16 November 2018


Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics

EMA has reviewed serious, disabling and potentially permanent side effects with quinolone and fluoroquinolone antibiotics given by mouth, injection or inhalation. The review incorporated the views of patients, healthcare professionals and academics presented at EMA’s public hearing on fluoroquinolone and quinolone antibiotics in June 2018.
EMA’s human medicines committee (CHMP) has endorsed the recommendations of EMA’s safety committee (PRAC) and concluded that the marketing authorisation of medicines containing cinoxacin, flumequine, nalidixic acid, and pipemidic acid should be suspended.
The CHMP confirmed that the use of the remaining fluoroquinolone antibiotics should be restricted. In addition, the prescribing information for healthcare professionals and information for patients will describe the disabling and potentially permanent side effects and advise patients to stop treatment with a fluoroquinolone antibiotic at the first sign of a side effect involving muscles, tendons or joints and the nervous system.
Restrictions on the use of fluoroquinolone antibiotics will mean that they should not be used:
• to treat infections that might get better without treatment or are not severe (such as throat infections);
• to treat non-bacterial infections, e.g. non-bacterial (chronic) prostatitis;
• for preventing traveller’s diarrhoea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder);
• to treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.

Importantly, fluoroquinolones should generally be avoided in patients who have previously had serious side effects with a fluoroquinolone or quinolone antibiotic. They should be used with special caution in the elderly, patients with kidney disease and those who have had an organ transplantation because these patients are at a higher risk of tendon injury. Since the use of a corticosteroid with a fluoroquinolone also increases this risk, combined use of these medicines should be avoided.

The CHMP opinion will now be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU countries. National authorities will enforce this decision for the fluoroquinolone and quinolone medicines authorised in their countries and they will also take other appropriate measures to promote the correct use of these antibiotics.

Information for patients

• Fluoroquinolone medicines (which contain ciprofloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin and rufloxacin) can cause long-lasting, disabling and potentially permanent side effects involving tendons, muscles, joints and the nervous system.
• These serious side effects include inflamed or torn tendon, muscle pain or weakness, and joint pain or swelling, walking difficulty, feeling pins and needles, burning pain, tiredness, depression, problems with memory, sleeping, vision and hearing, and altered taste and smell.
• Tendon swelling and injury may occur within 2 days of starting treatment with a fluoroquinolone but may even occur several months after stopping treatment.
• Stop taking a fluoroquinolone medicine and contact your doctor at once in the following cases:
o at the first sign of tendon injury, such as tendon pain or swelling – rest the painful area;
o if you get pain, feel pins and needles, tingling, tickling, numbness or burning, or weakness especially in the legs or arms;
o if you get swelling in the shoulder, arms or legs, have walking difficulty, feel tired or depressed or have problems with your memory or with sleeping or you notice changes with your vision, taste, smell or hearing. You and your doctor will decide if you can continue treatment or if you need to take another type of antibiotic.
• You may be more prone to joint pain or swelling or tendon damage if you are aged over 60 years, your kidneys do not work well or you have received organ transplantation.
• Speak with your doctor if you are taking a corticosteroid (medicines such as hydrocortisone and prednisolone) or need to have treatment with a corticosteroid. You may be especially prone to tendon damage if you are taking a corticosteroid and a fluoroquinolone medicine at the same time.
• You should not take a fluoroquinolone medicine if you have ever had a serious side effect with a fluoroquinolone or a quinolone medicine and you should speak with your doctor immediately.
• If you have any questions or concerns about your medicines, speak to your doctor or pharmacist.

