refer to the full prescribing information for Risperdal or visit or . http://www.risperdal.com/ http://www.janssen.com
Source: Janssen Pharmaceutica Products www.janssen.com
FDA approves Serono's Zorbtive for use in patients with short bowel syndrome
ROCKLAND, MASS., December 2, 2003 -- Serono, Inc., the US affiliate of Serono S.A., announced that the FDA has approved Zorbtive 1 [somatropin (rDNA origin) for injection] for use in the treatment of short bowel syndrome (SBS).
James Sapirstein, Executive Vice President, Metabolic Endocrinology, Serono, Inc. said, "There has been a substantial clinical need for additional effective treatment options for patients with this rare condition. We are pleased that continued discussions with the FDA following an Advisory Committee meeting in June have resulted in our being able to bring this product to patients."
SBS is a rare, serious and potentially life-threatening condition that follows extensive surgical removal of portions of the small intestine as a treatment for acute or chronic disorders of the intestine. Removal of a large portion of the bowel results in impaired absorption of nutrients. Currently the standard treatment for SBS involves careful management of dietary intake and hydration, or where appropriate, a process referred to as parenteral nutrition in which patients are fed through an intravenous tube. On rare occasions, surgical transplant of the intestine may also be performed for this condition. There are an estimated 10,000-20,000 patients in the United States who are receiving intravenous parenteral nutrition for SBS.
In a randomized double-blind, controlled, parallel group Phase III clinical study, Serono's recombinant human growth hormone administered with specialized nutritional support was shown to significantly reduce patient dependence on total parenteral nutrition as measured by total volume, total calories and frequency of infusion. Serono's recombinant human growth hormone was granted an orphan drug designation for use in the treatment of patients with short bowel syndrome by the FDA Office of Orphan Products Development.
Additional product information
The most common adverse events associated with growth hormone therapy are mild to moderate muscle and joint pain and swelling/edema, which occur in a dose-related manner and often subside with continued treatment or dose reduction. Cases of new onset impaired glucose intolerance, new onset type 2 diabetes mellitus and exacerbation of preexisting diabetes mellitus have been reported. Some patients develop diabetic ketacidosis and diabetic coma. In some patients, therapy with growth hormone necessitates initiation or adjustment of anti-diabetic treatment. Patients with a history of hyperglycemia or other risk factors for glucose intolerance should be monitored closely. Transient increases in glucose levels occur early in treatment and should be monitored.
Use of growth hormone is contraindicated in treatment of patients in intensive care units due to complications following open-heart surgery or abdominal surgery, multiple accidental trauma or acute respiratory failure; patients with active neoplasia; and patients with known hypersensitivity to growth hormone.
(1) Zorbtive(tm) [somatropin (rDNA origin) for injection] is a
name for Serono's recombinant human growth hormone.
(2) Package inserts for Serono's US marketed products are
or by calling 1-888-275-7376.
Source: Serono U.S.A. www.seronousa.com
SAB-Pharma launches Regonol "shortage product" for reversing the effects of muscle relaxants
LAKE FOREST, ILL., December 4, 2003 -- SAB-Pharma announced the availability of Regonol (pyridostigmine injection), a reversal agent to the neuromuscular blocking effects of muscle relaxants, also classified as an antimyasthenic.
Antimyasthenics are used in the treatment of the chronic
autoimmune condition known as myasthenia gravis, and are considered
a shortage product in the United States. The announcement serves as
a symbol of SAB- Pharma's long-term commitment to market niche
products reflecting a small market demand yet filling an important
"SAB-Pharma is committed to growth through internal pipeline and product acquisitions and collaboration with pharmaceutical leaders to deliver products that are difficult to manufacture or to source," said George Zorich, President, SAB-Pharma. "Regonol demonstrates our focus on bringing high- quality, greatly needed products to the hospital community, pharmacists and physicians."
Regonol is indicated as a reversal agent or antagonist to the neuromuscular blocking effects of nondepolarizing muscle relaxants. Myasthenia gravis causes antibodies to attack and destroy the receptors needed for muscle contraction resulting in muscles that tire and weaken easily. The disease initially affects eye and eyelid movement, but can progress to other muscle groups eventually making chewing, swallowing and breathing difficult with the potential to become life-threatening.
