Capsule archive end-Jan 04

Tentative approval for Barr's Metformin XR withdrawn by FDA

WOODCLIFF LAKE, N.J., January 9, 2004 -- Barr Laboratories has received notification from the FDA that tentative approval for its generic version of Bristol-Myers Squibb's Glucophage XR (metformin hydrochloride extended-release tablets) 500 mg Tablet has been withdrawn. The FDA's letter stated the withdrawal is based solely on concerns regarding the raw material supplied to Barr by a third party and used to manufacture the company's submission batch.

Barr says it is committed to obtaining approval of this product and is evaluating its options, including the use of a new raw material supplier. The company stated that it had planned to launch its generic product by the June 30, 2004. Tentative approval was granted on October 31, 2003.

Metformin Hydrochloride extended-release tablets, as a monotherapy, are indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes.

Source: Barr Pharmaceuticals www.barrlabs.com

Barr receives tentative approval for Modafinil Tablets 100 mg and 200 mg

WOODCLIFF LAKE, N.J., January 8, 2004 -- Barr Laboratories has received tentative approval from the FDA for its generic version of Cephalon's Provigil Tablets (modafinil tablets), 100 mg and 200 mg. The company is currently litigating whether its products infringe a patent held by Cephalon. A trial in the U.S. District Court of New Jersey is scheduled for January 2005.

Barr's tentatively approved Modafinil Tablets is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy.

Barr filed an Abbreviated New Drug Application (ANDA) for Modafinil Tablets, 100 mg and 200 mg, with the FDA on December 24, 2002, and received notification of the application's acceptance for filing in early February 2003. Following receipt of notice from FDA, Barr notified Cephalon on February 20, 2003 of Barr's challenge to the two patents that Cephalon had listed in the Orange Book in connection with Provigil. On March 28, 2003, Cephalon filed suit against four generic pharmaceutical companies, including Barr, for alleged infringement of one of two listed Cephalon patents in U.S. District Court for the District of New Jersey.

A tentative approval reflects FDA's preliminary determination that a generic product satisfies the substantive requirements for approval, subject to the expiration of all statutorily imposed non-approval periods. Such approval does not allow the applicant to market the generic drug product.

Source: Barr Pharmaceuticals www.barrlabs.com

FDA gives tentative approval for generic Ortho Tri-Cyclen oral contraceptive

FORT LAUDERDALE, FLA., January 8, 2004 -- Andrx Corporation announced that the FDA has tentatively approved its Abbreviated New Drug Application (ANDA) for Ortho Tri-Cyclen (norgestimate/ethinyl estradiol) tablets, an Ortho-McNeil oral contraceptive product. The Andrx ANDA is for 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, and 0.25 mg/0.035 mg strengths, packaged in 28-day cycle regimens.

According to the FDA's letter, pediatric exclusivity was granted for this product, thereby extending the effective expiration date of the patents pertaining to this product until March 26, 2004.

The Company has received inquiries regarding the January 7, 2004 update of new drug approvals issued by CDER (Center for Drug Evaluation and Research), which included Andrx's Norgestimate and Ethinyl Estradiol Tablets, without additional details. Andrx has advised FDA of the confusion resulting from this update, and the FDA has indicated that a correction has been or soon will be made.

As previously announced, Andrx has entered into a strategic collaboration with Teva Pharmaceutical Industries Ltd., whereby Teva has received exclusive marketing rights in the U.S. and Canada to Andrx's entire line of generic oral contraceptive products currently pending approval at the FDA, including Andrx's ANDA for Ortho Tri-Cyclen tablets.

Source: Andrx Corporation

FDA approves Pegasys Pre-filled Syringes for treatment of hepatitis C

NUTLEY, N.J., January 8, 2004 -- Roche announced that the FDA has approved pre-filled syringes of Pegasys (peginterferon alfa-2a) for the treatment of chronic hepatitis C.

Pegasys, a pegylated alpha interferon, and Copegus (ribavirin, USP) were approved by the FDA in December 2002, for use in combination for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not previously been treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis.

Pegasys is the most prescribed interferon therapy in the United States for the treatment of chronic hepatitis C. Roche expects Pegasys pre-filled syringes to be available in pharmacies by the end of the month. The syringes will be packaged four per box. Pegasys is currently available in vials as a pre-mixed solution.

"Taking a medication by self-injection can be challenging for some people," said Dr. David Bernstein, Director of Hepatology, North Shore University Hospital. "Reducing the number of steps involved can make the process less intimidating for patients and reduce the risk of errors."

Roche says that the introduction of pre-filled syringes is a further step in its program to improve management of hepatitis C. Other measures include:

  • developing approaches to reduce the duration of treatment with Pegasys and Copegus and the dose of Copegus therapy for certain patients
  • introducing Copegus with a list price or wholesale acquisition cost that is 43 percent less per milligram than the other available brand of ribavirin
  • backing Pegasys with the most extensive development program ever undertaken in hepatitis C
  • formulating Pegasys as a pre-mixed solution requiring no reconstitution prior to self-injection.

