FDA MEDWATCH and Health Canada ALERTS - 2008       
                                                    Links to previous Alerts

TUSSIONEX
Life-threatening adverse events and death have been reported with inappropriate use of the cough medicine Tussionex, which contains hydrocodone and clorpheneramine. Tussionex is an extended-release preparation and ingestion more often than every 12 hours could result in narcotic overdose and respiratory depression. Because risk for respiratory depression is greater in young children, Tussionex is contraindicated in children under age 6 years. If symptoms of hydrocodone overdose occur, such as difficulty breathing, slow heartbeat, severe sleepiness, cold clammy skin, or feeling faint, dizzy, or confused, immediate medical attention is required.

NATALIZUMAB
The monoclonal antibody natalizumab (Tysabri) has been available for resistant multiple sclerosis and was recently approved for treatment of moderate-to-severe Crohn's disease. It is available only through participation in a prescription-management registry program. Liver injury is a known serious adverse effect in patients receiving concurrent immunosuppresants. Warnings and Precautions have been added to the prescribing information concerning the possibility for natalizumab to cause marked elevations in hepatic enzymes and bilirubin as soon as 6 days after staring treatment. Natalizumab should be discontinued if patients show signs of jaundice or laboratory evaluations suggest liver injury.

TRANSDERMAL FENTANYL

Activis Inc. has recalled all transdermal fentanyl CII (Duragesic) patches sold in the U.S. because a manufacturing defect was found in several lots. This "fold-over defect" could cause active medication to leak from the patch, which can lead to patient overdose and respiratory depression. Caregivers who come in contact with leaked fentanyl gel should immediately rinse the exposed area with water only; exposed skin should not be washed with soap.

TAMIFLU
In 2006 the FDA issued a warning about neuropsychiatric adverse effects including delirium and self-injury in patients taking oseltamivir (TamiFlu). In 2007, the Pediatric Advisory Committee recommended updating the Precautions section of the label to include this information. The label has now been revised and includes data from postmarketing reports (primarily from Japan) of delirium and sometimes fatal abnormal behavioral in patients taking TamiFlu. Onset was usually abrupt and resolution of the symptoms was rapid. Although estimates of the occurrence can not be calculated based on available data, the events appear to be uncommon. Influenza can cause neurologic and behavioral symptoms such as hallucinations, delirium, and abnormal actions that lead to injury, and a causal association with TamiFlu has not been established.

ORTHO EVRA PATCH
Venous thromboembolism is a concern with all hormonal contraceptives. Because of differences in absorption, women who use transdermal Ortho Evra are exposed to about 60% more estrogen than women who take oral contraceptives. This could increase risk for adverse events. According to a recent epidemiological study in women aged 15–44 years, the Ortho Evra patch is associated with higher risk for VTE than oral birth control pills. Previous research had mixed results, with 1 study showing a 2-fold increase in risk with the patch and another showing no increase. The results of the newest research have been added to the product label.

EDTA NAME CONFUSION
Because they have similar names and are sometimes referred to as EDTA, edentate disodium (Endrate) has been administered in place of edetate calcium disodium (Calcium Disodium Versenate) and vice versa. The outcome of this substitution can be fatal. Edetate calcium disodium (Calcium Disodium Versenate) is approved as chelation therapy for lead poisoning and there are few other treatment options. In contrast, edetate disodium (Endrate) is approved to treat hypercalcemia and heart rhythm problems associated with high serum digitalis levels. Because there are newer drugs available to treat hypercalcemia and digitalis-related problems, the FDA is reviewing the risk/benefit profile for edetate disodium (Endrate) to determine if regulatory action should be taken.

PEDIARIC COLD MEDICINES
The FDA has completed its safety review of over-the-counter cough and cold preparations in children aged <2 years. The review of these medicines in children aged 2–11 years is still underway. The FDA now recommends that these agents not be used in children under 2 years because of the potential for serious and life-threatening adverse effects. Many manufacturers have withdrawn these products from the market, but others remain available. The agents are intended to treat the symptoms only and do not affect the underlying disease or the duration of illness. Many cough and cold medications contain more than 1 active ingredient and administering multiple preparation can result in overdose. In addition, the FDA reminds that only the measuring device that comes with a medication or one that is made specifically for measuring drugs should be used.