Information for healthcare professionals

• Fluoroquinolones are associated with prolonged (up to months or years), serious, disabling and potentially irreversible drug reactions affecting several, sometimes multiple, systems, organ classes and senses.
• The serious side effects include tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impaired hearing, vision, taste and smell.
• Tendon damage (especially to Achilles tendon but also other tendons) can occur within 48 hours of starting fluoroquinolone treatment but the damage may be delayed several months after stopping treatment.
• Patients who are older, have renal impairment or have had solid organ transplantation and those being treated with a corticosteroid are at higher risk of tendon damage. Concomitant treatment with a fluoroquinolone and a corticosteroid should be avoided.
• Fluoroquinolone treatment should be discontinued at the first sign of tendon pain or inflammation and patients should be advised to stop treatment with a fluoroquinolone and speak with the doctor in case of symptoms of neuropathy such as pain, burning, tingling, numbness or weakness so as to prevent development of potentially irreversible condition.
• Fluoroquinolones should generally not be used in patients who have had serious adverse reactions associated with the use of quinolone or fluoroquinolone medicines.
• Up-to-date summary of product characteristics should be consulted for authorised indications when considering treatment with a fluoroquinolone medicine. This is because the indications for these medicines have been restricted.
• The benefits and risks of fluoroquinolones will be monitored continuously and a drug utilisation study will evaluate the effectiveness of the new measures to reduce inappropriate use of fluoroquinolones by investigating changes in prescribing behaviour.
More about the medicine
Fluoroquinolones and quinolones are a class of broad-spectrum antibiotics that are active against bacteria of both Gram-negative and Gram-positive classes. Fluoroquinolones are of value in certain infections, including some life-threatening ones, where alternative antibiotics are not sufficiently effective.
The review covered medicines containing the following fluoroquinolone and quinolone antibiotics: cinoxacin, ciprofloxacin, flumequine, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, pipemidic acid, prulifloxacin and rufloxacin.
The review concerned only medicines given systemically (by mouth or injection) and inhaled medicines.
More about the procedure
The review of fluoroquinolones and quinolones was initiated on 9 February 2017 at the request of the German medicines authority (BfArM), under Article 31 of Directive 2001/83/EC.
The review was first carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines.
The final PRAC recommendations were adopted on 4 October 2018 and then sent to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which adopted the Agency’s opinion. The CHMP opinion will now be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.

FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq)

Safety Announcement

[05-18-2018] The U.S. Food and Drug Administration (FDA) is alerting the public that serious cases of neural tube birth defects involving the brain, spine, and spinal cord have been reported in babies born to women treated with dolutegravir used to treat human immunodeficiency virus (HIV). Preliminary results from an ongoing observational study in Botswana found that women who received dolutegravir at the time of becoming pregnant or early in the first trimester appear to be at higher risk for these defects.

Neural tube defects are birth defects that can occur early in pregnancy when the spinal cord, brain, and related structures do not form properly. To date, in this observational study there are no reported cases of babies born with neural tube defects to women starting dolutegravir later in pregnancy. We are investigating this new safety issue and will update the public when we have more information.

Dolutegravir is an FDA-approved antiretroviral medicine used in combination with other antiretroviral medicines to treat HIV, the virus that can cause acquired immunodeficiency syndrome (AIDS). Dolutegravir works by blocking integrase, an HIV enzyme, to prevent the virus from multiplying and can reduce the amount of HIV in the body. Stopping dolutegravir without first talking to a prescriber can cause the HIV infection to become worse. Approved in 2013, dolutegravir has been on the market for 5 years, and is available as a single ingredient product under the brand name Tivicay and as a fixed dose combination tablet with other HIV medicines under the brand names Juluca and Triumeq.

Patients should not stop taking dolutegravir without first talking to your health care professional because stopping your medicine can cause the HIV infection to worsen. In addition:

  • If you are already pregnant, stopping your dolutegravir-containing regimen without switching to alternative HIV medicines could cause the amount of virus to increase and spread HIV to your baby.
  • If you take a dolutegravir-containing regimen at the time of becoming pregnant and during the first trimester of pregnancy, there is a risk that your baby may develop neural tube defects. Neural tube defects happen early in pregnancy, before many women even know they are pregnant. For this reason, women of childbearing age should talk to their health care professional about other non-dolutegravir-containing antiretroviral medicines.
  • You should tell your health care professional if you are pregnant or are planning to become pregnant before you start a dolutegravir-containing regimen. Your health care professional may discuss other treatment options with you.
  • Women of childbearing age who decide to take a dolutegravir-containing regimen should consistently use effective birth control (contraception) while on HIV treatment. Women should talk to their health care professionals about an effective birth control method to use while taking a dolutegravir-containing regimen.
  • Before you start a dolutegravir-containing regimen you will need a pregnancy test to determine if you are already pregnant.

