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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.

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Presentation on theme: "1 Black Box Warnings (& Other Concerns) A to Z Emory S. Martin III, PharmD BCPS Vice President, Pharmacy Services Scott & White Healthcare."— Presentation transcript:

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

2 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 FDAs on-line tool for communicating new drug safety information Provide overview of the latest safety reports

3 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 4 25 Years of Drug Development During the period drugs approved in US 45 (8.2%) required 1 black box warning 16 (2.9%) were eventually withdrawn from the market –Amit Kalgutar, PhD, Pfizer Global Research and Development (2010)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 5 Retrospective review of 1 million outpatient Rx claims for 216 specific BBW drugs ( ) –About 40% of outpatients receive a prescription that carries a black box warning

6 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 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 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 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 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 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 12 Findings

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

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

15 15 The FDA website published updated BBW and other safety issues

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

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

18 18 Which A Drug to Choose?

19 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 20 ACE inhibitors and ARBs Fetal Harm

21 21 Bactrim® Skin Reactions

22 22 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).Fosamax, Fosamax Plus D, Actonel, Actonel with Calcium, Boniva, Atelvia, and Reclast FDA is looking at safety data past the 3-5 year time frame of original clinical trials.

23 23 Botox ® 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 Diaphragm paralysis

24 24 Diaphragm paralysis

25 25 Research Grade Toxin Diverted to Patient Use

26 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 27 Similar Side Chain Tables from Pediatrics 2005;115:1048–1057

28 28 OPIOID Cross Allergies

29 29 NSAID Cross Allergies

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

31 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 32 Cefipime & Ceftazidime (Chow et al) 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). 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)

33 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 34 Ciprofloxacin 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 Tendonitis

35 35 Ciprofloxacin Maybe Myasthenia Gravis

36 36 Antibiotics and Mysthenia

37 37 Colistimethate (Colistin) IV Apnea

38 38 Contrast Media - Iodinated 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 Acute Renal Failure

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

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

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

42 42 Dronedarone (Multaq®) Liver Failure

43 43 Epoetin and Darbopoetin 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. CV Events Survival

44 44 Fentanyl Transdermal System Apnea

45 45 Fentanyl Patch 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 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 47 Gadolinium-Based MRI contrast Nephrogenic Systemic Fibrosis

48 48 Glucophage®, metformin Lactic Acidosis

49 49 Glucophage®, metformin acidosis is so big…

50 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

51 51

52 52 Haloperidol (Haldol®) QT Prolongation

53 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. AmphoB prior to Azole propoxyphene Quinine

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

55 55 Januvia®, sitagliptan and Janumet® Pancreatitis

56 56 Keppra®, levetiracetam

57 57 Lansoprazole and other PPIs Fracture Likely due to decreased calcium absorption

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

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

60 60 Metoprolol (Lopressor®) and other BB Abrupt Cessation

61 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 62 Naproxen Preliminary data from the ADAPT trial (Alzheimers 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) CV events

63 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 64 Oxycodone …should be carefully monitored with the dose titrated as needed. Respiratory Depression

65 65 Oxycodone "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. Ledgers publicist Abuse

66 66 Penicillin Death

67 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 68 Quetiapine (Seroquel®) Carries an indication for treating depression with mania Death

69 69 Quetiapine (Seroquel®)

70 70 Rifampin P450 Induction

71 71

72 72 Rosiglitazone (Avandia®) 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.) Heart Failure and Other CV Risks

73 73 Rosiglitazone (Avandia®) 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. Heart Failure and Other CV Risks

74 74 Rosiglitazone (Avandia®) REMS 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. CV Risks

75 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 76 Sertraline (Zoloft®) & all SSRIs Serotonin Syndrome

77 77 Sertraline (Zoloft®) & all SSRIs Serotonin Syndrome

78 78 Drugs That Increase Serotonin & linezolid

79 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, Crohns disease, and ankylosing spondylitis

80 80 Ultram®, tramadol Seizure

81 81 Ultram®, tramadol Inhibitors Increase Risk for Seizure

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

83 83 Viagra® 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. Hypotension

84 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 85 Warfarin 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 Info about CYP 2C9 Variants

86 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 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 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 89 Xenical®, Alli®, orlistat Liver Injury

90 90 Yasmin® (drospirenone+ethinyl estradiol) Hyperkalemia

91 91 Zyvox®, linezolid Enhanced Pressor Activity

92 92 END

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


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