Presentation on theme: "Black Box Warnings (& Other Concerns) A to Z"— Presentation transcript:
1Black Box Warnings (& Other Concerns) A to Z Emory S. Martin III, PharmD BCPSVice President, Pharmacy ServicesScott & White Healthcare
2Outiline/Objectives Review literature findings regarding the frequency of use for common black box warning (BBW) drugsThe frequency of apparent violation of the BBWCategory: drug interaction, pregnancy, lab monitoringHighlight the FDA’s on-line tool for communicating new drug safety informationProvide overview of the latest safety reports
3Types of Labeling Cautions Precaution: Consideration must be taken in special situations/patient groupsWarning: Serious adverse events that have been observed and potential safety hazardsBlack Box warnings are the strongest warning the FDA requiresContraindication: Drug should not be used because risk much greater than possible benefit
425 Years of Drug Development During the period548 drugs approved in US45 (8.2%) required ≥1 black box warning16 (2.9%) were eventually withdrawn from the marketAmit Kalgutar, PhD, Pfizer Global Research and Development (2010)
5Retrospective review of 1 million outpatient Rx claims for 216 specific BBW drugs (1999-2001) About 40% of outpatients receive a prescription that carries a black box warning
6Among the most frequently dispensed BBW containing medications were: drugs with recommendations against rapid discontinuation (atenolol and metoprolol),drugs with alerts for specific indications in which the drugs should only be used (clindamycin, levothyroxine, metronidazole)or indications were not to be used (propoxyphene, medroxyprogesterone),drugs with warnings about adverse effects that require monitoring (triamterene, triamcinolone, fluticasone, metformin).
7Substudy -Compliance with BBW Subset of 216,694 patients & 19 drugs with BBWDrug Interactions:Were they concomitantly prescribed with contraindicated drugs?ketorolacContraindicated with other NSAID for GI riskmethotrexateDecreased renal clearance (toxicity) and increased GI toxicity when coadministered with NSAIDs, esp high dose MTXitraconazoleCoadministration with certain QT prolonging drugsritonavirCoadministration with certain QT prolonging drugs, sedative hypnotics or ergot alkaloids5199/55971 (9.3%) dispensed in violation
8Substudy -Compliance with BBW Pregnancy Risk:Was a pregnancy test performed?Retinoids:isotretinoin (Accutane®)acitretin (Soriatane®)methotrexateleflunomide (Arava®)antiproliferative used in Rheum. arthritisACE InhibitorsPO misoprostol (Cytotec®)megestrol (Megace®)synthetic progestogenribavirin/interferon (Hep C)95/78840 (0.3%) dispensed to possible pregnant patients
9Substudy -Compliance with BBW Initial Lab Testing Required:Was the test performed?valproic acid (LFT)carbamazepine (CBC + platelets),isoniazid (AST or ALT in patients >35 years old),triamterene and amiloride (serum K)50% dispensed in violation
10Retrospective review of 324,548 outpatients in 50 Boston-area ambulatory care practices with EMR E-prescribing with limited clinical decision support (allergy, dose)EMR contained demographics, medical problem list, medication lists, and lab test results33778/ (10.4%) got a BBW drugLasser et al, Harvard Medical SchoolArch Intern Med. 2006;166:
11Findings2354/33778 (7%) received a prescription in violation of a black box warningSeven drugs accounted for 1745 (74.1%) of the black box violations.azathioprine, carbamazepine, lithium, metformin, propoxyphene, triamterene, and valproateInadequate laboratory monitoring was commonlithium 69.1%carbamazepine24.5%valproate 30.1%Drug-disease state interactions were common
19AcetaminophenThe elimination of >325 mg APAP combination prescription drugs higher-dose prescription combination acetaminophen products will be phased in over three yearsShould not create a shortage of pain medication.New addition to label
22Unusual Femur Fractures BiphosphonatesUnusual Femur FracturesThe bisphosphonates affected by this notice are only those approved to treat osteoporosis, including Fosamax, Fosamax Plus D, Actonel, Actonel with Calcium, Boniva, Atelvia, and Reclast (and their generic products).FDA is looking at safety data past the 3-5 year time frame of original clinical trials.