Health care professionals should inform women of childbearing age about the potential risk of neural tube defects when a dolutegravir-containing regimen is used at the time of conception and early in pregnancy. In addition:

  • Health care professionals should weigh the benefits and the risks of dolutegravir when prescribing antiretroviral medicines to women of childbearing age. Alternative antiretroviral medicines should be considered. Discuss the relative risks and benefits of appropriate alternative antiretroviral therapies.
  • If the decision is made to use dolutegravir in women of childbearing age, health care professionals should reinforce the consistent use of effective birth control.
  • Perform pregnancy testing before initiating a dolutegravir-containing regimen in women of childbearing age to exclude pregnancy.


Ongoing monitoring will continue as part of the observational study in Botswana. Additional birth outcomes are projected from pregnant women who were exposed to dolutegravir at the time of becoming pregnant. We will conduct a comprehensive review of the results and any other data that becomes available. We will update the public with any new information. To monitor birth outcomes of pregnant women, report pregnancy exposures to the Antiretroviral Pregnancy Registry at 1-800-258-4263.

We urge health care professionals and patients to report side effects involving dolutegravir or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

Related Information


Kenya has been awarded as the 98th membership to the WHO Programme for International Drug Monitoring.


Through a letter dated 4th May 2010, signed by Dr. Lembit Rägo, Coordinator, Quality Assurance and Safety: Medicines, Essential Medicines and Pharmaceutical Policies of the World Health Organization (WHO), he confirmed that Kenya was the 98th full member with immediate effect. “WHO considers this Programme a vital network in promoting Pharmacovigilance throughout the world” he adds.

The WHO Programme for International Drug Monitoring was set up in 1968 as a consequence of the so-called “Thalidomide tragedy”. It was discovered that Thalidomide could cause limb deformities if ingested by mothers during pregnancy became the modern starting point of a science focusing on patient problems caused by the use of medicines. This science and activities associated with it is now most commonly called PHARMACOVIGILANCE.

The Programme provides a forum for WHO member states to collaborate in the monitoring of drug safety. Within the Programme, individual case reports of suspected adverse drug reactions are collected and stored in a common database, presently containing over 5 million case reports. In each of the countries participating in the Programme, the government has designated a National Centre for Pharmacovigilance.

The WHO Programme, which was established in 1968, consists of a network of the National Centres, WHO Headquarters, Geneva and the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre, in Uppsala, Sweden. As of May 2010, 98 countries had joined the WHO Drug Monitoring Programme, and in addition, 32 'associate members' were awaiting compatibility between the national and international reporting formats.

Functions of the WHO Programme for International Drug Monitoring include:

· Identification and analysis of new adverse reaction signals from the case report information submitted to the National Centres, and sent from them to the WHO ICSR database. A data-mining approach (BCPNN) is used at the UMC to support the clinical analysis made by a panel of signal reviewers
· Provision of the WHO database as a reference source for signal strengthening and ad hoc investigations. Web-based search facilities and customized services are available
· Information exchange between WHO and National Centres, mainly through 'Vigimed', an e-mail information exchange system
· Publication of periodical newsletters, (WHO Pharmaceuticals Newsletter and Uppsala Reports), guidelines and books in the Pharmacovigilance and risk management area
· Supply of tools for management of clinical information including adverse drug reaction case reports. The main products are the WHO Drug Dictionary and the WHO Adverse Reaction Terminology
· Provision of training and consultancy support to National Centres and countries establishing Pharmacovigilance systems
· Computer software for case report management designed to suit the needs of National Centres (VigiFlow)
· Annual meetings for representatives of National Centres at which scientific and organizational matters are discussed
· Methodological research for the development of Pharmacovigilance as a science.

The Programme has become a global network of Pharmacovigilance centres in over 120 countries around the world. In each participating country the Ministry responsible for Health has appointed a National Centre for Pharmacovigilance responsible for maintaining contacts with WHO on issues related to medicines safety. In Kenya, the National Pharmacovigilance Centre is located at the Pharmacy and Poisons Board, the Medicines Regulatory Authority in Kenya, located along Lenana Road, Nairobi.

The Uppsala Monitoring Centre (UMC), the WHO Collaborating Centre for International Drug Monitoring is located in Uppsala, Sweden and manages a database of Individual Case Safety Reports (ICSRs) received from the national centres worldwide. Currently, the database called VigiBase contains around 5 million ICSRs in which medicines, including vaccines and biologicals, have been suspected of contributing to an adverse reaction in the exposed patient.

