Follow-up to the January 25, 2008 Early Communication about an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor)
On January 25, 2008, FDA announced that it would be reviewing data from the ENHANCE trial (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia). (http://www.fda.gov/cder/drug/early_comm/ezetimibe_simvastatin.htm). Preliminary results from this trial had indicated that there was no significant difference between Vytorin and simvastatin-treated patients in the thickness of the carotid (neck) arteries despite greater lowering of LDL (bad) cholesterol with Vytorin compared to simvastatin. The thickness of the carotid arteries, also known as carotid intima-media thickness or cIMT, is a marker of risk for cardiovascular disease. The preliminary results from the ENHANCE trial raised several questions, some of which involve the relationship of cIMT to LDL cholesterol levels and the role of cIMT in drug development.
The FDA has completed its review of the final clinical study report of ENHANCE. Following two years of treatment, carotid artery thickness increased by 0.011 mm in the Vytorin group and by 0.006 mm in the simvastatin group. The difference in the changes in carotid artery thickness between the two groups was not statistically significant. However, the levels of LDL cholesterol decreased by 56% in the Vytorin group and decreased by 39% in the simvastatin group. The difference in the reductions in LDL cholesterol between the two groups was statistically significant.
The results from ENHANCE do not change FDA’s position that an elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease. Based on current available data, patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about Vytorin, Zetia, or the ENHANCE trial.
ENHANCE was a randomized, double-blind, active-controlled trial conducted in patients with heterozygous familial hypercholesterolemia (HeFH). A total of 725 patients were randomized 1:1 to receive either Vytorin 10/80 (ezetimibe 10 mg plus simvastatin 80 mg) or simvastatin 80 mg for 2 years. The primary efficacy outcome was the change in ultrasound-determined carotid artery thickness (or cIMT).
Based on data from a previously-conducted cIMT study1 and the anticipated degree of cholesterol lowering with Vytorin and simvastatin, it was projected that 2 years of treatment with Vytorin in ENHANCE would lead to a decrease in cIMT of approximately 0.03 mm whereas treatment with simvastatin would lead to an increase in cIMT of approximately 0.02 mm. There are several possible explanations for why the larger reduction in LDL cholesterol observed in the Vytorin group did not translate into significant improvement in cIMT. These include:
- enrollment of a patient population who had received prior lipid-altering or statin therapy and had relatively normal cIMT values at baseline which may make it harder to demonstrate a reduction or improvement in cIMT with Vytorin compared with simvastatin therapy
- the 2-year duration of ENHANCE which may have been too short to see a favorable effect of cholesterol lowering on cIMT
- some other unknown properties of ezetimibe that may negate the beneficial effects of LDL lowering on cIMT.
An ongoing trial known as IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) is examining whether treatment with Vytorin reduces the risk for cardiovascular events (composite endpoint of CV death, major coronary events, and stroke) compared with simvastatin alone. This trial of 18,000 patients is scheduled to be completed in 2012. IMPROVE-IT will provide additional data regarding Vytorin’s effect on the risk for cardiovascular disease.
Pending the results from IMPROVE-IT, patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about these medications.
Ezetimibe (Zetia) is an inhibitor of intestinal cholesterol absorption approved to reduce LDL cholesterol levels. Simvastatin (Zocor) is a lipid-lowering drug (“statin”) approved to reduce LDL (bad) cholesterol and increase HDL (good) cholesterol levels and reduce the risk of cardiovascular events such as heart attack and stroke. Vytorin is a combination of ezetimibe and simvastatin approved for reducing LDL and increasing HDL cholesterol levels.
This follow-up communication is in keeping with FDA’s commitment to informing the public about its ongoing safety reviews of drugs.
The FDA urges both healthcare professionals and patients to report side effects from the use of lipid lowering drugs to the FDA’s MedWatch Adverse Event Reporting program
- on-line at www.fda.gov/medwatch/report.htm
- by returning the postage-paid FDA form 3500 (available in PDF format at www.fda.gov/medwatch/getforms.htm) to 5600 Fishers Lane, Rockville, MD 20852-9787
- faxing the form to 1-800-FDA-0178
- by phone at 1-800-332-1088
1 Smilde T, et al. Effect of aggressive versus conventional lipid lowering on athersclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomized double-blind study; Lancet 2001;357:577-581
Follow-up to the March 27, 2008, Communication about the Ongoing Safety Review of Montelukast (Singulair)
This information reflects FDA’s current analysis of available data concerning this drug.