23Botox ®Diaphragm paralysisNew warning about unintended spreading of paralytic action beyond intended area (2009)Hospitalization and death occurred mostly in children treated for cerebral palsy-associated limb spasticity (off-label)Probably related to overdose
25Research Grade Toxin Diverted to Patient Use When Bonnie Kaplan wanted to hide a few wrinkles, she thought nothing of visiting a private clinic for a couple of shots of Botox. "I'm 53, I've got wrinkles. I wanted to get rid of them," she says. "All my friends were doing it." She had no idea that the doctor treating her would be an osteopath who had been struck off, nor that rather than using Botox, he would inject her with a diluted form of botulinum toxin, the highly poisonous substance from which Botox is derived, that was intended for lab research rather than use on humans. The consequences were horrific. Thirty-six hours after the injections, Bonnie started to have problems breathing and was so weak she couldn't walk. She was rushed to hospital and, as botulism set in, her nerves were damaged. Within hours, her whole body was paralysed. Doctors think she may have received up to 2,500 times the amount of toxin believed to be lethal if injected into the bloodstream. After spending months in hospital, breathing with the help of a ventilator and unable to speak, Bonnie was eventually able to move around in a wheelchair, but doctors warned that the possibility of a full recovery was slim and could take years. She wasn't the only one affected. Her husband, Eric, 52, was injected with the same deadly toxin, and, bizarrely, the doctor, Bach McComb, 47, had also injected himself and his girlfriend, Alma Hall, All three ended up being hospitalised like Bonnie. While this shocking incident took place in Florida, Lifestyle has discovered that the terrifying lack of regulation in the injectables industry in Britain means it could easily happen here.
26Beta-Lactam Antibiotics Cross-allergiesA careful inquiry into allergy history should be madeCross-hypersensitivity has been clearly documented and can occur in up to 10% of patients
27Similar Side Chain Tables from Pediatrics 2005;115:1048–1057
29NSAID Cross Allergies CLASS NSAIDs CLASS MEMBERS NOTES Non - selective COX inhibitorsaspirinketorolac (Toradol)ibuprofen (Motrin)naproxen (Aleve)& other NSAID'sNSAIDsSelective COX 2 inhibitorscelecoxib (Celebrex)Crossreactions are near100% because allergicsymptoms are caused bytheactionof the NSAIDdrug, rather than themolecularstructure.The newer COX2 inhibitors(such as Celebrex)may be tolerated by certainpatients, but this shouldonly be confirmed by aspecialist.Alternatives:Tylenol isgenerally tolerated;consideropioids.
30-CAINE Cross Allergies Procaine penicillin carries a double-risk of cross-reactions
31Ceftazidime and other beta-lactams SeizureThe occurrence of seizures attributed to ceftazidime has been 1/10,000Possible manifestations of neurotoxicity include confused state, dysarthria, somnolence, psychosis, myoclonus, seizures, and sometimes, coma.
32Cefipime & Ceftazidime (Chow et al) Mean age of 54 patientscefepime (61 yrs), ceftazidime (65 yrs)Confusion was the chief symptomcefepime (93%), ceftazidime (91%)Myoclonus was subsequently detectedcefepime (29%), ceftazidime (50%)The median interval between symptom onset and diagnosis of neurotoxicitycefepime (5 days), ceftazidime (3 days)Kai Ming Chow, Cheuk Chun Szeto, Andrew Che Fai Hui, et al. Retrospective Review of Neurotoxicity Induced by cefepime and ceftazidime. Pharmacotherapy, 23(3): (203).
33EEG patterns of AB Neurotoxicity Encephalopathic State (cefepime > ceftazidime)EEGs showed loss of background activity, increased slow rhythms in the theta and delta range, and triphasic waves.Symptoms abated with discontinuation of the drug rather than because of any change in degree of uremia.EEG Epileptic Activity (cefepime > ceftazidime)Epileptiform discharges such as polyspike discharges, rhythmic slow waves, or irregular spikes or sharps, which initially might be confined to one region and become more widespread, subsequently spreading to both cerebral hemispheres.Spike and wave discharges were suppressed after intravenous administration of benzodiazepines.EEG changes were accompanied by either overt convulsions or continuous subclinical seizures.Nonconvulsive status epilepticusCharacterized by prolonged clouding of consciousness and confusion associated with persistent epileptiform discharges seen on EEG in the absence of motor convulsive activity.cefepime group (35%) and 75% of the ceftazidime group (75%)
34CiprofloxacinTendonitisincreased risk of tendinitis and tendon rupture, a serious injury that could cause permanent disability (July 2008.)Do not rigorously exercise during the healing process
38Contrast Media - Iodinated Acute Renal FailurePrecaution:Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with preexisting renal disease).Dehydration in these patients seems to be enhanced by the osmotic diuretic action of contrast agents. Patients should be well hydrated prior to and following administration of any (iodinated) contrast medium
39Daptomycin (Cubicin®) New FormatNote: False elevation of PT
40Daptomycin (Cubicin®) Eosinophilic PneumoniaNote: False elevation of PT
41Daptomycin (Cubicin®) Myopathy & RhabdoNote: False elevation of PT
43Epoetin and Darbopoetin CV EventsSurvivalRenal failureCRF patients experienced greater risks for death and serious CV events when administered ESAs to target higher vs lower Hgb levels.Must individualize dosing to achieve and maintain Hgb levels within the range of 10 to 12 g/dL.PerisurgeryEpoetin increased the rate of DVTs in patients not receiving prophylactic anticoagulation.Consider DVT prophylaxis.CancerESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical CAs when dosed to target a Hgb of ≥ 12 g/dL.Use only for treatment of anemia due to concomitant myelosuppressive chemotherapy.Discontinue following the completion of a chemotherapy course.Use the lowest dose needed to avoid RBCs transfusions.
