Transcript paauw_drug

Drug Interactions and Important
Side Effects for 2013
Disclosure of Financial Relationships
Douglas Paauw
Has no relationships with any entity
producing, marketing, re-selling, or
distributing health care goods or services
consumed by, or used on, patients.
FDA Drug Warnings 2011
Do not start any new patients on 80 mg of
simvastatin.
 Avoid prescribing methylene blue or linezolid to
patients on serotonergic drugs
 Do not prescribe doses of Citalopram > 40 mg
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PPI’s and Recurrent C Difficile
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Retrospective, cohort study of 1166 patients with an
initial diagnosis of C Difficile infection (CDI)
Patients who received a PPI within 14 days after their
C diff dx were defined as PPI exposed.
45% of patients with CDI were PPI exposed.
Recurrent CDI was more common in PPI exposed
patients (25% vs 18%) HR 1.42,95% CI 1.11-1.82
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Arch Intern Med 2010;170:772-778.
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Also W J Gastroenterology 2010;16 (28):3573- 3577.
FDA Drug Warnings 2012
Statins and cognitive impairment, increased risk
of diabetes (worry level-low)
 Sitagliptan (Januvia) and pancreatitis (worry
level- moderate)
 PPI’s and Clostridia difficile (worry levelmoderate)
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Problems With PPI’s?
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Decreased Ca absorption
Decreased iron absorption
Increased fracture risk
Decreased thyroid absorption
Poor Magnesium absorption
Poor B12 absorption
Decreased Ketoconazole/Itraconazole absorption
Increased risk of C. difficile, and recurrent C Diff and
more severe C diff. FDA warning 2/12
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Pharmacist calls to tell you that you are
prescribing a triptan for a patient who is on
an SSRI (citalopram 20 mg a day). She is
on no other meds. What should you do?
Switch to another migraine treatment
Have patient not take citalopram for 24
hours after taking the triptan
Cut the dose of triptan by 50 %
Don’t worry
Triptans and SSRI’s
Concern for serotonergic syndrome
 Extremely unlikely if only a triptan + SSRI
(especially at lower doses of SSRI)
 Beware of patients on multiple drugs that can
trigger serotonergic syndrome ( tramadol,
linezolid,meperidine, dextromethorphan, TCA,
MAOI, buspirone, trazadone)
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Pharmacist calls you to tell you that she did
not fill the Tadalafil (10mg) prescription you
wrote for your patient because he is on
tamsulosin. What do you do?
Switch Tamsulosin to Finaseride
Switch Tamsulosin to Alfuzosin
Switch Tadalafil to Sidenafil
Ask that the prescription be filled
Alpha blockers and Tadalafil
.4 mg of tamsulosin was given for 7 days in
healthy volunteers, then tadalafil 10mg,20 mg
or placebo were given two hours after
tamsulosin dose
 No significant difference in standing SBP with
either dose of tadalafil and placebo, no one had
a SBP < 85, no dizziness.
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J Urol 2004; 172: 1935-1940.
Managing Drug Interactions with
PDE5 Inhibitors
Nitrates
Ok to give NTG > 4 hours after sildenafil use, 24 hours
after vardenafil use and 48 hours after tadalafil use
 Alpha Blockers
Ok to use in patients who are on stable alpha blocker
therapy. For patients on doxazosin or terazosin, should
not take within 4 hours of a dose to avoid potential
drop in BP
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Warfarin Interactions
Emergency Hospitalizations for Adverse
Drug Events in Older Americans
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National Electronic Injury Surveillance System–Cooperative
Adverse Drug Event Surveillance project (2007 through 2009)
was used to estimate the frequency of emergency
hospitalization for adverse drug events in patients 65 and
older
Almost 100,000 admissions annually in adults >65 due to
adverse drug events occurred during the study period
Four drug classes causes 67% of the mayhem- warfarin 33%,
Insulins 13.9%, oral antiplatelet drugs 13.3% and oral
hypoglycemics 10.7%.
N Engl J Med 2011;365:2002-2012.
