==============================================================
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES 
============================================================== 
1.)Life-Threatening Interaction of Mibefradil and -Blockers With Dihydropyridine Calcium Channel Blockers 
2.) ROCHE LABORATORIES ANNOUNCES WITHDRAWAL OF POSICOR FROM THE MARKET
3.) BAYER VOLUNTARILY WITHDRAWS BAYCOL- (LIPOBAY)
4.) RE: Market withdrawal of Baycol (cerivastatin)
5.) FDA PUBLIC HEALTH ADVISORY THE SAFETY OF SPORANOX® CAPSULES AND LAMISIL® TABLETS FOR THE TREATMENT OF NYCHOMYCOSIS
6.) FDA Issues Health Advisory Regarding the Safety of Sporanox® Products and Lamisil® Tablets to Treat Fungal Nail Infections
7.) Sporanox and LamisilPublic Health Advisory Questions and Answers
8.) Hypothermia with Nimesulide 
9.) NIMESULIDE (PAEDIATRIC) / Application for an export licence refused
10.) Nimesulide-induced acute icteric hepatitis
11.) Fatal hepatotoxicity secondary to nimesulide
12.) Re: Nimesulide and reasons for non-approval or withdrawal 
13.) E-DRUG: Nimesulide
14.) Eleven Deaths Among UK Vioxx Users
15.) Celebrex (celecoxib capsules)
16.) WIDELY-USED ANTI-INFLAMMATORY ARTHRITIS DRUGS LINKED TO ADVERSE SIDE EFFECTS 
17.) Public Health Advisory, Food and Drug Administration, Trovan, 09 June 1999
18.) Questions and Answers on Trovafloxacin Public Health Advisory
19.) Trovan (alatrofloxacin mesylate), Pfizer notifies
20.) FDA ISSUES PUBLIC HEALTH ADVISORY ON LIVER TOXICITY ASSOCIATED WITH THE ANTIBIOTIC TROVAN
21.) New Safety Recommendations for Use of Cisapride (Propulsid)
22.)JANSSEN PHARMACEUTICA STOPS MARKETING CISAPRIDE IN THE US
23.)JANSSEN PHARMACEUTICA ANNOUNCES THE WITHDRAWAL OF HISMANAL FROM THE MARKET
============================================================== 
============================================================== 
1.)Life-Threatening Interaction of Mibefradil and -Blockers With Dihydropyridine Calcium Channel Blockers 
==============================================================
JAMA. 1998;280:157-158

Michael E. Mullins, MD; B. Zane Horowitz, MD; Dennis H. J. Linden, MD; Gregory W. Smith, RPh; Robert L. Norton, MD; Jack Stump, MD 


Mibefradil is a T-type and L-type calcium channel blocker (CCB) released in the United States in 1997 for management of hypertension and chronic stable angina. Postmarketing surveillance revealed a potential serious interaction between mibefradil and -blockers, digoxin, verapamil, and diltiazem, especially in elderly patients. The manufacturer voluntarily withdrew mibefradil on June 8, 1998. We describe 4 cases of cardiogenic shock in patients taking mibefradil and -blockers who began taking dihydropyridine CCBs. One case resulted in death; the other 3 survived episodes of cardiogenic shock with intensive support of heart rate and blood pressure. Physicians who are preparing to switch patients' medications from mibefradil to other antihypertensive agents should be aware of these potentially life-threatening drug-drug interactions.

JAMA. 1998;280:157-158

============================================================== 
Ç LABORATORIES ANNOUNCES WITHDRAWAL OF POSICOR FROM THE MARKET
==============================================================
Source: The FDA.

Roche Laboratories of Nutley, NJ has announced that it is voluntarily withdrawing the heart drug, Posicor (mibefradil), from the market as a result of new information about potentially harmful interactions with other drugs. 
In many cases, drug interactions can be addressed by appropriate labeling changes and public education, but due to the complexity of the prescribing information needed in this case, and seriousness of side effects, FDA and Roche agreed that it would be difficult to administer Posicor safely. The following may be used to respond to inquiries. 

Posicor is a calcium-channel blocker, chemically unlike the other approved products in this class. Posicor was approved in June of last year, to be used in the treatment of patients with hypertension and chronic stable angina. 

Posicor reduces the activity of certain liver enzymes that are important in helping the body eliminate many other drugs. Inhibiting these enzymes can cause some of these other drugs to accumulate in the body to dangerous levels. 

When Posicor entered the market in August of 1997, its enzyme-inhibiting properties were described in the labeling. The labeling specifically listed three drugs (astemizole, cisapride, and terfenadine) that could be expected to accumulate to dangerous levels if Posicor was coadministered. 

In December, after learning of several cases in which patients suffered serious adverse reactions after taking Posicor with one or more of the other drugs, FDA strengthened the labeling of Posicor, and two more drugs (lovastatin and simvastatin) were added to the label's list of those that should never be coadministered with Posicor. FDA also issued a public warning about this problem and the company issued a Dear Doctor letter to physicians. 

From spontaneous reports and ongoing trials, FDA and Roche have continued to learn of adverse reactions related to coadministration of Posicor with several other drugs. At present, more than 25 drugs are known to be potentially dangerous if used with Posicor -- a number and diversity of drugs that cannot be practically addressed by standard label warnings. 

Since Posicor has not been shown to offer special benefits (such as treating patients who do not respond to other antihypertensive and anti-anginal drugs), the drug's problems are viewed as an unreasonable risk to consumers. 

Patients now taking Posicor should not simply discontinue treatment because stopping medications can be risky. Instead, patients should promptly consult with their physicians about appropriate alternative therapy. In addition, patients now taking Posicor should not add any new medication to their current treatment without consulting their physicians. 

Roche Laboratories is providing information in a "Dear Doctor" letter to physicians, pharmacists, nurse practitioners, and other health care professionals. Questions about the withdrawal of Posicor can be addressed to Roche's 24-hour hotline at 1-800-205-4611. 


The following is a list of drugs that depend on the same liver enzyme as Posicor (mibefradil). Use of them in combination with Posicor could be dangerous. 

Generic name Trade Name 

amiodarone Cordarone 

astemizole Hismanal 

bepridil Vesture 

cisapride Propulsid 

cyclosporine Neoral, Sandimmune 

cyclophosphamide Cytoxan 

desipramine Norpramin 

erythromycin Erythrocin, Ilosone, others 

etoposide VePesid 

flecainide Tambocor 

flutamide Eulexin 

halofantrine Halfan 

ifosfamide Ifex 

imipramine Tofranil 

lovastatin Mevacor 

mexiletine Mexitil 

pimozide Orap 

propafenone Rythmol 

quinidine Cardioquin, Quinaglute, Quinidex, others 

simvastatin Zocor 

tacrolimus Prograf 

tamoxifen tamoxifen 

terfenadine Seldane 

thioridazine Mellaril 

vinblastine Velban 

vincristine Oncovin 

==============================================================
3.) BAYER VOLUNTARILY WITHDRAWS BAYCOL- (LIPOBAY)
==============================================================

T01-34 Print Media: 301-827-6242 
August 8, 2001 Broadcast Media: 301-827-3434 
Consumer Inquiries: 888-INFO-FDA 


FDA today announced that Bayer Pharmaceutical Division is voluntarily withdrawing Baycol (cerivastatin) from the U.S. market because of reports of sometimes fatal rhabdomyolysis, a severe muscle adverse reaction from this cholesterol-lowering (lipid-lowering) product. The FDA agrees with and supports this decision.

Baycol (cerivastatin), which was initially approved in the U.S. in 1997, is a member of a class of cholesterol lowering drugs that are commonly referred to as "statins." Statins lower cholesterol levels by blocking a specific enzyme in the body that is involved in the synthesis of cholesterol. While all statins have been associated with very rare reports of rhabdomyolysis, cases of fatal rhabdomyolysis in association with the use of Baycol have been reported significantly more frequently than for other approved statins. 

Fatal rhabdomyolysis reports with Baycol have been reported most frequently when used at higher doses, when used in elderly patients, and particularly, when used in combination with gemfibrozil (LOPID and generics), another lipid lowering drug. FDA has received reports of 31 U.S. deaths due to severe rhabdomyolysis associated with use of Baycol, 12 of which involved concomitant gemfibrozil use.

Rhabdomyolysis is a condition that results in muscle cell breakdown and release of the contents of muscle cells into the bloodstream. Symptoms of rhabdomyolysis include muscle pain, weakness, tenderness, malaise, fever, dark urine, nausea, and vomiting. The pain may involve specific groups of muscles or may be generalized throughout the body.

Most frequently the involved muscle groups are the calves and lower back; however, some patients report no symptoms of muscle injury. In rare cases the muscle injury is so severe that patients develop renal failure and other organ failure, which can be fatal. 

Bayer Pharmaceutical Division has announced plans to withdraw Baycol to the pharmacy level. Pharmacies will be instructed to return the product to the manufacturer for a refund.

Patients who are taking Baycol should consult with their physicians about switching to alternate medications to control their cholesterol levels. Patients taking Baycol who are experiencing muscle pain or are also taking gemfibrozil should discontinue Baycol immediately and consult their physician. 

