Dangerous Drugs and How to Minimize the Dangers

DANGEROUS DRUGS AND HOW TO MINIMIZE THE DANGERS

April 17, 2014

Adapted from:American College of PhysiciansInternal Medicine 2012Dangerous Drugs and How to Minimize TheirDangersDouglas S. Paauw, MD, MACP

And...

Assessing Medication Appropriateness in the Elderly: Using Beers

& STOPP START Criteria

Julia BarehamBSc, BSP, MSc Candidate

[email protected]

RxFiles Academic Detailing Program

Disclosures

Dr. Anthony Weaver has no relationships to disclose.

Objectives

1. Review some of the most dangerous drugs used in general medicine practice (emphasizing drug-drug interactions).

2. Discuss ways to prescribe these drugs safely.1. Beers Criteria2. STOPP Criteria3. Most dangerous drug4. CYP 3A4 Interactions

3. Evaluate the interactions that make certain drugs dangerous.

Over 2 million serious ADRs annually 100,000 deaths annually Fourth leading cause of death Ambulatory patient’s ADR rate is unknown

Institute of Medicine. To err is human: building a safer health system. Washington, D.C.: National Academy Press; 2000. 2Lazarou J, Pomeranz B, Corey PN. Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA 1998;279:1200–1205. 3Gurwitz JH, Field TS, Avorn J, McCormick D, Jain S, Eckler M, et al. Incidence and preventability of adverse drug events in nursing homes. Am J Med 2000;109(2):87–94.

Medication Related Problems

Seniors = 12.9% of U.S. population, but 34% of total prescriptions.

> 65 40% take 5-9 medications per year 18% take 10 or more

ADRs among the top five threats to seniors’ health. 28% of hospitalizations among seniors due to ADRs. 32,000 seniors suffer hip fractures/yr due to falls

caused by medication-related problems.

American Society of Consultant Pharmacists


Drug related admissions for aged 65-84 increased by 96% from 1997 to 2008

Half of ADR hospitalizations occur in > 80 yo Rapidly growing senior population will magnify the

problem

Shepherd G et al. Ann Pharmacother 2012;46:169-175

Figure 2. Adverse drug reaction death rates by state (1999–2006).

Shepherd G et al. Ann Pharmacother 2012;46:169-175


Estimated Annual Cost $76.6 billion among ambulatory population$20 billion in acute-care facilities$7.6 billion in nursing facilitiesTotal annual direct medical cost in the US: $104.2 billion

American Society of Consultant Pharmacists

AGS UPDATED 2012 BEERS CRITERIA FOR POTENTIALLY INAPPROPRIATE MEDICATION USE IN OLDER ADULTS

Mark H Beers, MD 1954-2009

MD, Univ of Vermont First med student to do a geriatrics

elective at Harvard‘s Division on Aging Geriatric Fellowship, Harvard Faculty, UCLA/RAND Co-editor, Merck Manual of Geriatrics Editor in Chief, Merck Manuals

“A ballet-dancing opera critic who hiked the Alps and took up rowing after

diabetes cost him his legs”

Original Purpose

1991 Original Beers Criteria Evaluate inappropriate Rx used in NH residents in

“common” situations, but under “certain circumstances” might be appropriate

Clinical research on use of Potentially Inappropriate medications (PIMs)

QA/QI Education

Not included in Beer’s List

Drugs with risks not unique to elderly• Purpose is for PIMs specific to elderly

Drug-drug interactions• Not unique to elderly

List of alternatives• Too complex, requires patient specific judgment

2012 AGS Beers Criteria - Categories1st Category 2nd Category 3rd Category

PIMs for older people:

• Pose high risks of adverse effects OR

• Appear to have limited effectiveness in older pts

AND

• There are alternatives to these medications

PIMs for older people:

• Who have certain diseases/disorders

– b/c these drugs may exacerbate the specified health problems

Use with caution in older adults

• May be associated with more risks than benefits in general

–However, may be the best choice for a particular individual if administered with caution

• 53 medications or medication classes that should be avoided in older adults

• 14 that should be used with caution

FREE Beers Criteria Apps

Print off the Pocket Card

www.americangeriatrics.org/files/documents/beers/PrintableBeersPocketCard.pdf

Or, search “Beers pocket card”

Open access, available for free.

http://www.americangeriatrics.org/files/documents/beers/PrintableBeersPocketCard.pdf

http://www.americangeriatrics.org/files/documents/beers/PrintableBeersPocketCard.pdf

Drugs to Avoid (except if….)