On March 27, 2008, FDA announced that it was reviewing safety data that raised concerns about a possible association between the use of montelukast and behavior/mood changes, suicidality (suicidal thinking and behavior) and suicide.
FDA requested manufacturers of products indicated for the treatment of asthma and/or allergic rhinitis that act through the leukotriene pathway (montelukast, zafirlukast, zileuton) to submit adverse event data for suicidality adverse events as well as mood and behavioral-related adverse events from all available placebo-controlled clinical trials. (Early Communication About an Ongoing Safety Review of Montelukast (Singulair), http://www.fda.gov/cder/drug/early_comm/montelukast.htm). FDA stated at the time that it expected its preliminary review to take about 9 months and that it would communicate its conclusions and any resulting recommendations to the public at the completion of its review.
FDA requested that Merck, Astra Zeneca, and Cornerstone Therapeutics use the Columbia Classification Algorithm of Suicide Assessment (C-CASA) to classify suicidal events. Merck submitted results from 41 placebo-controlled clinical trials in patients 6 years of age and older, of which 9929 were treated with montelukast and 7780 were treated with a placebo. One adult patient (0.01%) out of 9929 patients treated with montelukast had suicidal ideation and there were no completed suicides. No patients in the placebo group had suicidal ideation or suicide. Astra Zeneca submitted results from 45 placebo-controlled clinical trials in patients 5 years of age and older, of which 7540 were treated with zafirlukast and 4659 were treated with a placebo. No patients treated with zafirlukast had suicidal ideation or completed suicide. Two patients in the placebo group (0.04%) had suicidality (one suicide attempt and one suicidal ideation). Cornerstone Therapeutics submitted results from 11 placebo-controlled clinical trials in patients 12 years of age and older, of which 1745 were treated with zileuton and 1063 were treated with a placebo. No patients treated with zileuton or placebo had suicidal ideation or completed suicide. Although these data do not suggest that montelukast, zafirlukast, or zileuton are associated with suicide or suicidal behavior, these clinical trials were not designed specifically to examine neuropsychiatric events. As a result, some events may not have been reported.
FDA is continuing to review clinical trial data to assess other neuropsychiatric events, (mood and behavioral adverse events) related to drugs that act through the leukotriene pathway (montelukast, zafirlukast, zileuton). As a result, FDA has not yet reached a definitive conclusion regarding the clinical trial data on mood and behavioral adverse events associated with montelukast, zafirlukast, and zileuton. We will communicate our conclusions and any resulting recommendations to the public at the conclusion of the review, which may take months to complete.
Post-marketing reports of neuropsychiatric events associated with montelukast, zafirlukast and zileuton have been reported to FDA’s Adverse Event Reporting System (AERS). Most of the reports of neuropsychiatric events are associated with montelukast, currently the most commonly prescribed drug that acts through the leukotriene pathway. The clinical details of some reports involving montelukast are consistent with a drug-induced effect. Because of the paucity of reports involving zafirlukast and zileuton, assessment of a drug–induced effect with these is limited. Accordingly, at this time, patients and prescribers should monitor for the possibility of neuropsychiatric events associated with these agents.
Singulair (montelukast) is a medicine in the drug class known as leukotriene receptor antagonists. Leukotriene receptor antagonists work by blocking substances in the body called leukotrienes. Leukotrienes are chemicals the body releases in response to an inflammatory stimulus, such as when a person breathes in an allergen. Singulair is used to treat asthma and the symptoms of allergic rhinitis (sneezing, stuffy nose, runny nose, itching of the nose) and to prevent exercise-induced asthma. Accolate (zafirlukast) is also a medicine in the drug class known as leukotriene receptor antagonists. Accolate is used to treat asthma. Zyflo and Zyflo CR (zileuton) are medicines in the drug class known as leukotriene synthesis inhibitors. Leukotriene synthesis inhibitors work by stopping the formation of certain natural substances that cause swelling, tightening, and mucus production in the airways. Zyflo and Zyflo CR are used to treat asthma.