There are five other statins available in the U.S. that may be considered as alternatives to Baycol. They are: lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), and atorvastatin (Lipitor).

For further information regarding the withdrawal of Baycol, patients and physicians can contact Bayer Customer Service 1-800-758-9794 or the FDA's Drug Information Office at 301-827-4573 or 1-888-INFO-FDA, or go to "Baycol Information" on FDA's Website.

==============================================================
4.) RE: Market withdrawal of Baycol (cerivastatin)
==============================================================
Source: The FDA.


This is the retyped text of a letter from Bayer Corporation. Contact the company for a copy of any referenced enclosures.

August 8, 2001


RE: Market withdrawal of Baycol (cerivastatin)


Dear Healthcare Professional:

I am writing to inform you of very important new safety information about Baycol (cerivastatin) and rhabdomyolysis.

Rhabdomyolysis is a serious, potentially fatal, adverse effect of all statin drugs, including Baycol. It can occur with statin monotherapy, though the risk appears to be increased significantly by concomitant use of gemfibrozil (Lopid).

Our ongoing scrutiny of post marketing reports of rhabdomyolysis, including fatalities, has revealed an increased reporting rate of rhabdomyolysis with Baycol relative to other statins, especially when gemfibrozil is co-prescribed. These data also suggest an increased reporting rate of rhabdomyolysis at the 0.8 mg dose of Baycol alone.

Bayer Corporation has already placed a contraindication in the Baycol product prescribing information sheet against co-prescription with gemfibrozil and issued letters to healthcare professionals warning against co-prescription of these two drugs. Despite these and other actions, Bayer has continued to receive reports of rhabdomyolysis when gemfibrozil is prescribed as a co-medication. Since the co-prescription of Baycol and gemfibrozil has continued despite communications by Bayer against this practice, the company has decided to take the following voluntary action to prevent further cases of rhabdomyolysis:

Effective immediately, Bayer has discontinued the marketing and distribution of all dosage strengths of Baycol. Patients who are currently taking Baycol should have their Baycol discontinued and be switched to an alternative therapy.

Bayer is taking this action as part of an ongoing commitment to patients and their healthcare providers to ensure patient safety.

It is important to you forward any adverse event information associated with the use of Baycol to Bayer Corporation at 1-800-288-8371. You can also report the information directly to the FDA via the MedWatch system at 1-800-FDA-1088, by mail (using a postage paid form), or the Internet at www.fda.gov/medwatch.

If you have further questions regarding this action on Baycol, please contact Bayer customer service at 1-800-758-9794.

Yours sincerely,


E. Paul Mac Carthy, MD
Vice President,
Head U.S. Medical Science

==============================================================
5.) FDA PUBLIC HEALTH ADVISORY THE SAFETY OF SPORANOX® CAPSULES AND LAMISIL® TABLETS FOR THE TREATMENT OF NYCHOMYCOSIS
==============================================================
Source: The FDA.

The Food and Drug Administration (FDA) is issuing a public health advisory concerning Sporanox® (itraconazole) Capsules and Lamisil® (terbinafine hydrochloride) Tablets for the treatment of onychomycosis. It is important for physicians to be aware of the association of congestive heart failure and hepatic adverse events with the administration of these therapies. Prior to prescribing systemic antifungal drug therapy for the treatment of onychomycosis, healthcare professionals should consider this new safety information.

Sporanox® Capsules and Lamisil® Tablets, synthetic antifungal agents, are approved in the United States for the treatment of onychomycosis [Sporanox® Capsules, Oral Solution, and Injection are also approved for the treatment of serious systemic fungal infections (e.g., esophageal candidiasis, aspergillosis, blastomycosis, and histoplasmosis).]

CARDIAC RISKS

FDA believes that there is a small but real risk of developing congestive heart failure associated with Sporanox® therapy. Recent studies conducted in dogs and healthy human volunteers revealed negative inotropic effects with intravenous (IV) itraconazole. In these studies, once the drug was stopped the negative inotropic effects resolved. The mechanism for these cardiac effects has not been determined.

Since becoming aware of these findings, FDA reviewed spontaneous post-marketing reports received between September 1992 and April 2001 for congestive heart failure (CHF) in association with itraconazole use. During this period, FDA received 94 U.S. and international spontaneous reports of CHF in which itraconazole was listed as a suspect drug. In 58 of the 94 cases, FDA believes itraconazole contributed to or may have been the cause of CHF. In 26 of the 58 cases, itraconazole was being administered for the treatment of onychomycosis. Of these 58 cases, 28 were hospitalized. Death was reported in 13 cases. However, the causal relationship between the 13 deaths and itraconazole is unclear because of confounding factors, including 10 of the 13 patients who had serious underlying conditions.

Because of the low but possible risk of cardiac toxicity, Sporanox® should NOT be administered for the treatment of onychomycosis in patients with ventricular dysfunction such as CHF or a history of CHF. If signs or symptoms of CHF occur during treatment for onychomycosis, Sporanox® should be discontinued.

If signs or symptoms of CHF occur during treatment for more serious systemic fungal infections, continued Sporanox® use should be reassessed as to the appropriate risk benefit analysis in relationship to any other therapeutic options.

HEPATIC RISKS

Both Sporanox® and Lamisil® have been associated with serious hepatic toxicity, including liver failure and death, including some cases involving patients who had neither pre-existing liver disease nor a serious underlying medical condition.

As of April 2001, the FDA is aware of 16 cases of liver failure in association with Lamisil® Tablet use (including 11 deaths and two liver transplantations). These patients received Lamisil® Tablets for the treatment of various dermatologic conditions, including onychomycosis.

FDA's concerns about hepatic risks associated with the use of Lamisil® do not apply to topically applied formulations of terbinafine, such as Lamisil® Solution and Lamisil® AT Cream.

As of March 2001, the FDA is aware of 24 cases of liver failure associated with Sporanox® use (including 11 deaths). These patients received Sporanox® for the treatment of either onychomycosis or systemic fungal infections.

Given the possible risks associated with both drugs, FDA wants healthcare providers to be aware of this new safety information for the two most commonly prescribed systemic onychomycosis drug therapies. Because of these risks, the new labeling for both Sporanox® and Lamisil® recommends that healthcare providers obtain nail specimens for laboratory testing prior to prescribing the medications for onychomycosis to confirm the diagnosis. However, there is insufficient data to allow FDA to make any kind of statement about the comparative safety of Sporanox® and Lamisil®.

============================================================== 
6.) FDA Issues Health Advisory Regarding the Safety of Sporanox® Products and Lamisil® Tablets to Treat Fungal Nail Infections
==============================================================
Source: The FDA.

T01-22 Print Media: 301-827-6242 
May 9, 2001 Broadcast Media: 301-827-3434 
Consumer Inquiries: 888-INFO-FDA 


The Food and Drug Administration (FDA) today issued a Public Health Advisory to announce significant safety-related updates to the labeling of Sporanox® (itraconazole) products and Lamisil® (terbinafine hydrochloride) tablets. Sporanox® and Lamisil® are used to treat nail (onychomycosis), skin and other systemic fungal infections. The following may be used to answer questions. 

The purpose of today's FDA Public Health Advisory is to alert healthcare professionals to serious risks associated with the use of Sporanox® and Lamisil®. 

FDA believes there is a small but real risk of developing congestive heart failure (CHF) associated with the use of Sporanox®. Both Sporanox® and Lamisil® have been associated with serious liver problems resulting in liver failure and death. However, there is insufficient data to allow FDA to make any kind of statement about the comparative safety of Sporanox® and Lamisil®. 

Results of recent studies of Sporanox® revealed a potential for the drug to weaken the force of the heart muscle's contractions. This so-called "negative inotropic effect" was observed when intravenous Sporanox® was injected into anesthetized dogs and healthy human volunteers. In these studies, the adverse effect on the heart muscle resolved once the drug was stopped. 

Since becoming aware of the study findings, FDA analyzed US and international post-marketing adverse event reports involving Sporanox that were received between its approval in September 1992 and April 2001. 

During this period, FDA received 94 cases in which patients receiving Sporanox® developed CHF. In 58 of the 94 cases, FDA believes Sporanox® contributed to or may have been the cause of CHF. In 26 of these 58 cases, Sporanox® was being administered to treat fungal nail infections. Of these 58 patients, 28 were hospitalized. Death was reported in 13 cases. However, the causal relationship between the 13 deaths and Sporanox® is very unclear because of confounding factors. For example, 10 of the 13 patients who died had serious underlying conditions. 

In response to the study findings and the analysis of the post-marketing adverse event reports, FDA has added additional information to the current "black box" warning in the Sporanox® labeling. The warning now states that Sporanox® should not be administered for the treatment of fungal nail infections in patients with evidence of cardiac dysfunction, such as CHF, or a history of CHF. The Sporanox® "black box" warning also includes important information about heart-related adverse events caused by drug interactions. 

If signs and symptoms of CHF occur during treatment of fungal nail infections, the revised labeling recommends that Sporanox® should be discontinued. If signs and symptoms of CHF occur during treatment for more serious fungal infections involving other parts of the body, the revised labeling recommends that continued use of Sporanox® should be reassessed by the physician.