A 72 y.o. male S/P AVR replacement two years ago
for aortic stenosis presents with wide spread
bruising on his back/legs and some bruising on
the back of both hands. His last INR was three
weeks ago and was 3.0. He states he saw an
M.D. six days ago for a cough and was put on a
medication described as a “white tablet.” His
chronic medications include: Coumadin 5 mg qd,
Albuterol inhaler 2 puffs 4 times a day and
Nortryptiline 25 mg qhs.
What medication was he placed on?
a) Amoxicillin
b) Codeine
c) Cefixime
d) Azithromycin
e) TMP/Sulfa
Warfarin Interactions
Decrease metabolism (increase PT)
Most Severe
TMP/Sulfa
Erythromycin
Amiodarone
Propafenone
Ketoconazole/fluconazole
Itraconazole
Metronidazole
Possible*
Quinolones
Omeprazole
Clarithromycin
Azithromycin
* Especially in elderly
and polypharmacy
Antibiotics and Warfarin
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Retrospective cohort study 104 patients on stable
warfarin therapy. Effect on INR of Terazocin (control),
Azithromycin (32 patients), Levofloxacin (27) and
TMP/Sulfa (16)
Mean change in INR: Terazocin -.15, Azithromycin +
.51 , Levofloxacin + .85, TMP/Sulfa +1.76
Percent patients having a INR > 4: Terazocin 5%,
Azithromycin 31%, Levofloxacin 33%, TMP/Sulfa
69%
JGIM 2005;20 (7);653-6.
Risk of Warfarin + Antibiotics for
Bleeding Risk in the Elderly
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Nested case control study of 38,000 elderly warfarin
users (on medicare D)
Cases were patients hospitalized for bleeding/each
matched with 3 control patients taking warfarin
Exposure to any antibiotic in the 15 days prior to
admission was a risk, greatest risk with azoles (aOR
4.57), Cotrimoxazole (aOR 2.70).
Am J Med. 2012 Feb;125(2):183-9
Antibiotics for UTI in Patients on
Warfarin
Penicillins/cephalosporins ok
 Nitrofurantion ok
 Quinolones- be worried
 TMP/Sulfa don’t use
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A 39 y.o. woman with a prosthetic aortic valve
presents with bruising. Her last INR 6 weeks
ago was 2.4, today’s INR is 6.5. She has not
taken any extra Coumadin. Which of the
following when taken on a daily basis could
explain her increased INR?
a) Acetaminophen
b) Calcium carbonate
c) OCP
d) Ranitidine
e) DOSS
Warfarin and Acetaminophen
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3 studies suggest increased INR with
Acetaminophen + Warfarin
> 9100 mg/week led to 10 x risk of having INR > 6*
In double blind crossover trial patients on Warfarin
+ 4 g/d of Acetaminophen had PT 1.75 x control +
Patients received 2 gm or 4 gm acetaminophen or
placebo with warfarin, 54% of those receiving
acetaminophen overshot INR goal vs 17% of
placebo #.
*JAMA 1998;279:657-662
+ Clin Res 1984;32:698a
# Pharmacotherapy 2007; 27 (5):675-83.
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A 76 yo man is admitted with increasing SOB. He has
a long history of COPD and has had a recent
productive cough. He is admitted to the hospital and
treated with amoxicillin, prednisone, codeine, and
albuterol. PMH: A fib, Hypertension, COPD, GERD.
Outpatient meds: Metoprolol, coumadin,
pantoprazole, lisinopril. His recent INR 2 weeks ago
was 2.2, on hospital day 6 it is 4.3. What is the most
likely interaction with coumadin?
A) Prednisone
B) Amoxicillin
C) Codeine
D) Amoxicillin + Pantoprazole
Effect of Oral Corticosteroids On
Warfarin Therapy
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Retrospective review of patients in ACC who received
oral corticosteroids. Patients were excluded if they
were treated with any drug with a known interaction
with warfarin.
Mean difference between pre steroid INR and the INR
when patients on steroids was 1.24, p<.001. 62% of
the patients had an INR above their targeted range.