2007

PROTON PUMP INHIBITORS
Earlier data from 2 large studies of the proton pump inhibitors omeprazole (Prilosec) and esomeprazole (Nexium) suggested a possible increase in heart-related problems. A follow-up safety review by the FDA indicated the risk was not likely to be increased with treatment, and now the results of the complete safety review support that conclusion and indicate omeprazole and esomeprazole do not increase cardiac risk.

CHANTIX
The FDA is conducting a safety review of varenicline (Chantix), indicated for smoking cessation, following reports of depressed mood, aggressive and erratic behavior, and suicidal ideation that occurred within days to several weeks after varenicline initiation. The association between the events and varenicline is unclear because nicotine withdrawal symptoms can exacerbate underlying psychiatric conditions. However, not all patients who experienced these effects had a psychiatric condition and not all had stopped smoking. Drowsiness that affects driving and machine-operating abilities has also been reported with varenicline. Until the safety review is completed, the FDA recommends patients starting varenicline be reminded to contact their physician if they experience behavioral or mood changes and to exercise caution while driving or operating machinery.

DESMOPRESSIN
Intranasal desmopressin (DDAVP) is a synthetic vasopressin analogue that acts by preventing excessive water loss in urine and it has been used to treat primary nocturnal enuresis in children. Because of increased risk for hyponatremia and resultant seizures, intranasal desmopressin is no longer indicated for this use. Oral desmopressin may continue to be used with caution. Patients taking desmopressin and consuming excessive fluids are at risk of hyponatremia and fluid should be restricted from 1 hour before to 8 hours after administration. The FDA has reviewed >60 postmarketing reports of hyponatremia-related seizures in patients treated with desmopressin. Two of these patients died. The intranasal formulation was used by 39 of the 61 patients, most of whom were aged <17 years. In more than half of the cases the patient was taking at least 1 other medication that may have contributed to the hyponatremia.


Previous Alerts from FDA MedWatch and Health Canada

An accidental overdose of Kaletra Oral Solution (lopinavir/ritonavir) lead to the death of a 1-month old infant. As a result, Abbott laboratories, the manufacturer of Kaletra, issued a reminder to prescribers that the oral solution is highly concentrated and that pediatric dosing is weight based and should in most cases be less than 5 mL. Special care should be taken when calculating pediatric doses and in the transcription of the medication order.
www.fda.gov/medwatch/safety/2007/safety07.htm#kaletra

Heart failure risk may be increased in patients with diabetes who take any of the thiazolidinedione antidiabetic drugs. Black box warnings about the risk will be added to the labels for Avandia (rosiglitazone), Actos (pioglitazone), Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin), and Duetact (pioglitazone and glimepiride).
www.fda.gov/medwatch/safety/2007/safety07.htm#rosi_pio

Unauthorized lovastatin (Mevacor) has been found in 3 red-yeast products marketed as dietary supplements for reducing cholesterol. Use of the products Red Yeast Rice, Cholestrix, and Red Yeast Rice/Policonsonal Complex, can cause serious muscle-related adverse events and kidney impairment particularly in patients taking other medications known to interact with lovastatin.
www.fda.gov/medwatch/safety/2007/safety07.htm#redyeast

Reversible, dose-related increases in transaminase levels as well as hepatitis and hepatic failure have occurred with the endothelin receptor antagonist Thelin (sitaxsentan sodium). Health Canada has issued a warning that liver enzymes must be measured prior to starting treatment and then at monthly intervals. Thelin is contraindicated in patients with liver impairment and in pregnant or nursing women.
www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/thelin_hpc-cps_e.html.

Off-label use of Fentora (fentanyl buccal tablet), an opioid approved for otherwise uncontrollable cancer pain, lead to the death of 4 patients.1 Three of these patients were treated with the drug for headache (an unapproved indication) and 1 death was a suicide in a patient who was not prescribed the drug by a doctor.2 Cephalon has issued a reminder to physicians that Fentora is to be used only for breakthrough cancer pain in patients already receiving and tolerant of continuous opiate pain control.
1www.fda.gov/medwatch/safety/2007/safety07.htm#Fentora
2Carreyrou J, Goldstein J: Cephalon drug is tied to several deaths. Wall Street Journal September 14, 2007: A9.