The advisory also alerts healthcare professionals to rare cases of serious liver problems including liver failure and death associated with the use of Sporanox® products and Lamisil® tablets. While adverse liver effects were already included in the labeling for both products, FDA decided to include this information in the advisory because some cases involved patients who had neither pre-existing liver disease nor a serious underlying medical condition. 

FDA's concerns do not apply to the topically applied versions of Lamisil® such as cream and solution.

As of April 2001, FDA has received and reviewed 16 possible Lamisil®-associated cases of liver failure, including 11 deaths and two liver transplantations.

As of March 2001, FDA has received and reviewed 24 cases of liver failure possibly associated with Sporanox®, including 11 deaths. Approximately half of the liver failure cases received Sporanox® for fungal nail infections or other dermatological infections. 

Given the possible serious risks associated with Sporanox® products and Lamisil® tablets, the new labeling for both products now recommends that healthcare professionals should obtain nail specimens for laboratory testing prior to prescribing the medications for fungal nail infections, to confirm the diagnosis. 

In conjunction with FDA's advisory, the manufacturer of Sporanox® (Janssen Pharmaceutica Products, L.P. of Titusville, NJ and Ortho Biotech Products, L.P. of Raritan, NJ) and Lamisil® (Novartis Pharmaceuticals of East Hanover, NJ) are notifying healthcare professionals of the labeling changes by issuing "Dear Healthcare Professional" letters. 

FDA encourages healthcare professionals and patients to report adverse events associated with the use of Sporanox® and Lamisil® to FDA's MEDWATCH Program. Reports may be submitted to MEDWATCH by phone at 1-800-FDA-1088, by fax at 1-800-FDA-1078, by mail at MEDWATCH, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787, or on the MEDWATCH web site at https://www.fda.gov/medwatch/index.html.

The full text of the FDA Public Health Advisory is available at FDA's MedWatch web site, https://www.fda.gov/cder/drug/advisory/sporanox-lamisil/advisory.html

For more information on this subject, see the Center for Drug Research and Evaluation's Sporanox and Lamisil Public Health Advisory Web Page. For general information about liver toxicity, see the Center's Web page on Drug-Induced Liver Toxicity.

==============================================================
7.) Sporanox and LamisilPublic Health Advisory Questions and Answers
==============================================================
Source: The FDA.

What is the Food and Drug Administration (FDA) announcing today?

The FDA issued a Public Health Advisory to announce important safety-related updates to the labeling of Sporanox® (itraconazole) and Lamisil® (terbinafine hydrochloride) Tablets.

FDA is advising healthcare professionals not to prescribe Sporanox® to treat fungal infections (onychomycosis) in patients who have congestive heart failure (CHF) or a history of CHF. The updated Sporanox® labeling also includes contraindications and precautions with certain medicines.

FDA’s advisory also alerts the public that both Sporanox® and Lamisil® Tablets have been associated with serious liver problems including liver failure and death.

What are Sporanox® Capsules and Lamisil® Tablets used for?

Sporanox® Capsules and Lamisil® Tablets are prescription medicines approved to treat toe and finger nail fungal infections. Sporanox® Capsules, Oral Solution, and Injection are also approved to treat serious fungal infections that may occur in other parts of the body.

Lamisil® is also available as cream and solution. This Public Health Advisory does NOT apply to these topically applied dosage forms.

What prompted the labeling updates for Sporanox® and Lamisil®?

These labeling changes are based on a safety evaluation of preclinical, clinical and post-marketing information.

Sporanox® Cardiac Risk Labeling Update:

As of April 2001, FDA has reviewed 94 cases in which Sporanox® treated patients developed congestive heart failure. In 58 of the 94 cases, FDA believes Sporanox® contributed to or may have been the cause of the congestive heart failure. Although the causal relationship is unclear, death was reported in 13 cases. 
Sporanox® and Lamisil® Hepatic Risk Labeling Update:

As of March 2001, the FDA has reviewed 24 cases of liver failure possibly associated with Sporanox® use, including 11 deaths. 
As of April 2001, the FDA has reviewed 16 possible Lamisil® associated cases of liver failure, including 11 deaths and two liver transplant patients. 
What are some warning signs of congestive heart failure?

Shortness of breath 
Swelling of the feet, ankles, legs, or abdomen 
Weight gain 
Unusually tired 
Coughing up of white or pink mucous 
Unusual fast heartbeats 
What are some warning signs of liver failure?

Nausea 
Vomiting 
Abdominal pain 
Fatigue 
Loss of appetite 
Dark urine 
Generalized skin discoloration 
If I develop heart or liver problems, do the warning signs happen while on drug treatment or can they develop years after stopping treatment?

Based on data known at present, the warning signs are most likely to be present while taking the drug or soon after stopping it.

Are there other treatments for my nail fungus that are safer?

No drug product is "perfectly" safe. Every single drug that affects the body will have some side effects.

For every drug FDA approves, the benefits are balanced against its risks. In addition, FDA makes sure the labeling (package insert) outlines the benefits and risks reported in the tested population and is updated, as new information becomes available. You and your healthcare professional should decide together if the benefits outweigh the risks for YOU based on the new safety information for Sporanox® and Lamisil®.

The new labeling for both Sporanox® and Lamisil® recommends that healthcare professionals obtain nail specimens for laboratory testing to confirm the diagnosis of onychomycosis before prescribing the medications for this indication.

What actions have FDA and the manufacturers taken to make the public aware of this safety information?

FDA has worked with the manufacturers of Sporanox® and Lamisil® to:

Revise the professional labeling to inform health care providers about these possible serious side effects, describe the types of patients that should not receive Sporanox® or Lamisil®, and explain when Sporanox® or Lamisil® therapy should be stopped. 
Distribute a "Dear Health Care Professional" letter which the manufacturers will send to health care providers to convey new information on safety. 
What should I do if I am currently taking Sporanox® or Lamisil®?

Tell your doctor about any side effects you experience while taking Sporanox® or Lamisil®.

Any decision about which drug product to take to treat your nail fungus should be made in consultation with your doctor based on an assessment of your specific treatment needs, specific risk profile, and other factors.

How can I report a serious side effect to the FDA?

The FDA has created MedWatch, the FDA Medical Products Reporting Program, to educate all health professionals about the critical importance of being aware of, monitoring for, and reporting adverse events and problems to FDA and/or the manufacturer. While participation in MedWatch is voluntary, FDA encourages anyone aware of a serious adverse reaction, including consumers, to make a MedWatch report.

============================================================== 
8.) Hypothermia with Nimesulide 
============================================================== 
Letters to the Editor

Indian Pediatrics 2001; 38: 799-800 

Nimesulide is a new nonsteroidal anti-pyretic drug which is now commonly being used in pediatric practice. Some studies have shown a better antipyretic effect than para-cetamol and salicylates(1).

Nimesulide is considered to be a safe drug with no significant side effects. It can cause mild gastrointestinal symptoms, excessive perspiration, heart burn, flushing and skin rashes. Hematuria has recently been reported after administration of this drug(2).

I have observed hypothermia in six cases administrated Nimesulide recently in the age group of 6 months to 5 years. The temperature of one child fell to 94ºF (axillary) after giving a therapeutic dose (5 mg/kg/day with a measured cup in divided doses). The child, suffering from acute tonsillitis with a temperature of 105ºF, developed hypothermia after 2 hours of medication in the summer season. The mother complained of severe cold, shivering and ice cold skin. There was no sweating but mild tachycardia was recorded. Blood pressure and other vitals were within normal limits. The child was wrapped in a blanket. Intravenous fluids were given prophy-lactically and vitals were observed closely. The temperature improved after 5-6 hours. The therapeutic dose was repeated next time and the child again developed the same symptoms. Similar observations were made subsequently in 5 other children during a period of 10 months. This side effect of severe hypothermia has not been reported earlier.

Small children below 1 year of age should be given this drug cautiously. More observa-tions are required to substantiate hypothermia as a side-effect of nimasulide administration.



Sudesh Sharma,
Professor, Department of Pediatrics, 
Medical College, Amritsar, Punjab, India



References 

1. Capella D, Guerra A, Laudizi L, Cava. Zu TT. Efficacy and tolerability of nimesulide and lysine acetyl salicylate in the treatment of pediatric acute upper respiratory tract inflam-mation. Drugs 1993; 46: (Suppl 1): 222- 325.

2. Anandakesvasan TM. Nimesulide toxicity. Indian Pediatr, 1999; 36: 324. 

==============================================================
9.) NIMESULIDE (PAEDIATRIC) 
==============================================================
Source: The WHO.

Application for an export licence refused

Portugal. The company Helsinn Pharmaceutical Products applied for an export licence for a paediatric formulation of nimesulide (Aulin Pediátrico, granules 50 mg), claiming that it intended to send the stock free of charge to East Timor for use in adults.

The application was refused because products containing nimesulide – including Aulin Pediátrico, granules 50 mg – were withdrawn from the market and the marketing authorizations were suspended on 24 March 1999 on the grounds that they were considered to present a public health risk. Under the terms of the decree they are also prohibited for export.