The Department of Pharmacovigilance is grateful to all of you who have supported the activities in Kenya by sending Suspected Adverse Drug Reaction reports, Poor Quality Medicines Complaints and supporting in other ways. You are encouraged to continue reporting to ensure patient safety.


Department of Pharmacovigilance Pharmacy and Poisons Board
Lenana Road
Ministry of Medical Services

November 19, 2010 — The US Food and Drug Administration (FDA) has asked that propoxyphene, sold under the brand names Darvon and Darvocet by Xanodyne Pharmaceuticals, be removed from the US market. The decision will also affect generic manufacturers and the makers of propoxyphene-containing products.

New clinical data showing that the drug puts patients at risk for potentially serious or even fatal heart rhythm abnormalities has prompted regulators to act. An estimated 10 million patients have used these products.

At a press conference today, John Jenkins, MD, director of the Office of New Drugs, said the new numbers tipped the risk–benefit ratio against the drug.

"For the first time, we now have data showing that the standard therapeutic dose of propoxyphene can be harmful to the heart," said Gerald Dal Pan, MD, director of the Office of Surveillance and Epidemiology.

The FDA is advising healthcare professionals stop prescribing propoxyphene. Patients who are currently taking the drug should not abruptly halt their medication but should contact their physician as soon as possible to discuss switching to another pain-management therapy.

"Long-time users of the drug need to know that these changes to the heart's electrical activity are not cumulative," Dr. Dal Pan added. "Once patients stop taking propoxyphene, the risk will go away."

Propoxyphene is an opioid typically used to treat mild to moderate pain. It was first approved by the FDA in 1957. It is sold by prescription under various names alone or in combination with acetaminophen. Since 1978, the FDA has received 2 requests to remove propoxyphene from the market.

In January 2009, an FDA advisory committee voted 14 to 12 against the continued marketing of propoxyphene products. At that time, the committee called for additional information about the drug's cardiac effects.

Withdrawal Already Underway in Europe

A phased withdrawal of propoxyphene is already underway in Europe. The European Medicines Agency made that decision in June 2009. The FDA had considered a withdrawal last year but decided instead to allow continued marketing with a new boxed warning alerting patients and healthcare professionals of the risk for fatal overdose. The agency also required Xanodyne to conduct a new safety study assessing questions about the effects of propoxyphene on the heart.

The results of this study, combined with new epidemiologic data and medical examiner reports, prompted this latest regulatory action.

Should the FDA have acted sooner? Dr. Dal Pan told Medscape Medical News that regulators did not feel there was sufficient evidence before now. "The new information on the effects of the electrical activity on the heart was the final piece to the puzzle," he said.

"These new heart data significantly alter propoxyphene's risk–benefit profile," Dr. Jenkins added. "The drug's effectiveness in reducing pain is no longer enough to outweigh the drug's serious potential heart risks."

From FDA

January 21, 2011 — New data showing nonsteroidal anti-inflammatory drugs (NSAIDs) have cardiovascular risks are putting the well-known pain relievers back in the headlines. Investigators evaluating available evidence report they have found little to suggest that any of the investigated options are safe.

Regulatory agencies have already pointed to cardiovascular signals with NSAIDs, but these concerns are based mainly on observational evidence. This new study provides a comprehensive analysis of all randomized controlled trials of the drugs.

During an interview with Medscape Medical News, senior investigator Peter Jüni, MD, from the University of Bern in Switzerland, said his team expected to see an increased risk but was surprised by the magnitude of the signal. "We never thought we'd see 2- and 4-fold increased risks," he said. "The doses were admittedly high," he pointed out, "however, this is clearly clinically relevant."

Several earlier meta-analyses were unable to resolve the debate over risk because they failed to include all randomized evidence in 1 study. This new network meta-analysis, published online January 11 in BMJ, includes all available evidence.

Investigators saw an increase in myocardial infarctions, stroke, and cardiovascular death in patients taking all of these NSAIDs. Not surprisingly, rofecoxib was associated with the highest risk for myocardial infarction, with a rate ratio of 2.12. The drug's manufacturer, Merck, voluntarily withdrew the product marketed as Vioxx in 2004 because of concerns over cardiotoxicity.

