1

Black Box Warnings(& Other Concerns)

A to ZEmory S. Martin III, PharmD BCPSVice 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the period 1975-1999• 548 drugs approved in US• 45 (8.2%) required ≥1 black box warning• 16 (2.9%) were eventually withdrawn from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• 33778/324548 (10.4%) got a BBW drug

Lasser et al, Harvard Medical SchoolArch Intern Med. 2006;166:338-344.

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?

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111085.htm

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 ARBsFetal Harm

21

Bactrim®Skin Reactions

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).

FDA is looking at safety data past the 3-5 year time frame of original clinical trials.

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

Diaphragm paralysis

25

Research Grade Toxin Diverted to Patient Use

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 AllergiesCLASS MEMBERS & SUBCLASSES NOTES Phenylpiperidines

Meperidine (Demerol) Diphenoxylate (Lomotil) Fentanyl; Sufentanil; Alfentanil

Phenylheptanones (diphenylheptanes) Methadone Propoxyphene (Darvocet)

Phenanthrenes Morphine (natural) Codeine (natural) Hydromorphone (Dilaudid) Hydrocodone (Vicodin) Oxycodone (Percocet) Oxymorphone; Buprenorphine

Butorphanol; Nalbuphine Pentazocine; Levorphanol

Cross-reactions between the 2 natural opiates (morphine and codeine) common

Cross-reactions between the 2 opiates within a chemical class are common.

Rather than being truly allergic, some patients are merely sensitive to the histamine-releasing chemical effects of opioids. Most common with IV or epidural morphine and meperidine.

ALTERNATIVES: Nonnarcotic analgesics should be considered.

29

NSAID Cross Allergies

CLASS CLASS MEMBERS NOTES

Non-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 symptoms 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

CLASS MEMBERS & SUBCLASSES NOTE AMIDES

lidocaine bupivacaine (Marcaine) prilocaine (Emla) ropivacaine (Naropin)

ESTERS

cocaine procaine (Novocain) chloroprocaine tetracaine (Pontocaine)

True allergies to a local anesthetic are rare. Patients who are allergic to ESTER local anesthetics should be treated with a preservative-free AMIDE local anesthetic. Patients who are allergic to AMIDE local anesthetics should be treated with a preservative-free ESTER local anesthetic.

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)

Kai Ming Chow, Cheuk Chun Szeto, Andrew Che Fai Hui, et al. Retrospective Review of

Neurotoxicity Induced by cefepime and ceftazidime. Pharmacotherapy, 23(3): 369 - 373 (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

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

• 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

Ciprofloxacin Maybe Myasthenia Gravis

36

Antibiotics and Mystheniahttp://www.mgauk.org/main/mgdrugs1.htm

37

Colistimethate (Colistin) IVApnea

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

Daptomycin (Cubicin®)

Note: False elevation of PT

New Format

40

Daptomycin (Cubicin®)

Note: False elevation of PT

Eosinophilic Pneumonia

41

Daptomycin (Cubicin®)

Note: False elevation of PT

Myopathy & Rhabdo

42

Dronedarone (Multaq®)Liver Failure

43

Epoetin and DarbopoetinRenal 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

Fentanyl Transdermal SystemApnea

45

Fentanyl PatchThe 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 chart

Additional DangersInadequate 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):951-973, 2003

47

Gadolinium-Based MRI contrastNephrogenic Systemic Fibrosis

48

Glucophage®, metforminLactic Acidosis

49

Glucophage®, metforminBBW

@lactic acidosis is so big…

50

Glucophage – Lactic Acidosis• Very rare - - 3 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

52

Haloperidol (Haldol®)QT Prolongation

53

Drugs Causing QT Prolongation

http://www.uspharmacist.com/index.asp?show=article&page=8_1960.htm

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

propoxypheneQuinine

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

Januvia®, sitagliptan and Janumet®

Pancreatitis

56

Keppra®, levetiracetam

57

Lansoprazole and other PPI’sFracture

Likely due to decreased calcium absorption

58

PPI’s & FractureIn 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

• 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)

CV events

63

OmeprazoleClopidogrel 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

…should be carefully monitored with the dose titrated as needed.

Respiratory Depression

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. Ledger’s publicist

Abuse

66

PenicillinDeath

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®)

Carries an indication for treating depression with mania

Death

69

Quetiapine (Seroquel®)

70

Rifampin P450 Induction

71http://imaging.ubmmedica.com/CME/pt/content/p040542b.gif

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

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

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

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 SSRIsSerotonin Syndrome

77

Sertraline (Zoloft®) & all SSRIsSerotonin Syndrome

78

Drugs That Increase Serotonin

http://uuhsc.utah.edu/poison/healthpros/utox/vol4_no4.pdf

& 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®, tramadolSeizure

81

Ultram®, tramadolInhibitors Increase Risk for Seizure

82

Viagra®, Sildenafil and other ED drugs

NTG & isosorbide products + ED drug -> excess cyclic guanosine monophosphate -> extreme hypotension

Hypotension

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

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• 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

WarfarinMicroemboli & 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

WarfarinMicroemboli & 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®, orlistatLiver Injury

90

Yasmin® (drospirenone+ethinyl estradiol)Hyperkalemia

91

Zyvox®, linezolidEnhanced Pressor Activity

92

END

93

PCN Cross Allergies

CLASS MEMBERS NOTES Penicillins

All penicillins including ampicillin/sulbactam (Unasyn); piperacillin-tazobactam (Zosyn); ticarcillin-clavulanate (Timentin)

Cephalosporins All cephalosporins including

cefaclor (Ceclor); ceftriaxone (Rocephin)

If patient is allergic to one penicillin, there is a strong chance of cross-sensitivity to other penicillins. If patient is allergic to penicillin, there is a 5-15% chance of cross-sensitivity to cephalosporins. If patient has PCN class allergy, but a history of cefazolin tolerance, other cephalosporins may be tolerated. Alternatives: Macrolide antibiotics; quinolone antibiotics

… May be mostly related to similar side chains