Reference: Communication from the Instituto Nacional da Farmácia e do Medicamento (INFARMED), Lisbon, 18 November 1999.

============================================================== 
10.) Nimesulide-induced acute icteric hepatitis
==============================================================
S.P. Dourakis,1 V.A. Sevastianos,1 K. Petraki,2 S.J. Hadziyannis1 
1Academic Dept. of Medicine, “Hippokration” General Hospital, Athens School of Medicine, University of Athens, 
2Department of Pathology, “Hippokration” General Hospital, Athens, Greece 
PUBLISHED MONTHLY BY THE
SOCIETY FOR MEDICAL STUDIES
MARCH 2001 VOLUME 79 No 3

ABSTRACT Drug-induced hepatotoxicity has been reported infrequently with nimesulide. Isolated case reports of nimesulide hepatotoxicity range from the increase in transaminase levels to fatal acute liver injury. The case of a female 68 year old patient, who developed acute icteric hepatitis 15 days after the administration of nimesulide for symptomatic relieve from lumbar and lower extremities pain is described. Other causes of acute hepatocellular necrosis were excluded. Liver histology showed acute hepatitis changes with bridging necrosis. The drug was withdrawn. The patient recovered clinically and the serum bilirubin and aminotransferases levels gradually returned to normal in 9 weeks time. Acute hepatitis was probably caused by an idiosyncratic adverse reaction to one of nimesulide metabolites. In conclusion, this case strongly suggests that nimesulide may induce acute icteric hepatocellular necrosis which can be confused clinically with acute viral hepatitis. Administration of the drug must be immediatelly withdrawn in patients with tests, demonstrating a derranged liver function to prevent the development of acute liver failure. 

Key words Nimesulide, acute hepatitis, drug-induced liver disease. 

==============================================================
11.) Fatal hepatotoxicity secondary to nimesulide
==============================================================
Source: © Springer-Verlag 2001
Eur J Clin Pharmacol, DOI 10.1007/s002280100312

Pharmacoepidemiology and Prescription

Giorgio Merlani1, Mark Fox2, Hans-Peter Oehen3, Gieri Cathomas3, Eberhard L. Renner2, Karin Fattinger4, Markus Schneemann1 and Gerd A. Kullak-Ublick2, 4, 

(1) Medizinische Klinik B, Department of Internal Medicine, University Hospital, 8091 Zurich, Switzerland 
(2) Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital, 8091 Zurich, Switzerland 
(3) Department of Pathology, University Hospital, 8091 Zurich, Switzerland 
(4) Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital, CH-8091 Zurich, Switzerland 

Abstract. This report describes a 57-year-old female patient with chronic lumbago, who died from the sequelae of acute liver failure induced by nimesulide medication. Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) which preferentially inhibits cyclo-oxygenase 2 and has been associated with a total of 13 reported cases of severe liver injury including our case. On the basis of the literature reports, the following features of nimesulide-associated hepatotoxicity were identified: female sex (84% of cases), age (mean age 62 years), jaundice as a primary manifestation (90%) and the absence of peripheral blood eosinophilia. The average duration of therapy of the published cases was 62 days (range 7-180 days). Based on spontaneous reports to the World Health Organization, nimesulide induces a high proportion of severe adverse hepatic reactions compared with other NSAIDs registered in Switzerland. Hepatotoxicity thus represents an important risk factor of nimesulide usage.

Keywords. Hepatitis - Non-steroidal antiinflammatory drugs - Adverse drug reaction

E-mail: [email protected]
Phone: +41-1-2554097
Fax: +41-1-2554411 

==============================================================
12.) Re: Nimesulide and reasons for non-approval or withdrawal 
==============================================================

Source: : www.essentialdrugs.org 

To: [email protected] 
Subject: [e-drug] Re: Nimesulide and reasons for non-approval or withdrawal (cont) 
From: helpline <[email protected]> 
Date: Mon, 30 Apr 2001 14:42:50 -0400 (EDT) 
Reply-To: [email protected] 
Sender: [email protected] 


E-drug: Re: Nimesulide and reasons for non-approval or withdrawal (cont)

Dear Dr. Maqsood,

Due to multiple reports of serious adverse drug reactions, pediatric nimesulide products have been suspended in Portugal as of April, 1999. Of the 17 reactions reported, the most frequent were dermatologic and hepatic in nature, including two cases of fatal Reyes syndrome. It is to be noted that concomitant therapy with other drugs (amoxicillin/clavulanic acid, lysine salicylate) in many of these cases prohibits a definitive causal link of the adverse reaction to nimesulide therapy. Further risk/benefit evaluation of pediatric nimesulide use is ongoing (Anon: SCRIP World Pharmaceutical News. PJB Publications, Ltd., London; No 2431, April 23, 1999, p 20).

In Israel too, the drug has been banned for pediatric use. At the Drug Information Helpline, I have maintained a complete file on the drug through information on e-drug. I have read that in Sri Lanka, the Ministry of Health did a lot of investigation about registering the drug and finally decided not to.

I believe when more safer drugs as paracetamol are already available it is irrational to prescribe me-too drugs of doubtful efficacy.helpline <[email protected]>Send mail for the `E-Drug' conference to `[email protected]'.Information and archive https://www.healthnet.org/programs/edrug.html

Mail administrative requests to `[email protected]'.For additional assistance, send mail to: `[email protected]'.

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13.) E-DRUG: Nimesulide
==============================================================
Source: : www.essentialdrugs.org 

to: [email protected] 
Subject: E-DRUG: Nimesulide 
from: E-drug <[email protected]> 
Date: Sun, 18 Jul 1999 10:17:08 -0400 (EDT) 
Reply-To: [email protected] 
Sender: [email protected] 


E-drug: Nimesulide (cont)
-------------------------
[the Lancet (Volume 353, Number 9170 19 June 1999) discussed Nimesulideas well. Interestingly, the Sri Lankese Regulatory Authority referred toE-drug as one of its sources for deciding on the application of Nimesulide.WB]Registration of new drugs in developing countriesSir--A Figueras and colleagues (April 24, p 1447) [1] describe fulminant
hepatic failure with nimesulide, a selective inhibitor of COX-2. Theyalso mention the difficulties associated with the registration of a newdrug in developing countries. Sri Lanka too has been confronted with thisissue. Nimesulide is registered in many countries (Spain, Italy, Portugal,Switzerland, and Greece) and is the best selling pharmaceutical productin Portugal.[2] There were six applications to the Sri Lankan DrugRegulatory Authority (DRA) by various manufacturers in 1998. However,nimesulide was not registered in Canada, the USA, the UK, Scandinavia,Australia, and New Zealand. The Sri Lankan DRA considers these countriesto be the reference DRAs and tends to consider only those drugs (thechemical entity, not the product) that are registered by theseauthorities. 

Various arguments were given by the applicants to make nimesulide theexception: it was an old drug, registered in Italy in 1985,[2] had beenassessed thoroughly, and there were many publications on it. A limitedliterature search found more than 30 publications. Nevertheless, the SriLankan DRA decided to be cautious and await further reports. Thisdecision was made easier by the fact that nimesulide did not have clearadvantages over other NSAIDs. 

During late 1998 and early 1999, there were reports of adverse eventswith nimesulide.[2-4] None of the applicants for registration informedthe Sri Lankan DRA about these events. The DRA came to know aboutfulminant hepatic failure with nimesulide through an e-mail discussiongroup ("E-drug") in May. The paediatric nimesulide preparation has nowbeen withdrawn from sale in Portugal[3] and Israel.[4] These discoverieswere fortuitous--the DRA simply does not have the funds to subscribe tomedical journals or the personnel to monitor reports. Nimesulide is nowunlikely to be registered in Sri Lanka because of these reports. 

As Figueras and colleagues underline, the World Trade Organisation andthe International Conference on Harmonisation are driving the proceduresfor registration of drugs. What should a developing country with littleor no information exchange, and inadequate regulation of drugs do, whenthe harmonised dossiers of the new drugs are submitted for registration? In the few situations in which the new drug has a clear advantage overexisting drugs, it should properly be assessed and registered promptly.However for the "me-too" drugs with no advantage over existing drugs,which make-up most of the applications, such speed may not be needed.There is a simple way to decide on "me-too" drugs; the approved productinformation (indications, adverse effects) for an existing drug from areference DRA would show little or no difference from that of the newer"me-too". Sri Lanka used this method and did not register mibefradil,[5]the caution was well placed since the drug was subsequently withdrawn
worldwide. 

An important issue in registering new drugs in developing countries iswhether health or trade should come first. Registering new drugs withoutdelay would help trade and free circulation of goods; adopting a cautiousattitude would serve health. Should not the government ensure thatcitizens are healthy before they begin to trade? 