• Table 1 in the pocket guide

Table 1. Drugs to Avoid (except if…)

Organ System or TC or Drug

Rationale Recommend. Quality of Evidence

Strength of Recommend.

Nitrofurantoin Pulmonary toxAlternativesLack of efficacy <60 mL/min

Avoid long term suppression; avoid if CrCl <60 mL/min

Moderate Strong

Antipsychotics (conventional or atypical)

Increase CVA and CV mortality in dementia

Avoid unless danger to self/others and non pharm has failed

Moderate Strong

Insulin, sliding scale

Hypoglycemia risk

Avoid Moderate Strong

Chlorpropamide Glyburide

Hypoglycemia risk

Avoid High Strong





BenzodiazepinesShort and long acting

Risk cognitive effects and injury (fall/MVA); rare use appropriate eg benzo withdrawal

Avoid for treatment of insomnia, agitation, or delirium

High Strong

Megestrol Minimal effect on weight; risk of thrombotic events and death


Metclopramide EPS and TD Avoid, unless gastroparesis

Moderate Strong

Non-COX NSAIDs, oral

GI bleeding; Protection w/ PPIs or misoprostol

Avoid chronic use

Moderate Strong





Non BenzodiazepinesHypnotic s (“z” drugs)

Risk cognitive effects and injury (fall/MVA); same ADE as benzo’s

Avoid chronic use, >90 days

Moderate Strong

Estrogens with or w/o progestin

Carcinogenic potential, lack of efficacy in dementia/CV dz prevention

Avoid oral and topical patch.Topical cream safe and effective for vaginal symptoms

High Strong

Muscle Relaxants Ineffective at tolerated doses, antichol, falls


Use of Caveats

“Z” drugs for sleep: avoid chronic use Testosterone: avoid unless indicated for moderate

to severe hypogonadism Topical vaginal estrogen: acceptable low dose use

for specific conditions Spironolactone: avoid >25 mg/day in pts with

heart failure or CrCl <30 Antipsychotics: avoid unless nonpharm treatment

has failed or threat to self/others

Table 2. Drug-disease/syndrome Interactions

Disease or Syndrome

Drug Rationale Rec. Quality of Evidence

Strength of Rec.

Syncope AChEIsPeripheral α- blockersTert. TCAsChlorpromazineThioridazineOlanzapine

Orthostatic hypotension or bradycardia

Avoid α- blockers: HighTCAs, AChEIs, antipsych: Moderate

AChEIs, TCAs: Strong

α- blockers, antipsych.: Weak

Insomnia Oral decongestantsStimulantsTheobromines

CNS stimulant effects


Drug-disease/syndrome Interactions


Table 3. Use with Caution

Drug Rationale Recommend Quality of Evidence

Strength of Recommend

Dabigatran Risk of bleeding; lack of evidence if CrCl < 30mL/min

Use with caution if >75 or if CrCl < 30mL/min

Moderate Weak

Drugs linked to SIADH/Hyponatremia (eg SSRI, TCA, CBZ, antipsychotics)

May exacerbate or cause SIADH/ hyponatremia; monitor

Use with caution

Moderate Strong

Use with Caution


Non-Drug Approaches

Dementia “T A DA” VA Health

Tolerate, Anticipate, don’t aggravate

Resistive Behaviors Needs Based Approach Sleep Cardiovascular

AGS Website Materials

Interprofessional Use of EHR/CDSS Target Groups Consumers

Targeting Behavior and Symptoms Educational Interventions

Target the sickest patients, use Beers criteria

Alternate Plan

JAGS July 2013; 61 (7)