Lumiracoxib had the next highest rate of myocardial infarction in the current study. Ibuprofen was associated with the highest risk for stroke with a rate ratio of 3.36 followed by diclofenac at 2.86. Etoricoxib was linked to the highest rate of cardiovascular death at 4.07 followed by diclofenac at 3.98.

Dr. Jüni recommends that physicians take special care in evaluating patients prone to cardiovascular events. Those who require treatment should take the lowest possible dose for the shortest period.

Dr. Jüni says he would like to see black box warnings added to drug packaging for the products still available on the market.

Of all the NSAIDs, naproxen seemed least harmful in this study. The finding is in agreement with recommendations made by regulatory agencies when rofecoxib was first removed from the market and physicians were evaluating alternatives.

"I think we should reserve our final judgment on naproxen until after we've completed the overall safety study," Dr. Jüni said. His team is currently studying the gastrointestinal safety of the drug and weighing the benefits and risks from that perspective.

"With naproxen, we tend to need a proton pump inhibitor to protect the stomach," Dr. Jüni added. "This is far from ideal."

No Clear Link Between Specificity and Risk

In an interesting twist, investigators found no clear relation between specificity of cyclooxygenase-2 inhibitors and risk for cardiovascular events. This finding contrasts with previous claims that increased selectivity for cyclooxygenase-2 inhibitors is associated with cardiovascular risk.

Several mechanisms have been proposed, but the hypothesis of an imbalance between prostacyclin and thromboxane A2 leading to an increased risk for thrombotic events is the most well known.

The researchers suggest the lack of a clear association between specificity of cyclooxygenase-2 inhibitors and cardiovascular risk implies that other mechanisms should be considered. "Multiple effects most probably contribute to the increased risk of cardiovascular events, including differential effects on prostacyclin and thromboxane A2 synthesis, endothelial function, nitric oxide production, blood pressure, volume retention, and other renal effects," they note.

Millions of Patients Taking NSAIDs

"Given that both mechanistic and clinical data suggest that individual NSAIDs may have different cardiovascular risk profiles," Dr. Ray noted, "a natural question is, 'Which NSAID is safest for patients with high cardiovascular risk?'"

He points out the ongoing PRECISION trial, otherwise known as the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen, will eventually provide more information on the relative cardiovascular safety of these options. "Until these results become available, naproxen seems to be the best choice with regard to cardiovascular safety."

Dr. Ray says the controversy and confusion about the cardiovascular safety of these products provides an important lesson. "Drugs for symptomatic relief must be evaluated with regard to the target symptoms as well as less frequent yet serious adverse effects. NSAIDs are not an ideal treatment with respect to efficacy or safety. Perhaps it is time for a larger more systematic evaluation of a broader range of alternatives."

Clinical Implications

A previous meta-analysis found that acetaminophen was more effective compared with placebo in the treatment of OA, but it was not as effective as NSAIDs. However, NSAIDs were more likely to promote gastrointestinal discomfort vs acetaminophen.
In the current study, naproxen was associated with the best cardiovascular safety among the NSAIDs.

The antidepressant citalopram should not be used in doses higher than 40 mg per day because of concerns that it can cause potentially fatal changes in heart rhythm, the US Food and Drug Administration warns.

An alert issued to healthcare professionals and patients cautions that the drug has been linked to prolonged QT interval in a dose-dependent manner. Patients at particular risk for developing the condition include those with underlying heart disease and individuals who are predisposed to low levels of potassium and magnesium in the blood.

"Citalopram should not be used in patients with congenital long QT syndrome. Patients with congestive heart failure, bradyarrhythmias, or predisposition to hypokalemia or hypomagnesemia because of concomitant illness or drugs, are at higher risk of developing Torsade de Pointes, a rare type of ventricular tachycardia," the alert states.

According to the alert, research has shown that doses of citalopram of greater than 40 mg/day confer no additional benefit on depression outcomes. However, the citalopram drug label previously stated that certain patients may require a dose of 60 mg per day.

The drug label has since been revised to include the new drug dosage and usage recommendations, as well as information about the potential for QT interval prolongation and Torsade de Pointes.

Adverse events or quality concerns related to the affected products should be reported to Pharmacovigilance department, The Pharmacy and Poisons Board.