K Weerasuriya 

*Department of Pharmacology, Faculty of Medicine, University of Colombo,
Colombo 00800, Sri Lanka; and Drug Evaluation Sub Committee Ministry of
Health, Colombo

email <<[email protected]>

1 Figueras A, Estevez F, Laporte J-R. New drugs, new adverse reactions,
and bibliographic databases. Lancet 1999; 353: 1447-48. 2 Nimesulide ADR controversy in Portugal. Scrip 1999; no 2406: 8. 3 Portugal suspends paediatric nimesulide. Scrip 1990; no 2431: 20. 4 Israel nimesulide suspension inquiry. Scrip 1999; no 2434: 23. 5 Weerasuriya K. Mibefradil: the sole exception. Lancet 1998; 351:1829-30. --Send mail for the `E-Drug' conference to `[email protected]'.Mail administrative requests to `[email protected]'.For additional assistance, send mail to: `[email protected]'.

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14.) Eleven Deaths Among UK Vioxx User
==============================================================

Source: www.Medscape.comLONDON, Sep 08 (Reuters Health) - Eleven deaths and more than1,000 reports of suspected adverse reactions to Merck's newosteoarthritis drug Vioxx (rofecoxib) have been reported in the UKsince its launch in June last year, British regulators said onThursday.The Medicines Control Agency (MCA) and the Committee onSafety of Medicines (CSM) said, "Up to July 2000, the MCA/CSMhad received a total of 1,120 reports, via the Yellow Card Scheme,of suspected adverse reactions to rofecoxib."Five patients died following gastrointestinal reactions, threefollowing cardiac failure and three following myocardial infarction,the agencies reported in their newsletter "Current Problems."An estimated 557,100 prescriptions for Merck's COX-2 inhibitorhave been dispensed in the UK up to the end of May 2000, theagencies said. The rate of reported adverse reactions is thereforeapproximately one per 500 prescriptions."Gastrointestinal adverse reactions account for almost half (554) ofthe reports, of which the majority (84%) were nausea, dyspepsia,diarrhoea and abdominal pain," the agency said."However there have been 68 reports (12%) of upper GIperforations, ulceration and bleeds (PUBs). Forty-four (65%) of the
patients with PUBs recovered, although five had a fatal outcome."

Eleven Deaths Among UK Vioxx Users

The agencies also received 177 reports of suspected cardiovascularreactions, including 101 reports of oedema, 31 reports ofhypertension and 19 reports of palpitations.There were 15 reports of cardiac failure, three of which had a fataloutcome, and nine reports of myocardial infarction, three of themfatal. In the majority of these cases, the patient had risk factors forcardiovascular disease.Psychiatric reactions were also reported, including 28 reports ofdepression, 14 reports of confusion and 11 reports of hallucinations.Adverse reactions recognised with other NSAIDs were also reportedwith rofecoxib. These included angioedema (35 reports),bronchospasm or exacerbation of asthma (25), renal failure (16), andabnormal hepatic function (12).The newsletter reminded prescribers that rofecoxib iscontraindicated in patients with active peptic ulceration, GIbleeding, and severe congestive heart failure. It also noted that"caution should be exercised in patients with a history of cardiacfailure, left ventricular dysfunction, or hypertension and in patientswith pre-existing oedema for any other reason".In conclusion, the agencies said, "As with all new drugs, the safetyof rofecoxib remains under close review." They pointed out thatanother COX-2 inhibitor, Pharmacia's celecoxib (Celebrex), hadbeen launched recently and promised to report on its safety profile ina forthcoming bulletin.Merck officials were not immediately available for comment.Copyright © 2000 Reuters Ltd. All rights reserved.Republication or redistribution of Reuters content isexpressly prohibited without the prior written consent ofReuters. Reuters shall not be liable for any errors or delaysin the content, or for any actions taken in reliance thereon.
 

ctions taken in reliance thereon.

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15.) Celebrex (celecoxib capsules)
==============================================================
source: : www.nursing.uiowa.edu 

Jo Eland PhD RN FNAP FAAN

Every attempt has been made to insure the accuracy of this material, however, medical science is constantly changing. If the information on this page differs from what you have been told by a nurse, pharmacist or physician, consult the person who told you differently or the manufacturer.

Celebrex has never been studied in children - it is currently not approved by the Food and Drug Administration for that reason. Unfortunately many drugs brought to market have not been studied in pediatrics or in elderly patients. Fortunately Celbrex has at least been studied in a large number of elderly people.

Actions: Celebrex is new type of drug that has been created to be very similar to the current drugs such as ibuprofen, naproxyn,clinoril etc. which are known altogether as NSAIDs. These drugs work by altering the production of one of the chemicals that cause pain called a prostaglandin. Prior to Celbrex all of the other NSAIDs had some common problems and side effects - they could give people stomach ulcers, hurt people's kidneys and alter the body's ability to clot blood. Celebrex is the first drug that alters the production of the pain chemical in a different way and it would appear after having studied over 5,000 people in research prior to making the drug available for prescription that it doesn't alter blood clotting, kidney function or irritate the stomach. It is also interesting to note that over 2,900 of these poeple were over 65 and they had good luck with the drug too. Elderly people's stomachs are more fragile than young peoples.

Indications: relief of the signs and symptoms of osteoarthritis, and rheumatoid arthritis in adults

When will it start to work.- 3 hours after oral dose

When will it be at peak effect: on or before day 5

How does the body get rid of the drug: primarily by the liver and then it is excreted by the kidney

Contraindications - known hypersenstivity to celecoxib (Celebrex), Celebrex should not be given to patients who have demonstrated allergic-type reactions to sulfonamides (sulfa drugs) .Should not be given to patients who have had severe reactions to other NSAIDs like ibuprofen etc.

GI Effects -Only 2 people out of 5,285 patients who received Celebrex in controlled clinical trials of 1 to 6 months duration (most were 3 month studies) of 200 mgm or more develped significant upper GI bleeding. NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gi bleeding.

Renal No information is avilable regarding the use of Celebrex in patients with advanced kidney disease. Therefore treatment with Celebrex is not recommended in these patients.

Pregnancy-Pregnancy Category C. Celecoxib was not teratogenic in rabbits. No studies have been conducted to evaluate the effect of celecoxib on the closure of he ductus arteriosus in humans. In late pregnancy Celebrex should be avoided because it may cause premature closure of the ductus arteriosus. Celebrex produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approx. 7 fold human exposure) Effects of Celebrex on labor and delivery in pregnant women are unknown. Nursing Mothers - Celecoxib is excred in the milk of lactating rats at concentrations similar to those in plasma. It is not known whether this drug is excreted in human milk.

Pediatrics: Use has not been evaluated

Geriatric: Was studied in elderly - 2,100 people 65-74 years old and an additional 800 patients as well were over 75. No substantial differences in safety and effectiveness were observed between these subjects and younger stubjects.


Precautions: Because Celebrex is an NSAID by definition if a patient is on long term therapy renal and liver function should be monitored. Anemia is sometimes seen in patients receiving Celebrex. Celebrex does not generally affect platelet counts or blood clotting.

Drug Interactions:

Ace Inhibitors:NSAIDs may inhibit the antihypertensive effects of Ace inhibitors.

Furosemide-NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients

Aspirin- Celebrex can be used with low dose aspirin Administering the 2 together can increase risk of GI problems. Becuase of it's lack of platelet effects Celebrex cannot be substituted for cardiovascular prophylaxis

Fluconazole: Concomitant administration of fluconazole 200 mg qd resulted in a 2 x increase in celecoxib plasma concentration. Celebrex should be introduced at the lowest recommended dose in patients receiving fluconazole.

Lithium: Man steady state lithium plasma levels increased by approximately 17% in subjects receiving lithium 450 mg bid with Celebrex 200 mg bid. Patients on lithium shoujld be closely monitored when Celebrex is introduced or withdrawn.

Methotrexate: In an interaction study of rheumatoid arthritis patients taking methotrexate, Celebrex did not have a significan effect on the phramocokinetics of methothrexate.

Warfarin: When studied with a group of healthy subjects taking 2-5 mg of warfarin the anticoagulant effect of warfarin was not altered as determined by prothrombin time. Howevere caution should be used when administrating Celebrex with warfarin.

Availability- 100 mgm capsule & 200 mgm capsules

Usual Dose: Osteoarthritis: 200 mgm as a single dose or 100 mgm bid Rheumatoid arthritis: 100-200 mg twice per day

Route: oral other forms not available

Side Effects: The following occurred in 0.1-1.9% of patients regardless of causality-note this is an extremely low per cent of side effects.