Mean time to INR elevation was 6.7 days after starting
steroids.
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Ann Pharmacother 2006;40:2101-6.
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Problems with Statins
A 65 yo man presents with cough and fever. He has
had severe diarrhea for 2 days. He was on a cruise
with a friend who was diagnosed with Legionella
yesterday. PMH – diabetes,
hyperlipidemia,hypertension. Meds: Lisinopril,
simvastatin, amlodipine, gemfibrozil,metformin.
Chest Xray shows patchy bilateral infiltrates. WBC
17,000 Na 125. What is the most appropriate
treatment?
A)Amoxicillin/clavulanate
B)Clarithromycin
C)Levofloxacin
D)Cefuroxime
E)Trimethoprim/sulfa
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Drugs That Increase Risk of
Statin Toxicity
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Fibrates (Gemfibrozil 15X >> Fenofibrate)
Azole antifungals
Amiodarone
Erythromycin/Clarithromycin
Protease inhibitors
Verapamil/Diltiazem
Least drug interactions with pravastatin, most with
simvastatin and lovastatin
Side Effects of Statins
 Rhabdomyolysis
(rare) 0.01%
 Hepatotoxicity (rare)
 Liver failure 0.0001%
 Myalgias 5-18 %
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Your 5 o’clock add on patient is a 55 yo man with DM
who has been having myalgias. His baseline LDL
cholesterol is 125 . He started having myalgias when
he took atorvastatin 3 months ago. The myalgias
stopped when he stopped the med. He was switched
to pravastatin 3 weeks ago and the myalgias started
again, What do you recommend?
A) Start ubiquinone (Conenzyme Q10)
B) Switch to simvastain
C) Add an NSAID
D) Stop pravastatin and start red yeast rice
Myalgias and Statins
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PRIMO study 10.5 % had muscle symptoms on statins
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For those receiving the highest doses of statins rates
of myalgia were
Fluvastatin XL 5.1%
Pravastatin
10.9%
Atorvastatin 14.9%
Simvastatin 18.2%
Cardiovasc Drugs Ther. 2005 Dec;19(6):403-14.
Myalgias And Statins
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Appears to be dose and possibly drug related
Check TSH level
More common inpatients with low body mass
More common in Asian patients
? Role of vitamin D
? Benefit of coenzyme Q10 (low ubiquinone levels?)
Biopsy of muscle in statin treated patients with myalgia
and normal CPK levels have shown myopathy
Biopsy of muscle in statin treated patients with no
symptoms have shown muscle cell damage.
Red Yeast Rice in Statin
Intolerant Patients
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62 patients with hyperlipidemia and discontinuation
of statin therapy due to myalgias
Randomly assigned to red yeast rice (RYR) 1800 mg
BID or placebo
In RYR group LDL decreased by 35 mg/dl compared
to 15 mg/dl in placebo group (p=.01).
Pain severity scores were no different between
groups
Ann Intern Med 2009;150: 830-839.
Approach to Management of Myalgias on Statins
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Check CK ,TSH.
Stop statin, when symptoms disappear restart statin
at lower dose or change statin
If recurrent symptoms try Fluvastatin 80mg XL QD or
alternate day or 2X weekly 10mg atorvastatin, or low
dose rosuvastatin daily,QOD or weekly
If symptoms continue try ezetimibe or colesevelam or
red yeast rice
Adapted from Harper and Jacobson Curr Atheroscler Rep.
2010 Sep;12(5):322-30.
What Should You Worry About When
Prescribing Simvastatin?
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Major interaction with grapefruit juice
Mild interaction with warfarin
Major interaction with amiodarone
Usual statin concern with
fibrates/clarithromycin/azoles
Red flags should go off when prescribing for A fib
patients, where they might be on both warfarin and
amiodarone (and a Ca channel blocker)
June 2011 FDA advisory to not put new patients on
80mg of simvastatin
A 36 yo man with a history of gout returns for follow
up. He has had a 2 day history cough and today
fevers. Chest xray shows a RLL infiltrate. PMH: CRI
baseline Cr 2.0. Meds : Allopurinol 200 mg a day,
colchicine .6 mg a day, citalopram 20 mg a day.