Introduction

PIM: potentially inappropriate medication. Pharmacological effects potentially harmful to an elderly adult

AIM: actually inappropriate medication. Risk of harm outweighs benefit

50% of elderly adults discharged on ≥ 1 PIM 85% of ICU survivors discharged on ≥ 1 PIM 80% of elderly adults discharged on ≥ 1 AIM 50% of ICU survivors discharged on ≥ 1 AIM 50% of PIMs and 59% of AIMs rx’d in ICU

Hypothesis

Opiates, sedatives, and antipsychotics are the PIMs most often AIMs in older ICU survivors

Older adults with delirium are at highest risk for discharge on PIMs and AIMs

Methods

Prospective nested cohort study Critically ill patients with respiratory failure or

shock admitted to Vanderbilt ICU Age ≥60, discharged alive Not hospice PIM determined by using 2003 Beers criteria AIM by chart review by a hospitalist, geriatrician,

and clinical pharmacist (2/3 wins)

Drug Categories

Benzodiazepines Non-BZD sedatives Typical antipsychotics Atypical

antipsychotics Opioids Anticholinergics

Antidepressants Drugs causing orthostasis NSAIDs Antiarrhythmics Muscle relaxants other

Results:PIMs

250 PIMs at discharge 4 most common PIMs

Opioids Anticholinergics Antidepressants Drugs causing orthostasis

Results: AIMs

90 AIMs Three most common (36%)

Anticholinergics Histamine blockers 61% Promethazine 15%

Non-BZD hypnotics Opioids

PIMs transitioning to AIMs

Three least common PIM-AIM Opioids (16% likelihood) Antidepressants (23% likelihood) Orthostatic drugs (10% likelihood)

Three most common PIM-AIM Anticholinergics (55% likelihood) Non-BZD hypnotics (67% likelihood) Benzodiazepines (67% likelihood) Atypical psychotics (71% likelihood) Muscle relaxants (100% likelihood)

Results

67% of anticholinergic AIMs started in ICU 46% of non-BZD hypnotics started in ICU 73% of AIM opioids started in ICU 80% of atypical antipsychotics started in ICU

1% on atypical anti-psychotic on admission 12% on atypical antipsychotic on discharge

Discussion

3 of the most commonly prescribed PIMs (opioids, antidepressants, and orthostatic drugs) were often appropriate for condition

Risk factors for PIMs did not predict AIMs We should (move beyond) labeling medicines as “potentially

inappropriate” Clinicians must actively determine which PIMs can be

discontinued at discharge/followup Screening tools using [Beers] PIMs to generate alerts could

lead to inappropriate discontinuation, and possibly more harmful alternatives

More Discussion

Screening tools should consider positive predictive value, highest in: Atypical antipsychotics (71%) Non-BZD hypnotics (67%) Benzodiazepines (67%) Anticholinergics (55%) Muscle relaxants (100%)

STOPP CriteriaScreening Tool of Older Persons’ potentially

inappropriate Prescriptions

65 rules relating to the most common and the most potentially dangerous instances of inappropriate

prescribing in older people

O’Mahony D, Gallagher P, Ryan C, Byrne S, Hamilton H, Barry P, O’Connor M, Kennedy J. STOPP & START criteria: A new approach to detecting potentially inappropriate prescribing in old age. European Geriatric Medicine. 2010 Jan 6; 1(1):45-51.

Hamilton H, Gallagher P, Ryan C, Byrne S, O'Mahony D. Potentially inappropriate medications defined by STOPP criteria and the risk of adverse drug events in older hospitalized patients. Arch Intern Med. 2011 Jun 13;171(11):1013-9.

A. Cardiovascular System 1. Digoxin at a long-term dose > 125µg/day with impaired renal function *

(increased risk of toxicity). * estimated GFR <50ml/min 2. Loop diuretics: • for dependent ankle oedema only i.e. no clinical signs of heart failure (no

evidence of efficacy, compression hosiery usually more appropriate). • as first-line monotherapy for hypertension (safer, more effective alternatives

available).