GI- constipation, diverticulitis, gastritis, gastroenteritis, hemorrhoids, hiatal hernia, stomatitis, vomiting

CV - aggravated high blood pressure, dry mouth, glaucoma

General: allergy aggravated, allergic reaction, chest pain, swelling generalized, face swelling, fatigue, fever, hot flashes, flu-like syndromes, pain, peripheral pain

CNS, PNS- leg cramps, migraine, neuralgia, neuropathy, paresthesia, vertigo

Female reproductive- breast fibroadenosis, breast neoplasm, breast pain, dysmenorrhea, menstrual disorder, vaginal hemorrhage, vaginitis

Male reproductive- prostatic disorder

Hearing and vestibular: deafness,ear abnormality, earache, tinnitus

Heart rate and rhythm: angina pectoris, coronary artery disorder, myocardial infarction, palpitation, tachycardia

Liver and biliary system: hepatic function abnormal

Metabolic and nutritional: kidney and liver function changes, DM, high cholesterol, high blood sugar, low potassium, weight increase

Musculoskeletal: Arthralgia, arthrosis, bone disorder, fracture accidental, neck stiffness, painful joints, tendinitis

Platelets: nose bleeds, bruising

Psychaiatric: anorexia, anxiety, appetite incnreased, depression, nervousness, somnolence

Hemic: anemia

Respiratory: bronchitis, trouble breathing, aggrevated, coughing, dyspnea, laryngitis, pneumonia

Skin & appendages: hair loss, dermatitis, nail disorder, sensitivity to light, itching skin, rashs, skin dry, sweating increased,

Special senses: taste changes

Urinary system: cystitis, dysuria, hematuria, going to the bathroom alot, renal stones, urinary tract infection

Vision: blurred vision, cataract, conjunctivitis, eye pain

References

https://www.celebrex.com/pi.html - Searle, the manufactures www site on the drug

Celebrex has never been studied in children - it is currently not approved by the Food and Drug Administration for that reason. Unfortunately many drugs brought to market have not been studied in pediatrics or in elderly patients. Fortunately Celbrex has at least been studied in a large number of elderly people.

EVERY attempt has been made to insure the accuracy of this material however medical science is constantly changing - if the information on this page differs from what you have been told by a nurse, pharmacist or physician. Consult the person who told you differently or the manufacturer.

==============================================================
16.) WIDELY-USED ANTI-INFLAMMATORY ARTHRITIS DRUGS LINKED TO ADVERSE SIDE EFFECTS 
==============================================================
Source: :https://www.hospitalmanagement.net

Hospital management.net

A group of new "miracle" drugs used to treat rheumatoid arthritis, Crohn's disease and other inflammatory diseases is creating debate on the appropriate level of trade-off between symptom relief and drug side effects. Recent studies have indicated that drugs such as Vioxx, Celebrex, Remicade and Enbrel, while being powerful anti-inflammatory agents capable of dramatic reductions in patients' symptoms, may adversely impact other domains of patient functioning. The ramifications of the debate are likely to be measured in tens of millions of dollars for pharmaceutical companies and health plans. Drugs like Vioxx have reached blockbuster status, supported by huge marketing budgets. Any restriction of their recommended use could potentially dampen this success for pharmaceutical companies. Conversely, health plans seeking to reign in costs must balance the tremendous patient demand for these expensive new drugs.

Rheumatoid arthritis and inflammation
It is estimated that rheumatoid arthritis affects (RA) over 2.5 million persons in the United States. Women are at increased risk for developing the disease and are also more likely to develop a more severe form of RA known as Type 2. The incidence of RA increases with age and is most likely to onset between the ages of 20 to 45. Genetic heredity also appears to play a role in determining RA cases. 

Rheumatoid arthritis is a condition in which the joints of the body become inflamed. This inflammation often instigates deterioration in joint function and symptoms such as swelling, joint pain, and joint stiffness. The inflammatory process begins with the membrane and fluid that surrounds the joints in a protective sac. This sac serves to cushion joints and provide oxygen and nutrients to the cartilage coating the bones in the joint. At onset of RA, the joint membrane becomes inflamed. Over time, this process erodes the collagen and damages the bones of the joint.

Progressive RA can cause rapid destruction of the cartilage as the inflammatory cells accumulate in the sac, producing a growth that, in turn, produces enzymes that compound cartilage destruction. This aggravation attracts more inflammatory white cells and the cyclical process is continued. In its most extreme form, the negative impact of RA can extend beyond the joints to body organs.

Among the risk factors for RA, the most powerful predictors include:

History of heavy or long-term smoking 
Stress and depression. Studies have found that patients with a history of persistent or recurrent major depression are more likely to have worse pain, joint fatigue, and RA-related disability that patients without a history of depression. 
Silicone breast implants. There has been only a limited amount of work done to date on the link between silicone breast implants and the onset of rheumatoid arthritis. However, in animal studies, exposure to silicone implants has been associated with the development of RA. Future studies will determine if these findings are applicable to humans. 
Obesity 
History of blood transfusion
Vioxx and Celebrex
Vioxx and Celebrex are from a class of drugs called the cox-2 inhibitors. They are also often referred to as the "super-aspirins." Unlike regular NSAID's, the cox-2 inhibitors block the effects of the enzyme responsible for inflammation without impacting the "cox-1" enzyme that helps to protect the stomach. Therefore, cox-2 inhibitors provide inflammation relief without the negative gastrointestinal side effects that are common among NSAID's. Intestinal bleeding may still occur, but in over two million prescriptions there have only been 10 reported instances of fatal intestinal bleeds. The long-term effects of the cox-2 drugs are less known and are increasingly becoming the subject of direct study.

Since their introduction, the cox-2 drugs have become some of the most widely prescribed pharmaceuticals in the world. In the United States alone, the drugs have brought in over $6 billion in sales from over 200 million prescriptions. However, their substantial cost has made them controversial among health planners, some of whom are hesitant to cover the prescription costs of such a popular and expensive medication.

Eric Topol of the Cleveland Clinic recently reported in the Journal of the American Medical Association that both Vioxx and Celebrex are associated with an increased risk of heart attack and stroke. The study analyzed over 8,000 patients taking Vioxx or the pain medication, naproxen. Among patients taking the Vioxx, the risk of cardiovascular problems (e.g., myocardial infarction and cerebrovascular stroke) was doubled. Two previous studies have also reported a small increased risk for cardiovascular complications among Vioxx users. In a separate group of patients, Celebrex was also found to increase the risk for heart problems. Topol considers this work preliminary, but says it is sufficient evidence that future work should investigate the links between cardiovascular risk and the cox-2 inhibitors. In spite of the recommendation of an advisory panel, the Food and Drug Administration has yet to rule on whether or not the Vioxx labeling should include additional warnings about the risk of cardiovascular complications.

The makers of Vioxx and Celebrex, Merck and Pharmacia, respectively, argue that the study is fundamentally flawed in that the patients participating had RA, which is a known risk factor for heart problems. They argue the findings could therefore be confounded and that the increased risk for heart attacks and strokes come not from the medications but from the influence of RA.

Remicade and Enbrel
Remicade and Enbrel are from a class of biologic response modifiers that are genetically engineered to interfere with the autoimmune process that develops in patients with RA. Unlike many immunosuppressant drugs, Remicade and Enbrel have more focussed biologic targets and therefore do not propagate as significant immune system damage. Specifically, these drugs target immune factors such as tumor necrosis factor (TNF) and interleukins that are thought to be primary culprits in the degenerative cascade of RA. 

Remicade, made by Johnson and Johnson's Centocor and approved for use in 1999, targets the tumor necrosis factor in the RA patient and may be used alone or in combination with methotrexate. Clinical studies have shown that Remicade is effective in stopping further joint damage and slowing joint degradation in patients with severe RA. A similar compound, Enbrel, made by Immunex, has been approved for use in both juvenile and adult RA patients. Clinical trials demonstrated that Enbrel was effective in reduction RA-related joint pain, and slowing joint erosion. It was found to have few side effects and to be even more effective when used in combination with methotrexate. The benefits of both Remicade and Enbrel are lost once their use is discontinued.

Although the original clinical trials reported only minimal side effects, more recent work has concluded that the risk for infection resulting from the immunosuppression may be of a magnitude great enough to warrant additional label warnings. Because TNF helps to fight infections, the TNF inhibition provided by Remicade may increase patients' likelihood of developing diseases that their body would otherwise have been able to ward off. In particular, the risk of tuberculosis may increase. To date, Remicade has been associated with 84 cases of tuberculosis worldwide, including 14 fatal cases. As a result, Centocor has amended its labeling to include a warning about the risk of infection. In addition, the company plans to mail letters to healthcare providers and distribute patients education materials to further explain the appropriate use of Remicade and warn of its potential side effects. The company will also continue to collect safety information on Remicade to ensure that its labeling is sufficient and encourage physicians to screen all patients for tuberculosis prior to administering Remicade. Immunex officials have gone on record saying that they do not anticipate their drug Enbrel to require additional warnings.

Meanwhile, the Food and Drug Administration is meeting to decide whether or not additional warnings and restrictions are needed for Remicade and Enbrel. Among the data they will consider are the following facts:

In the last four months of 2000, 22 patients died while taking Enbrel and 18 needed emergency care at a hospital 
Although indicated for use in juveniles, a 9-year old female taking Enbrel required hospitalization during this period 
In the same period, 48 persons died while taking Remicade, and 100 interventions were necessary to save patients from permanent damage 
Five patients developed lupus after taking Remicade. And researchers have reported that two patients developed lupus soon after starting Enbrel 
Other reported complications have included nervous system disorders, lung infection pneumocystis, tuberculosis, and sepsis
Possible Outcomes
It appears unlikely that any drastic reduction in the population of patients who are eligible for these medications will be the outcome of the current debate. However, given the extensive marketing of these drugs, the high patient demand and the reluctance of many health plans' to cover the costly medications, the new information on side effects is likely to complicate the struggle for prescription coverage. The probability is high that this issue will reoccur as more targeted therapies come to market, based with only limited data on the long-term collateral effects of the biotechnology on other organs and disease processes.

