Drug Interactions and Important Side Effects for 2013

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.

Disclosure of Financial Relationships

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

PPI’s and Recurrent C Difficile 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

Arch Intern Med 2010;170:772-778.

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 level- moderate)

Problems With PPI’s?

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

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?

A) Switch to another migraine treatment

B) Have patient not take citalopram for 24 hours after taking the triptan

C) Cut the dose of triptan by 50 %

D) 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)

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?

A) Switch Tamsulosin to Finaseride

B) Switch Tamsulosin to Alfuzosin

C) Switch Tadalafil to Sidenafil

D) 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.

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

Warfarin Interactions

Emergency Hospitalizations for Adverse Drug Events in Older Americans

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 InteractionsDecrease metabolism (increase PT)

Most Severe Possible*

TMP/Sulfa Quinolones

Erythromycin Omeprazole

Amiodarone Clarithromycin

Propafenone Azithromycin

Ketoconazole/fluconazole

Itraconazole

Metronidazole * Especially in elderly

and polypharmacy

Antibiotics and Warfarin 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

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

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) Acetaminophenb) Calcium carbonatec) OCPd) Ranitidinee) DOSS

Warfarin and Acetaminophen 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.

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

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.

Ann Pharmacother 2006;40:2101-6.

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/clavulanateB)ClarithromycinC)LevofloxacinD)CefuroximeE)Trimethoprim/sulfa

Drugs That Increase Risk of Statin Toxicity

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 %

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 PRIMO study 10.5 % had muscle symptoms on statins

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

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

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 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?

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

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

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. Exam- BP 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

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

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?

A) Isosorbide-clarithromycin interaction

B) Lisinopril-clarithromycin interaction

C) Diltiazem-clarithromycin interaction

D) Linezolid- clarithromycin interaction

E) Linezolid- isosorbide interaction

Hypotension Related to Macrolide- Calcium Channel Blocker Interaction

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!

Important Drug Side Effects

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 bradycardia ChE-I RR bradycardia 1.4 (95% CI, 1.1–1.6) Dose effect: donepezil > 10mg 2.1 risk

Clinical significance: ChE-I use associated with Syncope: 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)

Cholinesterase inhibitors and Syncope

J Am Geriatr Soc 2009;57:1997

Arch Intern Med 2009;169:867

As

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?

A) CitalopramB) OmeprazoleC) AlendronateD) MetoprololE) Hypothyroidism

Bisphosphonates and Musculoskeletal Pain

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):144-148.

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

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. PMH-HTN, 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

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) HyperlipidemiaB) LithiumC) Acute psychosisD) RabeprazoleE) Paroxetine

SSRI’s AND Hyponatremia

Older age Female Concomitant diuretic use Low body weight

Citalopram and QT Prolongation

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

Probable increased risk of UGI bleed

Often overlooked cause of hyponatremia

Sexual dysfunction (20-50%) QT prolongation with citalopram

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