Pegasys is dosed at 180mcg as a subcutaneous injection taken once a week. Copegus is available as a 200mg tablet, and is administered orally two times a day as a split dose.

Adverse events

  • Alpha interferons, including Pegasys, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping Pegasys therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE EVENTS in complete product information).
  • Use with Ribavirin. Ribavirin, including Copegus may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease. Ribavirin is genotoxic, mutagenic, and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE EVENTS in complete product information).
  • Pegasys is contraindicated in patients with hypersensitivity to Pegasys or any of its components, autoimmune hepatitis, and decompensated hepatic disease (Child-Pugh class B and C) before or during treatment with Pegasys. Pegasys is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. Pegasys and Copegus therapy is additionally contraindicated in patients with a hypersensitivity to Copegus or any of its components, women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
  • COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of
    effective contraception during treatment and during the six months after treatment has concluded. Routine monthly pregnancy test must be performed during this time. If pregnancy should occur during treatment or during six months post-therapy, the patient must be advised of the significant teratogenic risk of Copegus therapy to the fetus. Physicians and patients are strongly encouraged to report any pregnancies that do occur to Roche by calling 1-800-526-6367.
  • The most common adverse events reported for Pegasys and Copegus combination therapy, observed in clinical trials (n=451), were fatigue/asthenia (65%), headache (43%), pyrexia (41%), myalgia (40%), irritability/anxiety/nervousness (33%), insomnia (30%), alopecia (28%), neutropenia (27%), nausea/vomiting (25%), rigors (25%), anorexia (24%), injection site reaction (23%), arthralgia (22%), depression (20%), pruritus (19%) and dermatitis (16%).
  • Serious adverse events include neuropsychiatric disorders (suicidal ideation and suicide attempt), serious and severe bacterial infections, bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including psoriasis and lupus), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemiccolitis), pancreatitis, and opthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).

The complete package inserts for Pegasys and Copegus are available at www.pegasys.com, or by calling 1-877-PEGASYS.

Source: Roche www.rocheusa.com, www.pegasys.com

Barr receives tentative approval for Topiramate Tablets 25 mg, 100 mg and 200 mg

WOODCLIFF LAKE, N.J., January 6, 2004 -- Barr Laboratories has received tentative approval from the FDA for its generic version of Ortho-McNeil's Topamax Tablets (Topiramate Tablets), 25 mg, 100 mg and 200 mg.

The company anticipates receiving final approval and launching its generic product following the expiration of Ortho-McNeil's patent on September 26, 2004, or at a later date, as Ortho-McNeil is currently seeking a patent term adjustment of up to 5 years that would, if granted, expire on September 26, 2008.

Barr's tentatively approved Topiramate Tablets are indicated as adjunctive therapy for adults and pediatric patients ages 2-16 years with partial onset seizures, or primary generalized tonic-clonic seizures. Ortho-McNeil has been granted Orphan Drug Exclusivity through August 28, 2008 for Topiramate's indication in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.

Barr filed its Abbreviated New Drug Application (ANDA) containing a Paragraph III certification for Topiramate Tablets, 25 mg, 100 mg and 200 mg, with the FDA in December 2001 and received notice of the application's acceptance for filing in December 2001. The patent currently covering Topamax Tablets was due to expire on September 26, 2003. On February 24, 1997, Ortho-McNeil filed for an application for patent term adjustment seeking up to 5 years of extension under Hatch-Waxman Act. On March 11, 2003, Ortho-McNeil was granted an interim 1-year patent term extension that extended the patent covering Topamax Tablets to September 26, 2004. If Ortho-McNeil's original application for adjustment is granted, the patent term could be extended until September 26, 2008.

A tentative approval reflects FDA's preliminary determination that a generic product satisfies the substantive requirements for approval, subject to the expiration of all statutorily imposed non-approval periods. A tentative approval does not allow the applicant to market the generic drug product.

Source: Barr Pharmaceuticals www.barrlabs.com

FDA approves Invirase boosted with ritonavir for use in treatment of HIV/AIDS

NUTLEY, N.J., January 6, 2004 -- Roche announced FDA approval of its protease inhibitor Invirase (saquinavir mesylate 1000 mg) for use with ritonavir (100 mg) in combination regimens for the treatment of HIV infection. This new dosing strategy increases ("boosts") blood levels of saquinavir to enable twice-daily dosing and eliminates the inadequate drug levels associated with use of Invirase alone.