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17.) Public Health Advisory, Food and Drug Administration, Trovan, 09 June 1999
 =============================================================

(Trovafloxacin/Alatrofloxacin Mesylate) INTERIM RECOMMENDATIONS

Trovan (trovafloxacin / alatrofloxacin) was approved by FDA in 1997 for the treatment of a wide variety of infections. Based on new safety data related to serious liver injury, described below, the Food and Drug Administration is today advising physicians that the drug Trovan should be reserved for use ONLY in the treatment of patients who meet

ALL of the following treatment criteria: Have at least one of the following infections that is judged by the treating physician to be serious and life- or limb-threatening: nosocomial pneumonia, community acquired pneumonia, complicated intra-abdominal infections (including post-surgical infections) gynecologic and pelvic infections, or complicated skin and skin structure infections, including diabetic foot infections; Receive their initial therapy in an in-patient health care facility (i.e., hospital or long-term nursing care facility); and The treating physician believes that, even given the new safety information, the benefit of the product for the patient outweighs the potential risk. In most cases, it is expected that therapy in these patients would begin with the intravenous formulation of Trovan.

 Due to the bioavailability of oral Trovan, patients who have stabilized clinically on IV therapy may be switched to oral Trovan to complete their course of therapy, if deemed appropriate by the treating physician. In some patients with these kinds of serious and life- or limb-threatening infections, oral Trovan may be considered appropriate initial therapy. Use of oral Trovan to treat less serious infections is not warranted. Therapy with Trovan beyond 14 days duration generally should not be used, because the risk of liver injury may increase substantially with exposure beyond 14 days. Trovan should be discontinued prior to 14 days of therapy if the patient experiences any clinical signs or symptoms of liver dysfunction, including fatigue, anorexia, yellowing of the skin and eyes, severe stomach pain with nausea and vomiting, or dark urine.

NEW SAFETY DATA No reports of hepatic failure, liver transplant, or death due to possible hepatic etiology were reported in the 7000 patients in the pre-marketing clinical trials database exposed to Trovan. It is estimated that approximately 2,500,000 patients have received Trovan since approval for marketing. Following marketing of Trovan in the United States in February 1998,

FDA began receiving reports of patients who experienced serious hepatic reactions in association with the use of the product. In July of 1998, FDA had worked with Trovan’s manufacturer to add information about hepatic toxicity to the Precautions section of Trovan’s package insert. Since that time, FDA has received reports of over 100 cases of clinically symptomatic liver toxicity in patients receiving Trovan. Some of these patients developed serious liver injury leading to liver transplant and/or death. At present, FDA is aware of 14 cases of acute liver failure that are strongly associated with Trovan exposure. Four of these patients required liver transplant (one of whom subsequently died). Five additional patients died of liver-related illness.

 Three patients recovered without transplantation, and the final outcome is still pending on two patients. These numbers of patients with acute liver failure, although few, represent a rate that appears to be significantly higher than would be expected to occur idiopathically in the general population - despite the under-reporting of cases that generally occurs to our post-marketing surveillance system. Trovan-associated liver failure appears to be unpredictable.

 It has been reported with both short-term (as little as 2 days exposure) and longer-term drug exposure; therefore the efficacy of liver function monitoring in acceptably managing this risk is uncertain. Trovan use exceeding 2 weeks duration appears to be associated with a substantially increased risk of acute liver failure. Liver failure has also been reported following Trovan re-exposure.

These uncommon but very serious adverse reactions are typical of drug toxicities which, because of their rarity, may not always be detectable in clinical trials databases. However, such toxicities may become apparent after marketing when the product is used in a significantly broader population. As such, these adverse reactions are the types of important, new safety information the post-marketing spontaneous reporting system is designed to detect, as it did in this case.

CONCLUSIONS

 FDA does not wish to deprive patients and physicians of access to effective antimicrobials, if the risks associated with these drugs can be managed successfully by other means. Based on the new safety data presently available to the agency and based on the availability of alternative products to treat other less serious indications for which this product was originally approved, FDA is issuing the interim recommendations outlined above.

 FDA and Pfizer have agreed to a program that will limit the distribution of Trovan to in-patient health care facilities (hospitals and long-term nursing care facilities). Pfizer will be communicating in the near future with appropriate pharmacies to provide directions concerning possible return of their present inventories of Trovan.

FDA believes that this risk management program will better ensure that Trovan is used in clinical situations in which its benefits can be expected to outweigh its presently known risks. In this manner, FDA believes that Trovan can continue to be made available to those patients who may need it for treatment of serious and life- or limb-threatening infections, while minimizing other patients’ risk of exposure to the product.

FDA advises patients presently taking Trovan NOT to discontinue their therapy until they have discussed their treatment options with their physician. FDA and the manufacturer will continue to collect and evaluate data on Trovan’s safety and will continue to assess the drug’s benefit/risk profile.

As further information or recommendations about Trovan become available, FDA will continue to inform the health care and patient communities. FDA requests that any suspected adverse events thought associated with Trovan be reported to the agency through MedWatch, FDA’s adverse event reporting system. Reports may be submitted to FDA by telephone (800-332-1088), by fax (800-332-0178) or by mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, Maryland 20857. Reports can also be filed via the Internet at www.fda.gov/medwatch.

 Reports may also be filed directly to the manufacturer.

==============================================================
18.) Questions and Answers on Trovafloxacin Public Health Advisory
==============================================================

What action is FDA announcing today? FDA is issuing a Public Health Advisory to inform physicians and the public regarding new safety information about Trovan (trovafloxacin/alatrofloxacin), an antibiotic used to treat many different types of infections. Trovafloxacin was approved for marketing in December, 1997, and became available on the market in February, 1998.

Its approved indications include many (14) types of infections that constitute a wide range of degrees of seriousness. Based on new safety data related to serious liver injury, FDA is advising physicians that trovafloxacin should be reserved for treatment ONLY in patients who meet ALL of the following criteria:

Who have at least one of five types of serious and life or limb-threatening infections listed below that is judged by the treating physician to be serious and life or limb-threatening; Nosocomial pneumonia (pneumonia acquired in the hospital): Community acquired pneumonia Complicated intra-abdominal infections, including post-surgical infections Gynecololgical and pelvic infections Complicated skin and skin structure infections, including diabetic foot infections Who begin their therapy in inpatient health care facilities (i.e., hospitals and long term nursing care facilities).

The treating physician believes that, given the new safety information, the benefit of the product for the patient still outweighs the potential risk.

2. What are the problems occurring with the use of Trovan? Following the marketing of Trovan in the United States in February 1998,

FDA began receiving reports of patients who experienced serious liver reactions in association with use of the product. In July of 1998, FDA worked with the manufacturer to add further information about this toxicity of the drug to Trovan’s label, or package insert, in order to inform practitioners . Since that time, FDA has received over 100 reports of cases of patients who were ill with symptoms of liver toxicity, in addition to others in which patients were without symptoms.

 Some of these patients developed serious liver injury leading to liver transplant and/or death. At present, FDA is aware of 14 cases in patients whose livers actually failed to function that are strongly associated with Trovan exposure. Four patients required liver transplantation (one of whom subsequently died).

Five additional patients died of liver-related disease. Three patients recovered from their acute liver failure without requiring a liver transplant. The final outcome of two other patients is pending. Trovan-associated liver failure appears to be unpredictable. It has been reported with treatment duration as short as two days and also in longer term exposure.

 It has been reported to occur in individuals over a wide range of ages, in men and in women, and in patients who were being treated for a wide variety of types of infection, many of which would not be considered serious or life-threatening. Also, when use exceeds two weeks there appears to be a substantial increase in risk of this toxicity.

Liver failure has also been reported following Trovan re-exposure after some period of being off the drug. These uncommon, but very serious adverse reactions, are typical of drug toxicities which, because of their rarity, may not be detected in clinical trials of drugs before marketing. However, they may become apparent after marketing when wider use of products occur among significantly more people. In the studies of Trovan approximately 7,000 patients were exposed to the drug. No cases of acute liver failure were reported in these pre-market clinical trials.

3. What does "limit distribution" mean? In this case, the manufacturer of Trovan has agreed to direct distribution of the product only to pharmacies in inpatient health care facilities (i.e., hospitals and long-term nursing care facilities).

This, in combination with labeling changes, educational programs and other risk communication strategies, will better ensure that Trovan is only used in clinical situations in which its demonstrated benefits can be expected to outweigh its presently known risks. In this manner, FDA believes that the product can continue to be made available to those patients who need it to treat serious life or limb-threatening infections, while minimizing other patients’ risk of exposure to the product.

4. When will the labeling changes take effect?

 FDA is working with the manufacturer of Trovan to make appropriate changes to the product’s label expeditiously. While the details of that change are being worked out, we are putting forward a Public Health Advisory to inform physicians and patients of this new information.

5. What should patients do if they are currently using Trovan?

Patients should contact their physician. Patients should NOT stop taking Trovan until their physician has recommended that they do so.

6. What are alternative therapies? Alternative therapies are different depending on what infection the patient is currently being treated for. That is why it is extremely important that patients direct questions about alternative therapy to their physician, who can then make an appropriate recommendation tailored to their needs. 7. How many people are currently using Trovan? It is estimated that approximately 300,000 prescriptions are written for Trovan per month in the United States.