Source: Medscape medical news, August 24, 2011

Activated drotrecogin alfa is a recombinant form of human activated protein C. It was approved by the US Food and Drug Administration (FDA) nearly a decade ago to lower mortality rates in adults with severe sepsis and high mortality risk.
However, the efficacy of activated drotrecogin alfa has always been controversial. The original vote by the FDA advisory panel that recommended approval was 20 to 20. As of 2007, trials had failed to replicate favorable results from the pivotal Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study.
Eli Lilly is withdrawing activated drotrecogin alfa (Xigris), a drug intended to treat severe sepsis in high-risk patients, from all markets including the United States in the wake of a new study showing that the agent did no better than a placebo in reducing mortality risk.
The European Medicines Agency (EMA), the European equivalent of the FDA, announced on October 25 that the manufacturer had informed it of the decision to pull activated drotrecogin alfa from the market worldwide, as well as discontinue all ongoing clinical trials involving the drug.
The EMA stated that clinicians should stop ongoing treatment of patients with activated drotrecogin alfa and should no longer prescribe the agent to new patients — a warning repeated by the FDA.
The FDA announcement was also part of a worldwide voluntary market withdrawal of activated drotrecogin alfa. The agency warned that the drug should not be started in new patients and should be stopped in patients currently receiving the drug. Also, it has mandated that all remaining Xigris products be returned to the supplier.
Activated drotrecogin alfa is a recombinant form of human activated protein C. The drug’s efficacy has been questioned ever since the FDA authorized its use in the United States almost 10 years ago.
In an October 25 press release, the EMA stated that its Committee for Medicinal Products for Human Use had concluded in 2007 that ongoing studies could not reproduce the initial efficacy results reported by a pivotal clinical trial called the PROWESS trial. The committee asked the manufacturer to conduct a new test to confirm that "the benefits of Xigris outweigh its risks to patients with septic shock."
The new study, called PROWESS-SHOCK, reported a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study, according to the EMA, which did not deem the difference statistically significant. The risk for severe bleeding events, the main risk of the drug, was 1.2% and 1.0% for the activated drotrecogin alfa and placebo groups, respectively, "suggesting there is no increased harm." In contrast, a study published in 2009 had reported an increased risk for serious bleeding events and death in patients with sepsis who were treated with the drug.
Previous Study Findings: 2009
The 2009 study was a retrospective medical record review of 73 patients who received activated drotrecogin alfa (Gentry CA, Gross KB, Sud B, Drevets DA: Adverse outcomes associated with the use of drotrecogin alfa (activated) in patients with severe sepsis and baseline bleeding precaution. Crit Care Med. 2009;37:19-25).
Among 20 patients with risk factors of bleeding, serious bleeding events occurred in 7 patients (35%) vs only 2 (3.8%) of 53 patients without any bleeding risk factors. Mortality rate was 65% for patients with baseline risk factors of bleeding (13 of 20 patients) and 24.5% for patients without any bleeding risk factors at baseline (13 of 53 patients).
Definitive conclusions could not be drawn from these data because of study limitations including retrospective design and small sample size.
Baseline bleeding risk factors in this study were the same as described in the Contraindications and Warnings and Precautions sections of the Xigris package insert:
• Active internal bleeding
• Recent hemorrhagic stroke (within 3 months)
• Recent intracranial or intraspinal surgery (within 2 months), or severe head trauma
• Trauma with an increased risk of life-threatening bleeding
• Presence of an epidural catheter
• Intracranial neoplasm or mass lesion or evidence of cerebral herniation
More information about the withdrawal of activated drotrecogin alfa is available on the Web sites of the EMA andFDA.
News Author: Robert Lowes
Laurie Barclay, MD, contributed to this synopsis.
Source: Medscape

The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the label for Plavix, the anti-blood clotting medication. The Boxed Warning is about patients who do not effectively metabolize the drug (i.e. "poor metabolizers") and therefore may not receive the full benefits of the drug.

The Boxed Warning in the drug label will include information to:
* Warn about reduced effectiveness in patients who are poor metabolizers of Plavix. Poor metabolizers do not effectively convert Plavix to its active form in the body.
* Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function.
* Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.

Plavix is given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease. Plavix works by decreasing the activity of blood cells called platelets, making platelets less likely to form blood clots.
For Plavix to work, enzymes in the liver (particularly CYP2C19) must convert (metabolize) the drug to its active form. Patients who are poor metabolizers of the drug, do not effectively convert Plavix to its active form. In these patients, Plavix has less effect on platelets, and therefore less ability to prevent heart attack, stroke, and cardiovascular death. It is estimated that 2 to 14% of the population are poor metabolizers; the rate varies based on racial background.