FDA approval of Roche's supplemental New Drug Application (sNDA) for Invirase was based on data which showed that Invirase 1000 mg with ritonavir 100 mg twice-daily provides similar to or greater levels of saquinavir over a 24-hour period than those achieved with another formulation of saquinavir, Fortovase, 1200 mg three times per day.

Fortovase with ritonavir was studied in a heterogeneous population of 148 HIV-infected patients. Results showed that 91 of 148 subjects (61 percent) achieved and/or sustained an undetectable HIV RNA levels (<400 copies>

"Invirase with ritonavir is an attractive option for the treatment of HIV because it is designed to provide consistently therapeutic levels of saquinavir with twice-daily dosing," said Dr. Frank Palella, Assistant Professor of Medicine, Feinberg School of Medicine, Northwestern University, Chicago. "With saquinavir, physicians and patients have the benefit of eight years of clinical experience on which to base treatment decisions. Today's news confirms that only low, 100 mg doses of ritonavir are needed to achieve effective levels of saquinavir when given with 1000 mg Invirase."

Invirase capsules do not require refrigeration and are smaller in size than Fortovase capsules. Roche is developing a 500 mg formulation of Invirase, designed to be used in the new boosted dosing regimen, that will cut daily pill count in half. A filing for the 500 mg formulation is projected for submission to the FDA for review in 2004.

Important note

It is important to note that Invirase and Fortovase are not bioequivalent and cannot be used interchangeably. Invirase may be used only if it is to be combined with ritonavir, which significantly inhibits saquinavir's metabolism and provides plasma saquinavir levels at least equal to those achieved with Fortovase. Fortovase is the recommended formulation when using saquinavir as the sole protease inhibitor in an antiviral regimen.

"The approval of Invirase for boosted dosing is another important step in Roche's ongoing efforts to define the optimal use of saquinavir, which was developed from our company's laboratories as the first protease inhibitor for HIV," said Kathy Presto, Vice President, U.S. HIV Franchise, Roche. "We have invested significantly in clinical trials and will continue our commitment through development of the Invirase 500 mg tablet formulation."

Dosing of boosted Invirase

The FDA approved dosing for boosted Invirase is 1000 mg of Invirase (5 x 200 mg capsules) in combination with ritonavir 100 mg, twice a day. Ritonavir should be taken at the same time as Invirase. Invirase and ritonavir should be taken within 2 hours after a meal.

Indication and Safety Information

Invirase capsules (saquinavir mesylate) in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV infection (1000 mg saquinavir mesylate with 100 mg ritonavir). The twice daily administration of Invirase in combination with ritonavir is supported by safety data from the MaxCmin 1 study and pharmacokinetic data. The efficacy of Invirase with ritonavir or Fortovase (with or without ritonavir coadministration) has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.

Invirase capsules and Fortovase soft gelatin capsules are not bioequivalent and cannot be used interchangeably. Invirase may be used only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with Fortovase. When using saquinavir as the sole protease inhibitor in an antiviral regimen, Fortovase is the recommended formulation.

Invirase should not be administered concurrently with terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam, ergot derivatives, rifampin or antiarrhymic medications, which include amiodarone, bepridil, flecainide, propafenone, and quinidine. Inhibition of CYP3A4 by saquinavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation.

Concomitant use of Invirase with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including Invirase, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (eg, atorvastatin). Concomitant use of Invirase and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Garlic capsules should not be used while taking saquinavir as the sole protease inhibitor due to the risk of decreased saquinavir plasma concentrations. No data are available for the coadministration of Invirase/ritonavir and garlic capsules.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV- infected patients receiving protease- inhibitor therapy.

The recommended dose of Invirase and ritonavir is 1000 mg Invirase plus 100 mg ritonavir twice-daily. Coadministration of saquinavir and ritonavir has led to severe adverse events, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-existing liver disease. Invirase when administered with ritonavir is contraindicated in patients with severe hepatic impairment. Caution should be exercised when Invirase in combination with ritonavir is used by patients with hepatic impairment. Patients with severe renal impairment have not been studied and caution should be exercised when prescribing Invirase in combination with ritonavir. There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.

Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Cholesterol and triglyceride levels should be monitored prior to initiating combination dosing regimen of Fortovase or Invirase with ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.

Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy. A causal relationship between protease- inhibitor therapy and these events has not been established and the long-term consequences are currently unknown.

The following grade 2 to grade 4 adverse events, (considered at least possibly related to study drug or of unknown relationship) occurred in greater than or equal to 2% of patients receiving Invirase 600 mg tid alone or in combination with zidovudine and/or HIVID: abdominal discomfort, abdominal pain, appetite disturbances, asthenia, buccal mucosa ulceration, diarrhea, dizziness, dyspepsia, extremity numbness, headache, mucosa damage, musculoskeletal pain, myalgia, nausea, paresthesia, peripheral neuropathy, pruritus, and rash.