45Fentanyl Patch Overlooked Contraindications Additional Dangers The US FDA and ISMP have identified U.S. patient deaths when contraindications to fentanyl transdermal patch have NOT been followed.Overlooked ContraindicationsContraindicated in the management of acute or post-operative pain.Contraindicated in patients whose pain has NOT required at least one week of scheduled round-the-clock high doses of strong opioid.Prescribers must consult the approved conversion chartAdditional DangersInadequate patient monitoring at peak effect (12-24 hr p application)Not removing the previous patch when a new patch is appliedAccelerated release from the patch if heat is accidentally appliedDue to prolonged half-life, multiple doses of naloxone may be needed in overdose
46Notable Fentanyl Patch Cases 17-year-old who had been prescribed fentanyl for pain after a dental procedure was found dead on a heated waterbed.42-year-old female had an upper-body warming blanket placed over a 75 mcg/hr fentanyl patch during surgery – developed respiratory depression.Drug Safety. 26(13): , 2003
50Glucophage – Lactic Acidosis Very rare cases/100,000Primarily in DM with renal insufficiencyAvoid in hepatic disease (CLlactate)Key PointsRegular monitoring of CLcr keyHolding during periods of hypoxemia or dehydrationsurgery, sepsisInitial symptoms are non-specificMalaise, mylagias, respiratory, somnolence, GI symptomsWhile GI symptoms are common with initiation, watch out for “late”Hypothermia, hypotension, & bradyarrhythmias followLife-threatening
53Drugs Causing QT Prolongation Several drugs have been withdrawn from the U.S. market or have received black box warnings due to their potential to cause QT interval prolongation that leads to fatal ventricular arrhythmias and sudden cardiac death.QuinineAmphoB prior to Azolepropoxyphene
54Inhaled Long-Acting Beta-Agonists (Salmeterol & Formoterol) Deathmay increase the chance of severe asthma episodes and death when those episodes occur (2005)Wean patients as possible
60Metoprolol (Lopressor®) and other BB Abrupt Cessation
61Midodrine (ProAmatine®) for Orthostatic Hypotension Lack of EfficacyFDA recently notified manufacturers of their proposal to withdraw product approval for midodrine.The FDA's proposed action was based on the lack of required post-marketing data confirming the clinical benefit of the drug.A key point is that FDA's announcement did not represent the actual withdrawal of the medication from the market.It represented a step in the regulatory process –more data about the benefits of midodrine would help doctors and patients understand who can benefit from the drug and how best to use it.Shire has requested a public hearing in response to FDA's proposal to withdraw midodrine.That hearing will provide an opportunity for the company to present the agency with data supporting the clinical benefit of the drug and for an advisory committee to review those data.
62NaproxenCV eventsPreliminary data from the ADAPT trial (Alzheimer’s Disease Anti-Inflammatory Prevention ) indicated an apparent increase in reports of cardiovascular and cerebrovascular adverse events among the participants taking naproxen when compared with those on placebo.For OTC use, patients should not exceed 2 tablets (440 mg) in any 8 to 12 hour period and should not exceed 3 tablets (660 mg) in a 24-hour period.For prescription use, naproxen should always be prescribed within the recommended dosing range of 250 mg to 500 mg twice a day. (per FDA)
63Omeprazole Clopidogrel Interaction 10/27/2010 Pantoprazole (Protonix) or antacid may be an alternative.Pantoprazole is a weak inhibitor of CYP2C19 and has less effect.
64OxycodoneRespiratory Depression…should be carefully monitored with the dose titrated as needed.