The FDA urges both healthcare professionals and patients to report side effects from the use of Singulair, Accolate, Zyflo, and Zyflo CR to the FDA’s MedWatch Adverse Event Reporting program
- online at www.fda.gov/medwatch/report.htm
- by returning the postage-paid FDA form 3500 available in PDF format at www.fda.gov/medwatch/getforms.htm to 5600 Fishers Lane, Rockville, MD 20852-9787
- faxing the form to 1-800-FDA-0178
- by phone at 1-800-332-1088
Potential Hazards of Skin Products Containing Numbing Ingredients for Relieving Pain from Mammography and Other Medical Tests and Conditions
January 27, 2009 · Filed Under Side Effect Facts · CommentFDA is issuing this advisory to remind patients, healthcare professionals, and caregivers about potentially serious hazards of using skin numbing products, also known as topical anesthetics, for relieving pain from medical tests and conditions. In February 2007, FDA issued a Public Health Advisory- Life-Threatening Side Effects with the use of Skin Products Containing Numbing Ingredients for Cosmetic Procedures -that described the deaths of two young women who used topical anesthetics prior to laser hair removal [http://www.fda.gov/cder/drug/advisory/topical_anesthetics.htm]. Now, FDA is aware that lidocaine, a type of topical anesthetic, was studied to see if it may reduce discomfort during breast mammography1.
During the study, the topical product was spread over a wide area and covered with plastic wrap. Although no serious side-effects were reported in this study, it was not large enough to evaluate whether uncommon but serious reactions could occur with this use. FDA remains concerned about the potential for topical anesthetics to cause serious and life-threatening adverse effects when applied to a large area of skin or when the area of application is covered.
Topical anesthetics work by blocking pain sensation in the skin. Some of the medication in a topical anesthetic can pass through the skin into the blood stream. More of the medication will pass into the blood stream if the topical anesthetic is applied over a large area of the skin, if a large amount is applied, if it is applied to irritated or broken skin, or if the skin temperature increases. Skin temperature can increase during exercise, by covering the skin with a wrap, or with use of a heating pad. Under these circumstances, the amount of anesthetic medication that reaches the blood stream is unpredictable and may be high enough to cause life-threatening adverse effects such as irregular heartbeat, seizures, breathing difficulties, coma and even death.There are several topical anesthetics available by prescription and over-the-counter. When used appropriately, these products may provide safe and effective pain relief. Before recommending a topical anesthetic for any purpose, doctors should determine if the desired amount of pain relief can be achieved safely with a topical anesthetic, or if a different treatment would be more appropriate. If a topical anesthetic is determined to be the best choice, the lowest needed amount should be prescribed. Patients should speak with their doctor if they are considering using a topical anesthetic before a mammogram. If a topical anesthetic is recommended then patients should:
- use a topical anesthetic that contains the lowest amount possible of medication that will relieve the pain;
- apply the topical anesthetic sparingly and only to the area where pain exists or is expected to occur;
- not apply the topical anesthetic to broken or irritated skin.
- ask their doctor what side effects are possible and how to lower their chance of having life-threatening side effects from anesthetic drugs.
- be aware that if wrapping or covering the skin with any type of material or dressing is recommended or considered, this can increase the chance of serious side effects, as can applying heat to the treated area while the medication is still present.
FDA is working with healthcare professional organizations and other media that distribute healthcare information to spread the message about the potential hazards and safe use of topical anesthetics.
1Lambertz CK et al. Premedication to Reduce Discomfort during Screening Mammography. Radiology 2008; 248 (3): 765-72.
Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as Plavix)
January 27, 2009 · Filed Under Side Effect Facts · CommentThis information reflects FDA’s current analysis of available data concerning these drugs. Posting this information does not mean that FDA has concluded there is a cause and effect relationship between the drug products and the emerging safety issue. Nor does it mean that FDA is advising health care professionals to discontinue prescribing these products. FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action. FDA intends to update this document when additional information or analyses become available
The FDA is aware of published reports that clopidogrel (marketed as Plavix) is less effective in some patients than it is in others. Differences in effectiveness may be due to genetic differences in the way the body metabolizes clopidogrel,1, 2 or that using certain other drugs with clopidogrel can interfere with how the body metabolizes clopidogrel.3
Clopidogrel is an antiplatelet drug that is used to prevent blood clots that could lead to heart attacks or strokes in patients at risk for these problems. The drug clopidogrel is a “pro-drug” which means that it has to be metabolized by the body before it can be biologically active and have the effect of preventing blood clots. Understanding that there are differences in how the body metabolizes clopidogrel and there are effects that other drugs may have on its metabolism is important because decreases in the effectiveness of clopidogrel might be avoided, in part, by using other drugs with clopidogrel that do not interfere with its metabolism.
