Transcript Slide 1

Black Box Warnings
(& Other Concerns)
A to Z
Emory S. Martin III, PharmD BCPS
Vice President, Pharmacy Services
Scott & White Healthcare
1
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
2
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
3
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• 16 (2.9%) were eventually withdrawn from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)
4
• 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
5
• 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).
6
Substudy -Compliance with BBW
• Subset of 216,694 patients & 19 drugs with BBW
• Drug Interactions:
– Were they concomitantly prescribed with
contraindicated drugs?
5199/55971 (9.3%)
– ketorolac
dispensed in violation
• 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
7
Substudy -Compliance with BBW
• Pregnancy Risk:
– Was a pregnancy test performed?
• Retinoids:
– isotretinoin (Accutane®)
– acitretin (Soriatane®)
95/78840 (0.3%)
dispensed to possible
pregnant patients
• methotrexate
• leflunomide (Arava®)
– antiproliferative used in Rheum. arthritis
• ACE Inhibitors
• PO misoprostol (Cytotec®)
• megestrol (Megace®)
– synthetic progestogen
• ribavirin/interferon (Hep C)
8
Substudy -Compliance with BBW
– Initial Lab Testing Required:
50% dispensed in
violation
• Was the test performed?
– valproic acid (LFT)
– carbamazepine (CBC + platelets),
– isoniazid (AST or ALT in patients >35 years old),
– triamterene and amiloride (serum K)
9
• Retrospective review of 324,548 outpatients in 50 Bostonarea 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 School
Arch Intern Med. 2006;166:338-344.
10
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
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Findings
12
High Risk Patients
• Pts ≥75 yrs old with ≥4 medications and
≥ 7 medical problems had BBW
violations more often than other patients
13
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
14
• The FDA website published updated BBW
and other safety issues
15
• An FDA mandate for post-marketing safety
strategies are becoming common
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Black Box Warnings
(& Other Concerns)
A-Z
17
Which “A” Drug to Choose?
18
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111085.htm
Acetaminophen
• The elimination of >325 mg APAP
combination prescription drugs higherdose prescription combination
acetaminophen products will be phased
in over three years
– Should not create a shortage of pain
medication.
• New addition to label
19
ACE inhibitors and ARBs
Fetal Harm
20
Bactrim®
Skin Reactions
21
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.
22
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
23
Diaphragm paralysis
24
Research Grade Toxin Diverted to
Patient Use
25
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
26
Similar Side Chain Tables
from Pediatrics 2005;115:1048–1057
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OPIOID Cross Allergies
CLASS MEMBERS & SUBCLASSES
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
NOTES
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.
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NSAID Cross Allergies
CLASS
NSAIDs
CLASS MEMBERS
Non-selective COX inhibitors
 aspirin
 ketorolac (Toradol)
 ibuprofen (Motrin)
 naproxen (Aleve)
 & other NSAID's
Selective COX 2 inhibitors
 celecoxib (Celebrex)
NOTES
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.
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-CAINE Cross Allergies
CLASS MEMBERS & SUBCLASSES
AMIDES
 lidocaine
 bupivacaine (Marcaine)
 prilocaine (Emla)
 ropivacaine (Naropin)
ESTERS
 cocaine
 procaine (Novocain)
 chloroprocaine
 tetracaine (Pontocaine)
NOTE
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
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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.
31
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
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Neurotoxicity Induced by cefepime and ceftazidime. Pharmacotherapy, 23(3): 369 - 373 (203).
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.
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– cefepime group (35%) and 75% of the ceftazidime group (75%)
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
34
Ciprofloxacin
Maybe Myasthenia Gravis
35
http://www.mgauk.org/main/mgdrugs1.htm
Antibiotics and Mysthenia
36
Colistimethate (Colistin) IV
Apnea
37
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
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Daptomycin (Cubicin®)
New Format
Note: False elevation of PT
39
Daptomycin (Cubicin®)
Eosinophilic Pneumonia
Note: False elevation of PT
40
Daptomycin (Cubicin®)
Myopathy & Rhabdo
Note: False elevation of PT
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Dronedarone (Multaq®)
Liver Failure
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Epoetin and Darbopoetin
CV Events
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.
Survival
• 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.
43
Fentanyl Transdermal System Apnea
44
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
45
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
46
Gadolinium-Based MRI contrast
Nephrogenic Systemic Fibrosis
47
Glucophage®, metformin
Lactic Acidosis
48
Glucophage®, metformin
BBW
@lactic
acidosis is
so big…
49
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
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51
Haloperidol (Haldol®)
QT Prolongation
52
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
http://www.uspharmacist.com/index.asp?show=article&page=8_1960.htm
53
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
54
Januvia®, sitagliptan and Janumet®
Pancreatitis
55
Keppra®, levetiracetam
56
Lansoprazole and other PPI’s
Fracture
Likely due to decreased calcium absorption
57
PPI’s & Fracture
In the largest meta-analysis to
date, a 25% increased risk was
noted (Ditah et al)
58
Metoprolol (Lopressor®) w/Clonidine
Rebound Withdrawal Hypertension
59
Metoprolol (Lopressor®) and other BB
Abrupt Cessation
60
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 postmarketing 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.
61
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)
62
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.
63
Oxycodone
Respiratory Depression
…should be carefully monitored with the
dose titrated as needed.
64
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.“
65
– Mr. Ledger’s publicist
Penicillin
Death
66
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.”
67
Quetiapine (Seroquel®)
Death
Carries an indication for treating depression with mania
68
Quetiapine (Seroquel®)
69
Rifampin
P450 Induction
70
http://imaging.ubmmedica.com/CME/pt/content/p040542b.gif
71
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.)
72
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.
73
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.
74
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
75
Sertraline (Zoloft®) & all SSRIs
Serotonin Syndrome
76
Sertraline (Zoloft®) & all SSRIs
Serotonin Syndrome
77
Drugs That Increase Serotonin
& linezolid
78
http://uuhsc.utah.edu/poison/healthpros/utox/vol4_no4.pdf
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
79
Ultram®, tramadol
Seizure
80
Ultram®, tramadol
Inhibitors
Increase
Risk for
Seizure
81
Viagra®, Sildenafil and other ED drugs
Hypotension
NTG & isosorbide products + ED drug ->
excess cyclic guanosine monophosphate ->
extreme hypotension
82
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.
83
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
84
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
85
allele.4
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.
86
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.
87
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.
88
Xenical®, Alli®, orlistat
Liver Injury
89
Yasmin® (drospirenone+ethinyl estradiol)
Hyperkalemia
90
Zyvox®, linezolid
Enhanced
Pressor
Activity
91
END
92
PCN Cross Allergies
CLASS MEMBERS
Penicillins
 All penicillins including
ampicillin/sulbactam (Unasyn);
piperacillin-tazobactam (Zosyn);
ticarcillin-clavulanate (Timentin)
Cephalosporins
 All cephalosporins including
cefaclor (Ceclor); ceftriaxone
(Rocephin)
NOTES
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
93