The following grade 2 to grade 4 adverse events (all causality) occurred in greater than or equal to 2% of patients receiving Fortovase with ritonavir (1000/100 mg twice daily): abdominal pain, back pain, bronchitis, constipation, diabetes mellitus/hyperglycemia, diarrhea, dry lips/skin, eczema, fatigue, fever, influenza, lipodystrophy, nausea, pneumonia, pruritis, rash, sinusitis, and vomiting.

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of Invirase therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

Invirase is not a cure for HIV infection or AIDS. Invirase does not prevent the transmission of HIV. Ritonavir is manufactured by Abbott Laboratories.

Source: Roche www.rocheusa.com

FDA approves Dibenzyline Capsules for hypertension associated with pheochromocytoma

NEWTOWN, PA., January 6, 2003 -- Dibenzyline (phenoxybenzamine HCl) Capsules, a product of Wellspring Pharmaceutical Corporation, was approved by the FDA on December 30, 2003. Dibenzyline is an antagonist of alpha-adrenergic receptors, particularly those in smooth muscle and endocrine glands.

After oral administration, a "chemical sympathectomy" can be achieved. Dibenzyline is useful in the treatment of the severe hypertension associated with pheochromocytoma, a tumor of the adrenal gland. This condition, if not treated promptly and vigorously can lead to stroke, myocardial infarction, and death. Dibenzyline is the drug of choice for pheochromocytoma, and is administered before, during and after surgical removal of the tumor. Dibenzyline binds irreversibly to the alpha-receptor and has a long duration of activity. Because of its unique pharmacology, it is one of only two drugs approved in the management of severe hypertension or pheochromocytoma.

Pheochromocytoma

Pheochromocytoma occurs in approximately 0.1 % of the hypertensive population (20 to 25 million hypertensives exist in the US) but is, nevertheless, an important correctable cause of high blood pressure. Indeed, it is usually curable if properly diagnosed and treated, but it may be fatal if undiagnosed or mistreated. Postmortem studies indicate that most pheochromocytomas are unsuspected clinically-- even when the tumor is related to the fatal outcome.

Pheochromocytoma occurs at all ages, but is most common in young to mid-adult life. Some studies show a slight female predisposition. Most patients come to medical attention as a result of hypertensive crisis, paroxysmal symptoms suggestive of seizure disorder or anxiety attacks, or hypertension that responds poorly to conventional treatment. Less commonly, unexplained hypotension or shock associated with surgery or trauma will suggest the diagnosis. Most patients have hypertension in association with headaches, excessive sweating, and/or palpitations.

Hypertension is the most common manifestation. In approximately 60 percent of cases the hypertension is sustained, although significant blood pressure lability is usually present, and half of patients with sustained hypertension have distinct crises or paroxysms. The other 40 percent have blood pressure elevations only during an attack.

The hypertension is often severe, occasionally malignant, and may be resistant to treatment with standard antihypertensive drugs. The paroxysm or crisis occurs in over half of all patients. In an individual patient, the symptoms are often similar with each attack. The paroxysms may be frequent or sporadic, occurring at intervals as long as weeks or months. With time, the paroxysms usually increase in frequency, duration and severity.

The attack usually has a sudden onset. It may last from a few minutes to several hours or longer. Headache, profuse sweating, palpitations, and apprehension, often with a sense of impending doom, are common. Pain in the chest or abdomen may be associated with nausea and vomiting. Either pallor or flushing may occur during the attack. The blood pressure is elevated and is usually accompanied by tachycardia.

The successful surgical outcome of pheochromocytoma depends on the induction of stable preoperative alpha-adrenergic blockade. The drug of choice used for this purpose is Dibenzyline, as recommended by most medical authorities to induce a long-lived, noncompetitive alpha-receptor blockade (Harrison's Principle of Internal Medicine, McGraw Hill,1998; Cecil Textbook of Medicine, W.B. Saunders Company, 1996; Conn's Current Therapy, W.B. Saunders Company, 1999; et al.).

While other alpha-blocking agents are available commercially, all are competitive inhibitors of the alpha-adrenergic receptor, and have limited use in the treatment of pheochromocytoma. Dibenzyline is the only non-competitive, alpha-adrenergic blocker, and the preferred drug of treatment used to prepare patients for surgery.

Dibenzyline is marketed as 10-mg capsules in bottles of 100 capsules. There is no generic equivalent. The FDA approved the drug in 1953. Dibenzyline was one of the first alpha-adrenergic blockers to be approved in the United States. Other drugs in that same class followed years later. These drugs include prazosin (Minipress), terazosin (Hytrin), doxazosin (Cardura), and tamsulosin (Flomax).

The class of drugs has very interesting properties, and has been approved in the management of hypertension, Benign Prostatic Hypertrophy (BPH), and urinary incontinence.

Source: FDA

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.

Source: AstraZeneca

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Posted: August 2004


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