Healthcare professionals should be aware that a subgroup of patients are poor metabolizers and do not metabolize Plavix effectively; this can result in reduced effectiveness of Plavix. Healthcare professionals should consider use of other anti-platelet medications or alternative dosing strategies for Plavix in these patients.
Patients should not stop taking Plavix unless told to do so by their healthcare professional. They should talk with their healthcare professional if they have any concerns about Plavix, or to find out if they should be tested for being a poor metabolizer.

In May 2009, FDA added information about poor metabolizers of Plavix to the drug label. However, based on additional data reviewed by the agency (see Data Summary below) the Boxed Warning is now being added to highlight the reduced effectiveness of Plavix in these patients and to recommend that healthcare professionals consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.

Patients currently taking Plavix should:
* Be aware that some patients do not convert Plavix to its active form as well as other patients. These patients may not get the same benefit from Plavix and are known as poor metabolizers.
* Not stop taking Plavix unless told to do so by their healthcare professional.
* Talk with their healthcare professional if they have any concerns about Plavix.
* Talk with their healthcare professional to see if testing to determine their metabolizer status is appropriate.

FDA recommends that healthcare professionals should:
* Be aware that some patients may be poor metabolizers of Plavix. They do not effectively convert Plavix to its active form because of low CYP 2C19 activity.The effectiveness of Plavix as a preventive therapy is reduced in these patients.
* Be aware that tests are available to determine patients' CYP2C19 status.
* Consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients who have been identified as poor metabolizers.
* Be aware that although a higher dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response, an appropriate dose regimen for poor metabolizers has not been established in a clinical outcome trial.
* Review the newly approved Plavix drug label for complete information on the use of Plavix

The liver enzyme CYP2C19 is primarily responsible for the formation of the active metabolite of Plavix. Pharmacokinetic and antiplatelet tests of the active metabolite of Plavix show that the drug levels and antiplatelet effects differ depending on the genotype of the CYP2C19 enzyme. The following represent the different alleles of CYP2C19 that make up a patient's genotype:
* The CYP2C19*1 allele has fully functional metabolism of Plavix.
* The CYP2C19*2 and *3 alleles have no functional metabolism of Plavix. These two alleles account for most of the reduced function alleles in patients of Caucasian (85%) and Asian (99%) descent classified as poor metabolizers.
* The CYP2C19*4, *5, *6, *7, and *8 and other alleles may be associated with absent or reduced metabolism of Plavix, but are less frequent than the CYP2C19*2 and *3 alleles.
* A patient with two loss-of-function alleles (as defined above) will have poor metabolizer status.

The pharmacokinetic and antiplatelet responses to Plavix were evaluated in a crossover trial in 40 healthy subjects. Ten subjects in each of the four CYP2C19 metabolizer groups (ultrarapid, extensive, intermediate and poor) were randomized to two treatment regimens: a 300 mg loading dose followed by 75 mg per day, or a 600 mg loading dose followed by 150 mg per day, each for a total of 5 days. After a washout period, subjects were crossed over to the alternate treatment. Decreased active metabolite exposure and increased platelet aggregation were observed in the poor metabolizers compared to the other groups. When poor metabolizers received the 600 mg loading dose followed by 150 mg daily, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen. Healthcare professionals should note that an appropriate dose regimen for patients who are poor metabolizers has not been established in clinical outcome trials.

Source: Food and Drug Administration

On Feb. 8 the U.S. Food and Drug Administration approved the cholesterol-lowering medication Crestor (rosuvastatin) for some patients who are at increased risk of heart disease but have not been diagnosed with it.