65OxycodoneAbuse"Mr. Heath Ledger died as the result of acute intoxication by the combined effects of oxycodone, hydrocodone, diazepam, temazepam, alprazolam, and doxylamine," We have concluded that the manner of death is accident, resulting from the abuse of prescription medications."New York City Medical Examiner“Heath's accidental death serves as a caution to the hidden dangers of combining prescription medication, even at low dosage.“Mr. Ledger’s publicist
67Bicillin EventsIn 1996, inadvertent intravenous administration of Pen G benzathine in a 10 fold overdose in a Colorado hospital caused death in neonate.“Hoping to spare the infant unnecessary punctures, the nurses began investigating whether they could give the drug intravenously instead of intramuscularly. After research, they incorrectly concluded that they could.”
68Quetiapine (Seroquel®) DeathCarries an indication for treating depression with mania
72Rosiglitazone (Avandia®) Heart Failure and Other CV RisksAvandia® (rosiglitazone) and Actos® pioglitazone carry an increased risk of heart failureObserve patient carefullyNot recommended in symptomatic HFA meta-analysis of 42 trials showed that rosiglitazone also carries risk of heart attack if patients already have heart disease or are at high risk of suffering a heart attack. (November 2007.)
73Rosiglitazone (Avandia®) Heart Failure and Other CV RisksREMS: UPDATED 02/04/2011FDA notified healthcare professionals and patients that information on the cardiovascular risks (including heart attack) of rosiglitazone has been added to the physician labeling and patient Medication Guide.This information was first announced by FDA on September 23, 2010 as part of new restrictions for prescribing and use of this drug a heart attack.
74Rosiglitazone (Avandia®) REMS CV RisksFDA will require that GSK develop a REMS.Under the REMS, Avandia will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (pioglitazone)Current users of Avandia who are benefiting from the drug will be able to continue using the medication if they choose.Physicians will have document patient eligibilityPatients will have to review statements describing the CV concerns and acknowledge they understand the risks.FDA anticipates that the REMS will limit use of Avandia significantly.
75Sertraline (Zoloft®) & all Antidepressants Suicidality in children, adolescents (2004)Suicidality in young adults (2007)< 25 years oldMonitor for agitationEducate family membersDispense small quantities
76Sertraline (Zoloft®) & all SSRIs Serotonin Syndrome
77Sertraline (Zoloft®) & all SSRIs Serotonin Syndrome
79TNF Blockers Malignancies TNF blockers are approved for the treatment of one or more of a number of immune system diseases including juvenile idiopathic arthritis (JIA), rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ankylosing spondylitis
81Inhibitors Increase Risk for Seizure Ultram®, tramadolInhibitors Increase Risk for Seizure
82Viagra®, Sildenafil and other ED drugs HypotensionNTG & isosorbide products + ED drug ->excess cyclic guanosine monophosphate ->extreme hypotension
83Viagra®HypotensionAfter patients have taken VIAGRA, it is unknown when nitrates, if necessary, can be safely administered.Single 100 mg oral dose given to healthy normal volunteers – results in peak level of 440 ng/mL, 24 hour trough = 2 ng/mLIn the following patients:age >65,hepatic impairment (e.g., cirrhosis),severe renal impairment (e.g., CRCL <30 mL/min), andconcomitant use of potent cytochrome P450 3A4 inhibitors…plasma levels at 24 hours are 3 to 8 times higher than those seen in healthy volunteers.Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely coadministered at this time point.
84WarfarinInfo about CYP 2C9 VariantsA meta-analysis of 9 studies including 2775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients. 3 studies assessed bleeding risks; 8 studies assessed daily dose requirements.The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles.Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the homozygous CYP2C9*1 ptsFor patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the homozygous CYP2C9*1 pts
85WarfarinInfo about CYP 2C9 VariantsIn an observational study, the risk of achieving INR >3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype.The relative risk of overanticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele.4
86WarfarinMicroemboli & Purple ToesAnticoagulation therapy with COUMADIN may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the “purple toes syndrome.”Discontinuation of COUMADIN therapy is recommended when such phenomena are observed.
87WarfarinMicroemboli & Purple ToesSystemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms including:purple toes syndrome, livedo reticularis, rash, gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, pancreatitis, symptoms simulating polyarteritis, or any other sequelae of vascular compromise due to embolic occlusion.The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver.Some cases have progressed to necrosis or death.
88WarfarinMicroemboli & Purple ToesPurple toes syndrome is a complication of oral anticoagulation characterized by a dark, purplish or mottled color of the toes, usually occurring between 3 to 10 weeks, or later, after the initiation of therapy with warfarinMajor features of this syndrome include purple color of plantar surfaces and sides of the toes that blanches on moderate pressure and fades with elevation of the legs; pain and tenderness of the toes; waxing and waning of the color over time.While the purple toes syndrome is reported to be reversible, some cases progress to gangrene or necrosis which may require debridement of the affected area, or may lead to amputation.