Which drug would be most dangerous to prescribe?
A) Azithromycin
B) Clarithromycin
C) Levofloxacin
D) Erythromycin
E) Chloramphenicol
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Colchicine Drug Interactions
Higher risk in patients with renal insuff
 Many (over 100) reports of death with
interaction with clarithromycin, a strong
CYP3A4 inhibitor
 Avoid clarithromycin, protease
inhibitors, itraconazole and
ketoconazole
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A 85 yo man is brought to the ED for evaluation
of weakness and nausea. He was diagnosed 10 days
ago with prostatitis. His other problems include
hypertension, CHF and CRI. Meds: Carvedilol,
furosemide, TMP/Sulfa, verapamil, digoxin. ExamBP 100/60 P-100 T 36.9 cardiac- grade 2/6 SEM
lower extremity edema present. Lab: Na- 132 K -6.8
BUN 37 Cr- 2.3. What is the most likely cause of his
hyperkalemia?
A) Chronic renal insufficiency
B) Carvedilol
C) TMP/Sulfa
D) Verapamil
E) Digoxin
Trimethoprim Induced
Hyperkalemia
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More common in elderly and patients with
renal impairment
More likely if patient is on an ACEI or ARB
More likely if patient is receiving high doses
of steroids
Mechanism is that trimethoprim acts like
amiloride, a potassium sparing diuretic, and
reduces urinary potassium excretion by 40%
When Not to Use TMP/Sulfa
Patient taking warfarin
 Patient taking methotrexate
 Allergy
 Elderly patients with renal insufficiency
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78 yo man is brought to the ED with hypotension.
His BP is 70/50. He has a history of atrial fibrillation
and CAD and was diagnosed with pneumonia 3
days ago. Medications: Isosorbide mononitrate,
Lisinopril, Diltiazem, clarithromycin and linezolid.
What is the most likely cause of his hypotension?
Isosorbide-clarithromycin interaction
Lisinopril-clarithromycin interaction
Diltiazem-clarithromycin interaction
Linezolid- clarithromycin interaction
Linezolid- isosorbide interaction
Hypotension Related to MacrolideCalcium Channel Blocker Interaction
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Nested, case-crossover study of patients age 66 and
older prescribed a CCB over a 15 year period.
Study group was those admittd to the hospital with
hypotension/shock
Compared risk of exposure to macrolide in 7 days
before hospitalization with 7 day control interval the
month prior
RR of hypotension 5.8 for erythromycin, 3.7 for
clarithromycin. Azithromycin was not associated with
hypotension
CMAJ 2011;183 (3):303-307.
Beware of Clarithromycin
Major statin interaction (especially
simvastatin/lovastatin)
 Major interaction with CCB
 Increase levels of glypizide/glyburide
(hypoglycemia)
 Major interaction with colchicine
 82 Major drug interactions reported!
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Important Drug Side Effects
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85 yo woman is brought to the ED after a syncopal episode.
Her care givers report a similar episode 2 weeks ago,but she
recovered so quickly they did not seek evaluation for her.
Meds: Omeprazole 20 mg, pravastatin 40 mg, citalopram 10
mg, albuterol, donepezil 10 mg, isosorbide mononitrate 60mg
and calcium. On exam BP 100/60 P 55. ECG Bradycardia with
normal intervals. What drug most likely caused of her
syncope?
A) Citalopram
B) Pravastatin
C) Donepezil
D) Isosorbide
E) Calcium
Cholinesterase inhibitors and Syncope
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Cholinesterase inhibitors and bradycardia
 RR bradycardia  1.4 (95% CI, 1.1–1.6)
 Dose effect: donepezil > 10mg  2.1  risk
 ChE-I
J Am Geriatr Soc 2009;57:1997
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Clinical significance: ChE-I use associated with
HR  1.76 (95% CI, 1.57-1.98)
 ED visits for bradycardia: HR  1.69
 Pacemaker placement: HR  1.49
 Hip Fx: HR  1.18 (95% CI, 1.03-1.34)
 Syncope:
Arch Intern Med 2009;169:867
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A 66 yo woman presents with symptoms of
severe muscle pain and joint pain. This has been
present for the past 3 weeks. She has had no
fevers, chills or trauma. She has a past history of
HTN,Hypothyroidism, CAD, Osteoporosis , GERD
and depression. Meds: Omeprazole, Metoprolol,
Alendronate, Citalopram, Levothyroxine . What is
the most likely cause of her pain?