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19.) Trovan (alatrofloxacin mesylate), Pfizer notifies
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[January 12, 1999 ( Letter) - Pfizer] Pfizer notifies health care professionals that the prescribing information for Trovan I.V. (alatrofloxacin mesylate injection) has been amended to include information on the potential incompatibility of alatrofloxacin mesylate injection with two commonly used diluents, 0.9% sodium chloride injection, USP (usually referred to as normal saline solution) and Lactated Ringer's, USP.

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20.) FDA ISSUES PUBLIC HEALTH ADVISORY ON LIVER TOXICITY ASSOCIATED WITH THE ANTIBIOTIC TROVAN =============================================================

Source: The FDA The Food and Drug Administration

today issued a public health advisory to physicians concerning the risks of liver toxicity associated with the use of Trovan (trovafloxacin, an oral antibiotic) and Trovan-IV (alatrofloxacin, the intravenous formulation of the drug). This action follows postmarketing reports of rare but severe liver injuries leading to transplants and deaths. In issuing this advisory, FDA is informing physicians that Trovan should be reserved for use only in patients who meet all of the following criteria:

Patients who have at least one of several specified infections such as nosocomial (hospital-acquired) pneumonia or complicated intra-abdominal infections that, in the judgment of the treating physician, is serious and life- or limb-threatening;

 Patients who begin their therapy in in-patient health care facilities (hospitals or longterm nursing care facilities); And patients for whom the treating physician believes that even given the new safety information, the benefit of the product outweighs the potential risks. FDA is further informing physicians that, in general, therapy with Trovan should not continue for longer than 14 days. Therapy should be discontinued sooner if the patient experiences any clinical signs of liver dysfunction, including fatigue, loss of appetite, yellowing of the skin and eyes, severe stomach pain with nausea and vomiting, or dark urine.

FDA is also advising physicians that for most patients who meet the treatment criteria, therapy would most likely begin with intravenous Trovan. After clinical stabilization patients may be switched to the oral dosage form. Although oral therapy might be appropriate in some cases as an initial therapy, the agency emphasizes that the oral form of Trovan is not warranted for infections other than those specified. In addition, the manufacturer has agreed to limit distribution of the product to hospitals and long-term nursing care facilities.

The manufacturer will be communicating in the near future with other appropriate pharmacies to provide directions concerning possible return of their present inventories of Trovan. FDA is taking this action to reduce the potential risk from Trovan, while at the same time preserving for physicians and patients alike the clinical option of an effective broad-spectrum antibiotic for serious and life- threatening infections.

The agency considers this advisory an interim measure until revised labeling for the product can be approved. It is estimated that 2.5 million prescriptions have been written for Trovan, a quinolone antibiotic, since its February 1998 market launch in oral and intravenous formulations. Trovan was initially approved for treating a broad range of infections, from minor skin infections to severe infections in hospitalized patients.

No reports of liver failure, liver transplant, or death due to liver problems were reported in the 7,000 patients studied in premarketing clinical trials for Trovan. In July 1998, FDA worked with the manufacturer to strengthen the product's labeling concerning liver problems after receiving reports of elevated liver enzymes and symptomatic hepatitis in patients after short- and long-term therapy. Since then, FDA has continued to receive reports of liver toxicity, including reports of a more serious nature.

FDA is now aware of 14 cases of acute liver failure that it has concluded are strongly associated with the drug. Six of these patients died: five due to liver failure and one of four additional patients who received liver transplants. Three patients recovered without requiring liver transplants, and for the remaining two patients the final outcome is still pending. More information about Trovan, including

FDA's public health advisory, is available on the World Wide Web at www.fda.gov/cder/news/trovan/default.html

 and from Pfizer, the manufacturer of the drug, at 1-800-438-1985. The FDA asks that any adverse events associated with Trovan be reported to the agency through MedWatch, FDA's adverse event reporting system. Reports may be submitted to FDA by telephone (800-332-1088), by fax (800-332-0178) or by mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, Md. 20857. Reports can also be filed via the internet at www.fda.gov/medwatch. Reports may also be filed directly to the manufacturer.

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21.) New Safety Recommendations for Use of Cisapride (Propulsid)
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Source: Harvard Heart Letter
April 2000 

Heart Lines

This month the Food and Drug Administration will hold a public advisory committee meeting to further discuss the safety of cisapride (Propulsid) and how to reduce the chances that someone will experience a severe adverse event from this drug.

The FDA first approved cisapride in tablet form in 1993 and then in liquid form in 1995. It is used to treat severe nighttime heartburn, usually due to gastroesophageal reflux disease (a condition where the band of muscle that prevents stomach acid from leaking back into the esophagus relaxes spontaneously, creating a painful heartburn-like sensation). Many drugs used to treat this condition suppress production of stomach acids. Cisapride works a little differently, moving the harmful acids through the digestive tract thereby preventing their painful reflux into the esophagus. Because this drug can be risky, it is generally reserved for use in patients who have not responded well to lifestyle changes or other medications used to manage gastroesophageal reflux disease.

In June 1998, several reports of serious adverse reactions in patients taking cisapride prompted the FDA to issue a warning about the drug. The medical problems included heart-rhythm disorders and death (most often occurring in people with certain health problems or who were taking other medications). Although it could not find a direct link between the reported problems and cisapride, the FDA did strengthen the precautions for use of this drug. A more recent analysis of 270 adverse event reports (including 70 deaths) suggests that roughly 85% of these cases were patients with these identifiable risks.

In January 2000, the FDA bolstered its efforts to reduce the likelihood of complications from cisapride by recommending that physicians consider performing an electrocardiogram and certain blood tests before prescribing it. New labeling lists drugs and underlying conditions that put patients at increased risk. Cisapride should not be used by patients taking some of the following types of medications: anti-allergy, anti-angina, anti-arrhythmics (to treat an irregular heart rhythm), antibiotics, antidepressants, anti-fungals, anti-nausea, antipsychotics, and protease inhibitors (to treat HIV infection). Also, patients with any of the following conditions should not take the drug: history of irregular heartbeats; abnormal electrocardiogram; heart disease; kidney disease; lung disease; low potassium, calcium, or magnesium levels; an eating disorder (such as bulimia or anorexia); dehydration or persistent vomiting.

If you are taking Propulsid (cisapride), then most likely your doctor is aware of the potential problems, but it may be worth having a conversation about it. If you are not on this medication but your doctor recommends it, be sure that he or she knows your complete medical history and is aware of all other medications you take. And ask about what, if any, medical tests you might need before you start taking this drug.

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22.)JANSSEN PHARMACEUTICA STOPS MARKETING CISAPRIDE IN THE US
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Janssen Pharmaceutica Inc., of Titusville, N.J., has announced that it has decided to stop marketing cisapride (Propulsid) in the United States as of July 14, 2000. The effective date of the voluntary action is intended to provide adequate time for patients and physicians to make alternative treatment decisions.
Cisapride is a prescription drug treatment approved only for severe nighttime heartburn experienced by adult patients with gastroesophageal reflux disease (GERD) that does not adequately respond to other therapies.

As of December 31, 1999, use of cisapride has been associated with 341 reports of heart rhythm abnormalities including 80 reports of deaths. Most of these adverse events occurred in patients who were taking other medications or suffering from underlying conditions known to increase risk of cardiac arrhythmia associated with cisapride.

Patients who are currently prescribed cisapride are urged to promptly contact their health care providers to discuss alternative treatments.

Physicians who are treating patients with severely debilitating conditions for whom they believe the benefits of the cisapride may still outweigh its risks are encouraged to contact Janssen at 1-800-JANSSEN. The company will continue to make the drug available to patients who meet specific clinical eligibility criteria for a limited-access protocol.

Since the drug’s approval in 1993, Cisapride’s labeling has been revised several times (most recently in January 2000, see FDA Talk Paper T00-6) to inform health care professionals and patients about the drug’s risks. Despite these risk management efforts, the firm decided in consultation with the Food and Drug Administration that continued general US prescription access to the drug poses unacceptable risks.

A public advisory committee meeting, previously scheduled for April 12 to discuss ways to reduce the occurrence of adverse events associated with cisapride, has been cancelled.

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23.) JANSSEN PHARMACEUTICA ANNOUNCES THE WITHDRAWAL OF HISMANAL FROM THE MARKET
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June 21, 1999 

Janssen Pharmaceutica, Inc., of Titusville, N.J., has announced that it isvoluntarily withdrawing the prescription antihistamine, Hismanal (astemizole) 10 mg., from the market.

Since the drugís approval in 1988, new adverse reaction data has required a series of labeling changes and warnings. In light of the choices of other prescription antihistamines now available, and the overall risk benefit profile of this drug, FDA supports the decision of the company to withdraw the product.

Patients who have been taking Hismanal for their allergy symptoms should consult with their doctors to determine an appropriate alternative treatment

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DATA-MEDICOS/DERMAGIC-EXPRESS No 3-(110)  15/12/ 2.001 DR. JOSE LAPENTA R. 
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