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Black Box Warnings (& Other Concerns) A to Z

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1 Black Box Warnings (& Other Concerns) A to Z
Emory S. Martin III, PharmD BCPS Vice President, Pharmacy Services Scott & White Healthcare

2 Outiline/Objectives Review literature findings regarding
the frequency of use for common black box warning (BBW) drugs The frequency of apparent violation of the BBW Category: drug interaction, pregnancy, lab monitoring Highlight the FDA’s on-line tool for communicating new drug safety information Provide overview of the latest safety reports

3 Types of Labeling Cautions
Precaution: Consideration must be taken in special situations/patient groups Warning: Serious adverse events that have been observed and potential safety hazards Black Box warnings are the strongest warning the FDA requires Contraindication: Drug should not be used because risk much greater than possible benefit

4 25 Years of Drug Development
During the period 548 drugs approved in US 45 (8.2%) required ≥1 black box warning 16 (2.9%) were eventually withdrawn from the market Amit Kalgutar, PhD, Pfizer Global Research and Development (2010)

5 Retrospective 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

6 Among 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).

7 Substudy -Compliance with BBW
Subset of 216,694 patients & 19 drugs with BBW Drug Interactions: Were they concomitantly prescribed with contraindicated drugs? ketorolac Contraindicated with other NSAID for GI risk methotrexate Decreased renal clearance (toxicity) and increased GI toxicity when coadministered with NSAIDs, esp high dose MTX itraconazole Coadministration with certain QT prolonging drugs ritonavir Coadministration with certain QT prolonging drugs, sedative hypnotics or ergot alkaloids 5199/55971 (9.3%) dispensed in violation

8 Substudy -Compliance with BBW
Pregnancy Risk: Was a pregnancy test performed? Retinoids: isotretinoin (Accutane®) acitretin (Soriatane®) methotrexate leflunomide (Arava®) antiproliferative used in Rheum. arthritis ACE Inhibitors PO misoprostol (Cytotec®) megestrol (Megace®) synthetic progestogen ribavirin/interferon (Hep C) 95/78840 (0.3%) dispensed to possible pregnant patients

9 Substudy -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

10 Retrospective 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 results 33778/ (10.4%) got a BBW drug Lasser et al, Harvard Medical School Arch Intern Med. 2006;166:

11 Findings 2354/33778 (7%) received a prescription in violation of a black box warning Seven drugs accounted for 1745 (74.1%) of the black box violations. azathioprine, carbamazepine, lithium, metformin, propoxyphene, triamterene, and valproate Inadequate laboratory monitoring was common lithium 69.1% carbamazepine24.5% valproate 30.1% Drug-disease state interactions were common

12 Findings

13 High Risk Patients Pts ≥75 yrs old with ≥4 medications and ≥ 7 medical problems had BBW violations more often than other patients

14 ADE’s A subset of 575 records were reviewed for ADE’s
4 related ADE’s were noted 3 serious, 1 significant 92 potential ADE’s noted 18 potentially fatal or life-threatening

15 The FDA website published updated BBW and other safety issues

16 An FDA mandate for post-marketing safety strategies are becoming common

17 Black Box Warnings (& Other Concerns) A-Z

18 Which “A” Drug to Choose?

19 Acetaminophen The elimination of >325 mg APAP combination prescription drugs higher-dose prescription combination acetaminophen products will be phased in over three years Should not create a shortage of pain medication. New addition to label

20 ACE inhibitors and ARBs
Fetal Harm

21 Bactrim® Skin Reactions

22 Unusual Femur Fractures
Biphosphonates Unusual Femur Fractures The 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.

23 Botox ® Diaphragm paralysis New 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

24 Diaphragm paralysis

25 Research 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.

26 Beta-Lactam Antibiotics
Cross-allergies A careful inquiry into allergy history should be made Cross-hypersensitivity has been clearly documented and can occur in up to 10% of patients

27 Similar Side Chain Tables from Pediatrics 2005;115:1048–1057

28 OPIOID Cross Allergies

selective COX inhibitors aspirin ketorolac (Toradol) ibuprofen (Motrin) naproxen (Aleve) & other NSAID's NSAIDs Selective COX 2 inhibitors celecoxib (Celebrex) Cross reactions are near 100% because allergic s ymptoms are caused by the action of the NSAID drug, rather than the molecular structure. The newer COX 2 inhibitors (such as Celebrex) may be tolerated by certain patients, but this should only be confirmed by a specialist. Alternatives: Tylenol is generally tolerated; consider opioids.

30 -CAINE Cross Allergies
Procaine penicillin carries a double-risk of cross-reactions

31 Ceftazidime and other beta-lactams
Seizure The occurrence of seizures attributed to ceftazidime has been 1/10,000 Possible manifestations of neurotoxicity include confused state, dysarthria, somnolence, psychosis, myoclonus, seizures, and sometimes, coma.

32 Cefipime & Ceftazidime (Chow et al)
Mean age of 54 patients cefepime (61 yrs), ceftazidime (65 yrs) Confusion was the chief symptom cefepime (93%), ceftazidime (91%) Myoclonus was subsequently detected cefepime (29%), ceftazidime (50%) The median interval between symptom onset and diagnosis of neurotoxicity cefepime (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).

