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DEAR DOCTOR LETTERS SENT REGARDING SEVERE ADRS TO AVELOX

FRANKFURT, Feb 14, 2008 (Reuters) - Bayer (BAYG.DE: Quote, Profile, Research) is sending letters warning doctors in Europe of rare incidents of severe liver and skin side effects in patients taking its Avelox antibiotic, the German drugs and chemicals group said on Thursday.

Bayer has included the additional warnings in the packaging of Avelox products since autumn last year after some incidents of severe side effects were monitored, but is now reinforcing this by writing to doctors.

"The side effects are very rare. But when it happens, it is quite severe to patients. We want doctors to be more aware," said Yvonne Moeller, a spokeswoman at Bayer.

Avelox, one of Bayer's top-selling drugs, saw sales of almost 400 million euros ($584.4 million) in 2006.

This is a copy of the European Dear Doctor Letter

February 2008
IMPORTANT INFORMATION REGARDING SERIOUS ADVERSE REACTIONS AND SAFETY MEASURES
Direct Healthcare Professional Communication regarding moxifloxacin (Avelox®) and serious hepatic and bullous skin reactions
Dear Healthcare Professional,
In agreement with EU regulatory authorities, including the Medicines and Healthcare products Regulatory Agency (MHRA), Bayer would like to inform you of important safety information. A recent assessment of adverse reactions associated with the use of moxifloxacin resulted in the following information and recommendations:
• Treatment with moxifloxacin is associated with a risk of developing fulminant hepatitis potentially leading to life threatening liver failure and risk of potentially life threatening bullous skin reactions like Stevens-Johnson-Syndrome (SJS) or toxic epidermal necrolysis (TEN).
• Due to limited clinical data, moxifloxacin is contraindicated in patients with impaired liver function (Child Pugh C) and in patients with transaminases increased > 5 fold the upper limit of normal (ULN).
• Patients should be advised to stop treatment and to contact their physician if early signs and symptoms of these reactions occur.
• The product information has been appropriately updated.
• Healthcare professionals are encouraged to report any suspected adverse reactions associated with the use of moxifloxacin.
Background
Moxifloxacin is known to impair liver function, and the product information was updated to include Stevens-Johnson-Syndrome (SJS) in 2002. A review of worldwide serious, including fatal, cases of both hepatotoxicity and bullous skin reactions such as SJS and toxic epidermal necrolysis (TEN) reported for moxifloxacin was recently performed.
Safety Concern
The liver injuries possibly related to moxifloxacin were more frequently of cholestatic or mixed hepatocellular-cholestatic than of hepatocellular type. Onset of symptoms was usually between 3 and 10 days. Isolated cases of delayed hepatotoxic effects were also identified and usually occurred 5 to 30 days after cessation of moxifloxacin therapy. Eight reports of fatal hepatic injuries were considered as possibly related to moxifloxacin therapy. Cases of positive re-challenge gave further evidence of a causal relationship. However, the majority of patients experiencing serious liver injuries where the outcome was reported improved or recovered.
TEN was reported in several cases where a causal relationship was considered possible; this included two cases with fatal outcome. Additionally, a total of 35 individual cases of SJS were
reported, including three cases where there was a fatal outcome and seven cases which were considered life-threatening. In these 10 cases of severe SJS, a progression to TEN was documented in three patients.
Based on the large patient exposure, the incidence of both life threatening liver injuries and TEN is very low, although a definite frequency cannot be calculated from these reports.
As a consequence of this review, Bayer has revised the product information for moxifloxacin across the EU.
Recommendations to Healthcare Professionals
We would like to remind you that moxifloxacin is contraindicated in patients with impaired liver function (Child Pugh C) and in patients with transaminases increased > 5 fold ULN.
We would like to further remind you to be vigilant for the early signs and symptoms of severe liver injury and bullous skin reactions like SJS or TEN. Patients should be advised to stop treatment immediately and to contact a physician if relevant signs or symptoms occur, including rapidly developing asthenia associated with jaundice, dark urine, bleeding tendency and hepatic encephalopathy.
When prescribing moxifloxacin, consideration should be given to official guidance on the appropriate use of antibacterial agents which is especially relevant with regard to treatment of less severe infections.
Call for reporting
If you have observed similar cases, please report adverse reactions to the MHRA or to Bayer HealthCare.
Suspected adverse reactions should be reported directly to the MHRA via the Yellow Card Scheme (information can be found at Hwww.yellowcard.gov.ukH) or to Bayer HealthCare Drug Surveillance Department either by phone on 01635 563500, fax 01635 563703, by e-mail to Hphdsguk@bayer.co.ukH.
Communication information
If you have any further questions please do not hesitate to contact Bayer HealthCare Medical Information department on 01635 563116 or by e-mail at medical.science@bayer.co.uk.
Yours sincerely,
Medical Director
Bayer Schering Pharma, Bayer plc