One class of drugs commonly used with clopidogrel is proton pump inhibitors (PPIs). Some reports suggest that use of certain PPIs may make clopidogrel less effective3, 4 by inhibiting the enzyme that converts clopidogrel to the active form of the drug. Other reports do not suggest this effect.5, 6 Proton pump inhibitors decrease stomach acid and are used to treat frequent heartburn and stomach ulcers. Clopidogrel can irritate the stomach so PPIs are commonly used with clopidogrel to help reduce this irritation. PPIs include omeprazole (Prilosec, Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), rabeprazole (Aciphex), and esomeprazole (Nexium), which are all available by prescription. Omeprazole (Prilosec OTC) is also sold without a prescription (over-the-counter) for frequent heartburn.
Currently, we have no evidence that other drugs that reduce stomach acid, such as H2 blockers (e.g., Zantac, Pepcid, Tagamet and Axid) or antacids interfere with the antiplatelet activity of clopidogrel.
The makers of Plavix, Sanofi-Aventis and Bristol-Myers Squibb, have agreed to work with FDA to conduct studies to obtain additional information that will allow us to better understand and characterize the effects of genetic factors and other drugs (especially the PPIs) on the effectiveness of clopidogrel. This information should lead to a better understanding about how to optimize the use of clopidogrel. The FDA recognizes the importance of obtaining these data promptly. The drug manufacturers have agreed to a timeline for completing the studies. The FDA will review the new information expeditiously upon receipt from the drug manufacturers and will communicate its conclusions and any recommendations to the public at that time. It could take several months to complete the studies and analyze the results.
Until further information is available FDA recommends the following:
- Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke.
- Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel.
- Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI, including Prilosec OTC.
This early communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs.
The FDA urges both healthcare professionals and patients to report side effects from the use of clopidogrel to the FDA’s MedWatch Adverse Event Reporting program
- online at www.fda.gov/medwatch/report.htm;
- by returning the postage-paid FDA form 3500 available in PDF format at www.fda.gov/medwatch/getforms.htm to 5600 Fishers Lane, Rockville, MD 20852-9787;
- faxing the form to 1-800-FDA-0178; or
- by phone at 1-800-332-1088
1 Frere C et al, Effect of cytochrome P450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008; 101:1088-93.
2 Trenk et al. Cytochrome P450 2C19 681G A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925-34.3 Gilard M et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopidogrel Aspirin) Study. J Am Coll Cardiol 2008: 51:256-60.
4 Gilard M et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost 2006; 4:2508-9.
5 Small DS et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 2008; 48: 475-484.
6 Siller-Matula JM et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009; 157:148e1-148.e5.Bromazepam 3 mg Side Effect occurred on 2009-01-25
January 25, 2009 · Filed Under Side Effect Facts · Commentinsomnia,confusion,depressionGlucusamine 1500mg Side Effect occurred on 2009-01-20
January 20, 2009 · Filed Under Uncategorized · Commentcartilage forming in my palms of my hands, finger joints and thumbs jointsGlucusamine 1500mg Side Effect occurred on 2009-01-20
January 20, 2009 · Filed Under Uncategorized · Commentcartilage forming in my palms of my hands, finger joints and thumbs jointsForavance Side Effect occurred on 2009-01-20
January 20, 2009 · Filed Under Side Effect Facts · Commentfatigue, listless, join painEzetimibe Side Effect occurred on 2009-01-15
January 15, 2009 · Filed Under Side Effect Facts · CommentItching around eyes and face along with sleeplessnEzetimibe Side Effect occurred on 2009-01-15
January 15, 2009 · Filed Under Side Effect Facts · CommentItching around eyes and face along with sleeplessn
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