33 EEG 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 epilepticus Characterized 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%)

34 Ciprofloxacin Tendonitis increased risk of tendinitis and tendon rupture, a serious injury that could cause permanent disability (July 2008.) Do not rigorously exercise during the healing process

35 Ciprofloxacin Maybe Myasthenia Gravis

36 Antibiotics and Mysthenia

37 Colistimethate (Colistin) IV

38 Contrast Media - Iodinated
Acute Renal Failure Precaution: 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

39 Daptomycin (Cubicin®)
New Format Note: False elevation of PT

40 Daptomycin (Cubicin®)
Eosinophilic Pneumonia Note: False elevation of PT

41 Daptomycin (Cubicin®)
Myopathy & Rhabdo Note: False elevation of PT

42 Dronedarone (Multaq®)
Liver Failure

43 Epoetin and Darbopoetin
CV Events Survival Renal failure CRF 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. Perisurgery Epoetin increased the rate of DVTs in patients not receiving prophylactic anticoagulation. Consider DVT prophylaxis. Cancer ESAs 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.

44 Fentanyl Transdermal System

45 Fentanyl 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 Contraindications Contraindicated 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 chart Additional Dangers Inadequate patient monitoring at peak effect (12-24 hr p application) Not removing the previous patch when a new patch is applied Accelerated release from the patch if heat is accidentally applied Due to prolonged half-life, multiple doses of naloxone may be needed in overdose

46 Notable 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

47 Gadolinium-Based MRI contrast
Nephrogenic Systemic Fibrosis

48 Glucophage®, metformin
Lactic Acidosis

49 Glucophage®, metformin
acidosis is so big…

50 Glucophage – Lactic Acidosis
Very rare cases/100,000 Primarily in DM with renal insufficiency Avoid in hepatic disease (CLlactate) Key Points Regular monitoring of CLcr key Holding during periods of hypoxemia or dehydration surgery, sepsis Initial symptoms are non-specific Malaise, mylagias, respiratory, somnolence, GI symptoms While GI symptoms are common with initiation, watch out for “late” Hypothermia, hypotension, & bradyarrhythmias follow Life-threatening


52 Haloperidol (Haldol®)
QT Prolongation

53 Drugs 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. Quinine AmphoB prior to Azole propoxyphene

54 Inhaled Long-Acting Beta-Agonists (Salmeterol & Formoterol)
Death may increase the chance of severe asthma episodes and death when those episodes occur (2005) Wean patients as possible

55 Januvia®, sitagliptan and Janumet®

56 Keppra®, levetiracetam

57 Lansoprazole and other PPI’s
Fracture Likely due to decreased calcium absorption

58 PPI’s & Fracture In the largest meta-analysis to date, a 25% increased risk was noted (Ditah et al)

59 Metoprolol (Lopressor®) w/Clonidine
Rebound Withdrawal Hypertension

60 Metoprolol (Lopressor®) and other BB
Abrupt Cessation

61 Midodrine (ProAmatine®) for Orthostatic Hypotension
Lack of Efficacy FDA 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.

62 Naproxen CV events Preliminary 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)

63 Omeprazole Clopidogrel Interaction 10/27/2010
Pantoprazole (Protonix) or antacid may be an alternative. Pantoprazole is a weak inhibitor of CYP2C19 and has less effect.

64 Oxycodone Respiratory Depression …should be carefully monitored with the dose titrated as needed.

65 Oxycodone Abuse "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

66 Penicillin Death

67 Bicillin Events In 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.”

68 Quetiapine (Seroquel®)
Death Carries an indication for treating depression with mania

69 Quetiapine (Seroquel®)

70 Rifampin P450 Induction


72 Rosiglitazone (Avandia®)
Heart Failure and Other CV Risks Avandia® (rosiglitazone) and Actos® pioglitazone carry an increased risk of heart failure Observe patient carefully Not recommended in symptomatic HF A 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.)

73 Rosiglitazone (Avandia®)
Heart Failure and Other CV Risks REMS: UPDATED 02/04/2011 FDA 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.

74 Rosiglitazone (Avandia®) REMS
CV Risks FDA 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 eligibility Patients 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.

75 Sertraline (Zoloft®) & all Antidepressants
Suicidality in children, adolescents (2004) Suicidality in young adults (2007) < 25 years old Monitor for agitation Educate family members Dispense small quantities

76 Sertraline (Zoloft®) & all SSRIs
Serotonin Syndrome

77 Sertraline (Zoloft®) & all SSRIs
Serotonin Syndrome

78 Drugs That Increase Serotonin
& linezolid

79 TNF 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

80 Ultram®, tramadol Seizure

81 Inhibitors Increase Risk for Seizure
Ultram®, tramadol Inhibitors Increase Risk for Seizure

82 Viagra®, Sildenafil and other ED drugs
Hypotension NTG & isosorbide products + ED drug -> excess cyclic guanosine monophosphate -> extreme hypotension

83 Viagra® Hypotension After 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/mL In the following patients: age >65, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., CRCL <30 mL/min), and concomitant 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.

84 Warfarin Info about CYP 2C9 Variants A 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 pts For 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

85 Warfarin Info about CYP 2C9 Variants In 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

86 Warfarin Microemboli & Purple Toes Anticoagulation 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.

87 Warfarin Microemboli & Purple Toes Systemic 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.

88 Warfarin Microemboli & Purple Toes Purple 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 warfarin Major 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.

89 Xenical®, Alli®, orlistat
Liver Injury

90 Yasmin® (drospirenone+ethinyl estradiol)

91 Enhanced Pressor Activity
Zyvox®, linezolid Enhanced Pressor Activity

92 Questions? END

93 PCN Cross Allergies … May be mostly related to similar side chains

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