Because of the presence of medical-grade silicone particulates in Normal Saline Flush Syringes, B. Braun Medical has recalled all lots ending in SFR. Introducing the particulates into the bloodstream could cause phlebitis or damage vital organs. The possibility for pulmonary embolism or silicone embolism syndrome also exists.
www.fda.gov.medwatch/safety/2007/safety07.htm#SalineFlush

Increased risk for heart attack, stroke, and unstable angina lead to the market withdrawal of Zelnorm (tegaserod) in March 2007. The FDA will now allow restricted use of the drug by women aged <55 years with irritable bowel syndrome with constipation or chronic idiopathic constipation. Patients must have no known heart problems, and treatment must be declared "medically necessary" by their physician. Patients will be required to sign consent forms to ensure they are properly informed of the potential risks.
www.fda.gov/medwatch/safety/2007/safety07.htm#Zelnorm

Kidney, liver, and red blood cell damage is possible with a natural smoking cessation aid marketed in Canada as Resolve. The active ingredient Cestemenol-350, compounded from passion flower and fir balsam, blocks the nervous system effects of nicotine, but can be harmful in excessive amounts.
www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2007/index_f.html

Cardiovascular events may occur more frequently in patients with severe GERD who take omeprazole (Prilosec) or esomeprazole (Nexium), compared with patients who undergo surgical procedures, according to 2 long-term studies. The safety results are preliminary and both the FDA and Health Canada are reviewing the data. At this time, both agencies conclude that the present data do not confirm the risk and clinicians should not change their prescribing practices.
www.fda.gov/medwatch/safety/2007/safety07.htm#Omeprazole
www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2007/index_e.html

Five cases of Kawasaki disease, a serious and uncommon illness, occurred among >36,000 infants who received the RotaTeq vaccine in a Phase 3 clinical trial. In comparison, only 1 infant who received the placebo vaccine contracted the illness. No cause and effect relationship has been established between this or any vaccine and development of Kawasaki disease. RotaTeq is the only licensed vaccination for prevention of rotavirus, which can cause severe diarrhea, vomiting, fever, and dehydration in children, and the FDA and the CDC will continue to monitor its safety.
www.fda.gov/medwatch/safety/2007/safety07.htm#RotaTeq2

Acute febrile reactions occurred in several clusters of patients shortly after they received propofol (Diprivan) for sedation or general anesthesia. No evidence of bacterial contamination was found when multiple lots were examined, but patients who experience this reaction should be evaluated for bacterial sepsis. To minimize the risk of bacterial contamination propofol vials and prefilled syringes should be used within 6 hours of opening and vials should not be used for more than 1 patient.
www.fda.gov/medwatch/safety/2007/safety07.htm#Diprivan

Risk of heart attack and other heart-related adverse events was found to be significantly elevated with Avandia (rosiglitazone) in a pooled analysis of clinical trials. Treatment groups were diverse and the medication regimens differed among the trials but overall Avandia was associated with a 30% increase in risk of myocardial ischemia. Other studies showed no increase in risk with Avandia compared with metformin (Glucophage). An FDA risk analysis is ongoing. www.fda.gov/medwatch/safety/2007/safety07.htm#Avandia

A warning has been issued concerning the possibility for under dosing due to improper capsule disintegration with 2 valproic acid formulations marketed in Canada. Depakene 500 mg and ratio-VALPROIC ECC 500 mg, manufactured by Abbott Laboratories and ratiopharm Inc., have been recalled. Patients should contact their health care provider immediately to obtain a replacement product.
www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2007/2007_55_e.html

The potential for heart valve damage had led to the market withdrawal of pergolide (Permax), indicated for treatment of Parkinson's disease. Stopping pergolide treatment too quickly can have serious adverse effects and the dose should be gradually tapered. Other dopamine agonists that are not associated with heart valve damage are available for patients who require continued therapy. The FDA and the manufacturer of pergolide are evaluating the possibility of continuing availability for patients in whom a switch to another dopamine agonist is unsuccessful.
www.fda.gov/medwatch/safety/2007/safety07.htm#Pergolide

Serious cardiovascular events including angina, heart attacks, and stroke occurred in a small percentage (<1%) of patients treated with Zelnorm (tegaserod maleate) and have prompted its removal from the market. It may be reintroduced with availability limited to patients for whom the benefits clearly outweigh the risk. Zelnorm was indicated for short-term treatment of irritable bowel syndrome with predominant constipation in women and for treatment of chronic constipation in those younger than 65 years. www.fda.gov/medwatch/safety/2007/safety07.htm#Zelnorm