PRESS RELEASE Jan. 3, 2008

Antibiotic Leads to Tendon Ruptures; FDA Ignores Risks

Public Citizen Sues FDA in Federal Court to Force Agency to Act On
Petition Seeking Stricter Fluoroquinolone Warnings

WASHINGTON, D.C. – Despite long-standing evidence that
fluoroquinolone antibiotics can cause tendon ruptures, the Food and
Drug Administration (FDA) has failed to increase its warnings to
patients and physicians about the dangers of the medicines, Public
Citizen told a federal court Thursday.

Public Citizen sued in the U.S. District Court for the District of
Columbia, asking the court to force the FDA to act upon a petition
the consumer group filed with the agency 16 months ago. The FDA has
failed to respond to the petition, which asked the agency to put
a "black box" warning on fluoroquinolone antibiotics (such as Cipro,
Levaquin and others) to make doctors and patients more aware of the
risk of serious tendon injury before tendons actually rupture.

The petition also urged the FDA to send a warning letter to
physicians, as well as require an FDA-approved medication guide to be
dispensed when prescriptions are filled. Public Citizen contends that
the FDA is violating the Administrative Procedure Act by not acting
upon the petition.

Stronger warnings could lead to earlier intervention and prevent
needless injuries by allowing doctors to switch patients to other
antibiotics, said Dr. Sidney Wolfe, director of Public Citizen's
Health Research Group.

"While the FDA sits idly by and ignores the problem, more people
will suffer serious tendon ruptures that could have been prevented,"
Wolfe said. "The current warning is buried in a long list of possible
adverse reactions and is far too easy to miss."

From November 1997 through December 2005, the FDA received 262
reports of tendon ruptures, mainly of the Achilles tendon, 258 cases
of tendinitis and 274 cases of other tendon disorders in patients
using fluoroquinolone antibiotics. An additional 74 tendon ruptures
have subsequently been reported to the FDA for a total of 336.
Because only a small fraction of cases are typically reported to the
FDA, the actual number of ruptures and other tendon injuries
attributable to the antibiotic is much higher.

WASHINGTON - A consumer group sued the Food and Drug Administration Thursday, charging the agency is ignoring calls for stronger warnings that Cipro and similar antibiotics may cause serious tendon injuries.

Labels of the fluoroquinolone family of antibiotics — drugs that include the popular Cipro and Levaquin — already warn about rupture of tendons and other tendon injuries, but at the bottom of a list of other side effects.

The consumer group Public Citizen wants those warnings upgraded to the FDA's most severe type, a so-called black-box warning — and for patients to get pamphlets with every bottle that describe the risk. It argues that too few patients know they're supposed to quit using the drugs if they experience symptoms such as pain or inflammation, before the tendon actually ruptures.

Public Citizen filed a petition seeking the stronger warning in August 2006. The state of Illinois had filed a similar petition the previous year.

The FDA is violating its own statutes and putting patients at risk in taking so long to settle the issue, Public Citizen said in the suit filed in U.S. District Court for the District of Columbia.

When Public Citizen first filed the petition, FDA's database showed 262 reports of tendon ruptures between November 1997 and December 2005, along with hundreds of other tendon problems in users of these antibiotics. Since then, the FDA has received an additional 74 reports of tendon ruptures, said Public Citizen's Dr. Sidney Wolfe. Only a fraction of drug side effects typically are reported to the agency, he noted.

An FDA spokesman said the agency was evaluating the lawsuit and declined comment.