Citalopram
Omeprazole
Alendronate
Metoprolol
Hypothyroidism
Bisphosphonates and Musculoskeletal
Pain
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612 consecutive patients treated in an osteoporosis
clinic with oral alendronate or residronate were
evaluated for side effects
The frequency of severe musculoskeletal side effects
was 5.6%. All severe side effects occurred in once
weekly treated patients- 20.1% of alendronate treated
patients and 25% of risedronate treated patients
J Musculoskelet Neuronal Interact 2007; 7(2):144148.
FDA Advisory on Bisphosphonates
and Musculoskeletal Pain
Strongly consider bisphosphonate as cause for
musculoskeletal pain in patients who are taking
them who have severe pain
 Strongly consider temporarily or permanently
stop the medication
 Much more likely with weekly or monthly dosing
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e
A 66 yo woman presents with hypotension and confusion. She
was in her usual state of health until 4 hours prior when she felt
ill and vomited a small amount of bloody material. She did not
seek medical attention for 2 additional hours . She had another
episode of emesis this time of a large amount of bloody
material. She has also had one episode of maroon stool. PMHHTN, Osteoporosis and depression. Meds: fluoxetine,
benazapril, hydrochlorathiazide, acetominophen, and
estrogen/progestin.
What medication has the the strongest association with UGI
bleeding?
A) Fluoxetine
B) Benazapril
C) Hydrochlorathiazide
D) Acetominophen
E) Estrogen
SSRI’S and GI Bleeding
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Multiple retrospective studies show relative risk for UGI
bleeding of 3-4 with the use of SSRI’s
Risk is further increased with concurrent use of a nonsteroidal,
Odds ratio 6.33 if SSRI combined with NSAID
Risk is highest in the elderly
Strongly consider gastroprotection if combination used in
patients with history of UGI bleeding, in patients taking NSAIDS
or the elderly
Arch Intern Med 2003;163:59-64
BMJ 1999; 319 (7217):1106-9.
Aliment Pharmacol Ther 2008; 27: 31-40. Meta-analysis
Clin Gastroenterol Hepatol. 2009 Dec;7(12):1314-21.
A 66 yo woman presents with fatigue. She has a history
of bipolar disorder and reflux disease. She has felt well
the past few months until the last few weeks.
Medications: Rabeprazole, lithium, paroxetine, calcium.
Physical exam is normal. As part of her workup she is
found to have the following labs: Na 120, K 3.6 Bun 3 Cr
0.7 What is the most likely cause of her low sodium?
A) Hyperlipidemia
B) Lithium
C) Acute psychosis
D) Rabeprazole
E) Paroxetine
SSRI’s AND Hyponatremia
Older age
 Female
 Concomitant diuretic use
 Low body weight
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Citalopram and QT Prolongation
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Dose dependent QT prolongation
Maximum dose recommended for citalopram 40 mg
(maximum dose 20 mg for age >65)
Contraindicated in patients with congenital long QT
syndrome
Important interaction with CYP2C19 inhibitors
(fluvoaxamine-luvox, fluoxetine, PPI’s, cimetidine,
clopidogrel)
Avoid use with other QT prolonging drugs
Think Before Putting SSRI’S
in the Drinking Water
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Probable increased risk of UGI bleed
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Often overlooked cause of hyponatremia
Sexual dysfunction (20-50%)
 QT prolongation with citalopram
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What To Remember From This
Talk
Watch carefully for interactions with
TMP/Sulfa , simvastatin and
clarithromycin.
 You can use PDE5 inhibitors with
tamsulosin
 Statin myalgias are common
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