Delayed-onset anaphylaxis has been reported in patients who received sub-cutaneous Xolair (omalizumab) injections for allergy-related asthma.Anaphylaxis has been listed as a possible adverse effect but most cases occur within 2 hours of administration. A boxed warning has been added to the label regarding the possibility for anaphylaxis to develop up to 24 hours after administration and after any dose even if no reaction occurred with prior doses. www.fda.gov/medwatch/safety/2007/safety07.htm#Xolair

Fracture risk was increased in females receiving Avandia (rosiglitazone), Actos (pioglitazone), or combination products that include either agent. An independent safety analysis of another rosiglitazone trial also found increased risk. Most fractures occurred in the upper arm, hand, or foot and are not likely to be associated with postmenopausal osteoarthritis. www.fda.gov/medwatch/safety/2007/safety07.htm#rosiglitazone
www.fda.gov/medwatch/safety/2007/safety07.htm#actos

Haloperidol has been substituted for the active ingredient in several drugs including Ambien, Xanax, Lexapro, and Ativan, purchased from online sellers. Several patients sought emergency treatment for difficulty breathing and/or muscle stiffness or spasms associated with haloperidol ingestion. The origin of the products has not been determined but all packages were postmarked in Greece. The FDA has reissued a warning about purchasing prescription medications on the internet. www.fda.gov/medwatch/safety/2007/safety07.htm#internet

Anaphylaxis and other severe allergic reactions as well as complex sleep behaviors including sleep-driving can occur with sedative hypnotic drugs. The label warnings for these agents will be strengthened to reflect the risks and the FDA has requested that the manufacturers produce medication guides detailing the safety information.
www.fda.gov/medwatch/safety/2007/safety07.htm#Sedative

Liviro3, marketed as a dietary supplement, has been recalled because it contains undeclared tadalafil (Cialis), which can interact with nitrates and cause dangerously low BP.
www.fda.gov/medwatch/safety/2007/safety07.htm#Liviro3

A higher incidence of stroke was found in patients treated with 0.5 mg vs 0.3 mg ranibizumab (Lucentis) in an interim analysis of a trial in neovascular age-related macular degeneration. Risk seems to be greater in patients with a history of prior stroke, but the incidence in this study is lower than that found in premarketing clinical trials. MI and vascular death risks do not appear to be dose-related. www.fda.gov/medwatch/safety/2007/safety07.htm#Lucentis

Telithromycin (Ketek) is no longer approved for treatment of acute bacterial sinusitis or acute exacerbations of chronic bronchitis. Ketek will continue to be available for mild-to-moderate community acquired pneumonia. Other changes include the addition of a boxed warning that Ketek is contraindicated in patients with myasthenia gravis and stronger warnings about the possibility for visual disturbances and loss of consciousness.
www.fda.gov/medwatch/safety/2007/safety07.htm#Ketek

An over-the-counter preparation of the weight loss agent orlistat (Xenical) has received FDA approval. The OTC version, which will be marketed as Alli, delivers a lower dose of orlistat than the prescription strength. Alli is to be used in combination with a low-fat, reduced-calorie diet and an exercise regimen.
www.fda.gov/bbs/topics/NEWS/2007/NEW01557.html

A fatal viral infection, progressive multifocal leukoencephalopathy (PML), has been reported in 2 patients treated with off-label Rituxan (rituximab) for systemic lupus erythematosus. The infection is caused by reactivated JC virus, which is present in about 80% of adults. Signs of PML include: confusion; dizziness or loss of balance; difficulty with speech or walking; and vision problems. www.fda.gov/medwatch/safety/2006/safety06.htm#Rituxan

Risk for renal dysfunction and the resulting need for dialysis is increased in patients who receive Trasylol (aprotinin). The agent is now indicated only for perioperative use in patients undergoing coronary artery bypass who are at increased risk for blood loss and resulting transfusion. Anaphylactic reactions are also possible and re-exposure to Trasylol is contraindicated in patients who received the agent in the previous 12 months. Additional safety data is under investigation and further changes to the prescribing information are possible. www.fda.gov/medwatch/safety/2006/safety06.htm#Trasylol