The new indication is for reducing the likelihood of a heart attack or stroke or the need for a procedure to treat blocked or narrowed arteries in patients who have never been told they have heart disease but are nevertheless at increased risk of a cardiac event.
Specifically, this includes men 50 years of age and older and women 60 years of age and older who have an elevated amount of a substance known as high sensitivity C-reactive protein in their blood and at least one additional traditional cardiovascular risk factor such as smoking, high blood pressure, a family history of premature heart disease, or low amounts of high-density lipoprotein or HDL cholesterol, the so-called “good cholesterol.”
This new indication does not support the use of Crestor in individuals who have an elevated high sensitivity C-reactive protein but no traditional cardiovascular risk factors.
Crestor is in a class of drugs called statins, which work by stopping an enzyme called HMG-CoA reductase from making cholesterol. High amounts of low-density lipoprotein or LDL cholesterol, the so-called “bad cholesterol,” is a known risk factor for heart attacks, strokes, and heart disease.
“This expanded indication for Crestor will provide health care providers with a new therapeutic option to help appropriately-identified people lower their risk for a cardiac event,” said Eric Colman M.D., deputy director, Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research.
The new indication was based on results from a study called the JUPITER trial, which compared 8,901 patients who received Crestor for two years to the same number of patients who received a placebo. Patients who took Crestor experienced fewer cardiac events, including heart attacks and strokes, and underwent fewer procedures such as coronary angioplasty or coronary artery bypass surgery to treat or revascularize their arteries.
High sensitivity C-reactive protein is a nonspecific indicator of inflammation, which is associated with the buildup of cholesterol and other fatty material in the coronary arteries.
Crestor is already approved for use in combination with diet and exercise to lower LDL cholesterol and a related substance known as triglycerides in patients with a high amount of these substances in their blood. The medication is also approved to slow the progression of atherosclerosis – a thickening of the artery wall due to the buildup of cholesterol and other fatty materials.
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February 19, 2010 -- The U.S. Food and Drug Administration today announced that drugs in the class of long-acting beta agonists (LABAs) should never be used alone in the treatment of asthma in children or adults. Manufacturers will be required to include this warning in the product labels of these drugs, along with taking other steps to reduce the overall use of these medications.

These new requirements are based on FDA analyses of clinical trials showing that use of these long-acting medicines is associated with an increased risk of severe worsening of asthma symptoms, leading to hospitalization in both children and adults and death in some patients with asthma. The drugs involved include the single agent products Serevent and Foradil and combination medications Advair and Symbicort that also contain inhaled corticosteroids. These medications improve a patient’s ability to breathe freely and reduce the symptoms of asthma by relaxing muscles in the lung’s airways.

The FDA will now require that the product labels reflect the following:

* The use of LABAs is contraindicated without the use of an asthma controller medication such as inhaled corticosteroid. Single-agent LABAs should only be used in combination with an asthma controller medication; they should not be used alone;
* LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications;
* LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller medication.
* Pediatric and adolescent patients who require a LABA in addition to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA to ensure compliance with both medications.

“Although these medicines play an important role in helping some patients control asthma symptoms, our review of the available clinical trials determined that their use should be limited, whenever possible, due to an increased risk of asthma exacerbations, hospitalizations and death,” said Badrul Chowdhury, M.D., director of the Division of Pulmonary and Allergy Products in the FDA’s Center for Drug Evaluation and Research.

“The risks of hospitalization and poor outcomes are of particular concern for children; parents need to know that their child with asthma should not be on a LABA alone,” said Dianne Murphy, M.D., director of the FDA’s Office of Pediatric Therapeutics.

LABAs are approved to treat both people with asthma or with chronic obstructive pulmonary disease (COPD). The new recommendations only apply to the use of LABAs in the treatment of asthma.

The FDA will be requiring the manufacturers of LABAs to conduct additional studies to further evaluate the safety of LABAs when used in combination with inhaled corticosteroids. The FDA will seek input on the design of these studies at a public advisory committee meeting in March 2010.

In addition to these actions, FDA will work with public and private partners under the agency’s ongoing Safe Use Initiative to study LABA prescribing practices.

“We will collaborate with our Safe Use partners to evaluate whether prescribing patterns adjust to the new recommendations for this class of asthma drugs. If prescribing patterns don’t adjust, we will determine the reasons and consider additional steps to support safe prescribing,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

The Safe Use Initiative, launched in November, strives to reduce preventable harm by identifying specific, preventable medication risks and developing, implementing and evaluating cross-sector interventions with public and private partners who are committed to safe medication use.

Advair and Serevent are marketed by Collegeville, PA-based GlaxoSmithKline.

Foradil is marketed by Lebanon, PA-based Novartis AG. Symbicort is marketed by Wilmington, DE-based AstraZeneca.

Source: Food and Drug Administration

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