"Pyridostigmine injection has not been available for over a year," said Erin Fox, Pharm.D., Drug Information Specialist, University of Utah Hospitals and Clinics, Drug Shortage Group. "The availability of this drug fills an important and unmet patient need."
Symbicort study sets new standards for treatment of COPD
LUND, SWEDEN, 1 December, 2003 -- A new clinical study shows that Symbicort reduces exacerbations requiring medical intervention*, and significantly improves Health Related Quality of Life and lung function compared to placebo, long-acting beta-2 agonist alone and inhaled corticosteroid alone.(1) Symbicort is the first therapy to demonstrate such clear benefits in the pharmaceutical treatment of COPD.(1)
Professor Peter Calverley, University Hospital Aintree, Liverpool, UK said: This study shows that Symbicort is a valuable treatment for COPD. Health care professionals should be encouraged to use Symbicort to help improve the quality of life of their COPD patients.'
The effect of Symbicort on quality of life was evaluated using the St. George's Respiratory Questionnaire (SGRQ) where a reduction in score of four is considered a clinically relevant improvement, noticeable by the patient. The results showed that over one year, Symbicort showed a sustained reduction of the SGRQ score (an improvement) by 7.5 compared to placebo. This was a superior improvement to that seen with formoterol alone (reduction of 4.1 vs. placebo) and budesonide alone (reduction of 3.0 vs. placebo).
Professor Paul Jones, St George's Hospital Medical School, London, UK said: "COPD is a distressing and disabling disease, and treatments to reduce the burden of the disease and provide clinically meaningful benefits for patients are extremely important. Symbicort has been seen to reduce the restrictive effect of symptoms on patient's daily lives and activities, improving their quality of life which makes a real difference to patients with COPD."
The randomised, double-blind clinical study investigated 1022 patients with severe COPD (according to GOLD guidelines2) with FEV1 <50% predicted and a history of exacerbations. Following optimisation with the oral steroid prednisolone (30µg once daily) and inhaled formoterol (9µg twice daily) for two weeks, patients were randomised to receive Symbicort (budesonide/formoterol 160/4.5µg, 2 inhalations twice daily), budesonide alone (200µg, 2 inhalations twice daily), formoterol alone (4.5µg, 2 inhalations twice daily), or placebo for one year. All patients were also allowed to take terbutaline as needed as reliever medication.(1)
The results demonstrated that Symbicort extends the time to first severe exacerbation by 158 days more than placebo alone, 100 days more than formoterol alone, and 76 days more than budesonide alone.(1) Symbicort reduced the risk of a severe exacerbation by 22.7%, 29.5% and 28.5% versus budesonide, formoterol and placebo respectively.(1) Also, Symbicort was significantly better than either monocomponent or placebo in maintaining patients' lung function improvement after optimisation, with the effect sustained throughout the treatment year.(1)
"Exacerbations are particularly distressing for patients with severe COPD, and greatly impact their lives both physically and psychologically," said Professor Peter Calverley, University Hospital Aintree, Liverpool, UK. He continues: "Reducing exacerbations improves patients' quality of life, and should be a key goal of the management of COPD. This study shows that Symbicort significantly reduces the risk of an exacerbation, and helps to give patients the ability to return to everyday activities.
Symbicort, which contains the inhaled corticosteroid budesonide and the long-acting bronchodilator formoterol in a single inhaler, was the first inhaled steroid/long-acting bronchodilator to be approved in the EU for the treatment of patients with severe COPD and a history of repeat exacerbations.
COPD is a progressive disease characterised by airflow limitation that is not fully reversible, decline in lung function and worsening symptoms such as dyspnoea, cough and sputum hypersecretion.(2)
* worsening of the disease requiring hospitalisation and/or the use of oral corticosteroids and/or antibiotics
1. Calverley PM, Boonsawat Z, Zhong N, Peterson S and Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Resp J 2003; 22;912-919.
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD NHLBI/WHO Workshop Report (updated version for 2003). http://www.goldcopd.com
Posted: December 2003