3. Thiazide diuretic with a history of gout (may exacerbate gout).

4. Beta-blockers:• with Chronic Obstructive Pulmonary Disease (COPD) (risk of increased

bronchospasm). • in combination with verapamil (risk of symptomatic heart block).

5. Use of diltiazem or verapamil with NYHA Class III or IV heart failure (may worsen heart failure).

6. Calcium channel blockers with chronic constipation (may exacerbate constipation).

7. Dipyridamole as monotherapy for cardiovascular secondary prevention (no evidence for efficacy).

8. Aspirin: • with a past history of peptic ulcer disease without histamine H2 receptor

antagonist or • Proton Pump Inhibitor (risk of bleeding). • at dose > 150mg day (increased bleeding risk, no evidence for increased efficacy). • with no history of coronary, cerebral or peripheral vascular symptoms or

occlusive event (not indicated). • to treat dizziness not clearly attributable to cerebrovascular disease (not

indicated).

9. Warfarin:• for first, uncomplicated deep venous thrombosis for longer than 6 months

duration (no proven added benefit). • for first uncomplicated pulmonary embolus for longer than 12 months duration

(no proven benefit).

10. Use of aspirin and warfarin in combination without histamine H2 receptor antagonist (except cimetidine because of interaction with warfarin) or proton pump inhibitor (high risk of gastrointestinal bleeding).

11. Aspirin, clopidogrel, dipyridamole or warfarin with concurrent bleeding disorder (high risk of bleeding).

B. Central Nervous System and Psychotropic Drugs

1. Tricyclic antidepressants (TCA’s):• with dementia (risk of worsening cognitive impairment).

• with glaucoma (likely to exacerbate glaucoma).

• with cardiac conductive abnormalities (pro-arrhythmic effects).

• with constipation (likely to worsen constipation).

• with an opiate or calcium channel blocker (risk of severe constipation).

• with prostatism or prior history of urinary retention (risk of urinary retention).

2. Long-term (i.e. > 1 month)• long-acting benzodiazepines e.g. chlordiazepoxide, fluazepam,

nitrazepam, chlorazepate and benzodiazepines with long-acting metabolites e.g. diazepam (risk of prolonged sedation, confusion, impaired balance, falls).

• neuroleptics as long-term hypnotics (risk of confusion, hypotension, extra-pyramidal side effects, falls).

• neuroleptics in those with parkinsonism (likely to worsen extra-pyramidal symptoms)

3. Phenothiazines in patients with epilepsy (may lower seizure threshold).

4. Anticholinergics to treat extra-pyramidal side-effects of neuroleptic medications (risk of anticholinergic toxicity).

5. Selective serotonin re-uptake inhibitors (SSRI’s) with a history of clinically significant hyponatraemia (non-iatrogenic hyponatraemia <130mmol/l within the previous 2 months).

6. Prolonged use (> 1 week) of first generation antihistamines i.e. diphenhydramine, chlorpheniramine, cyclizine, promethazine (risk of sedation and anti-cholinergic side effects).

C. Gastrointestinal System

1. Diphenoxylate, loperamide or codeine phosphate for treatment of:

• diarrhea of unknown cause (risk of delayed diagnosis, may exacerbate constipation with overflow diarrhoea, may precipitate toxic megacolon in inflammatory bowel disease, may delay recovery in unrecognised gastroenteritis).

• infective gastroenteritis i.e. bloody diarrhea, high fever or severe systemic toxicity (risk of exacerbation or protraction of infection)

2. Prochlorperazine or metoclopramide with Parkinsonism (risk of exacerbating Parkinsonism).

3. PPI for peptic ulcer disease at full therapeutic dosage for > 8 weeks (dose reduction or earlier discontinuation indicated).

4. Anticholinergic antispasmodic drugs with chronic constipation (risk of exacerbation of constipation).

D. Respiratory System

1. Theophylline as monotherapy for COPD (safer, more effective alternative; risk of adverse effects due to narrow therapeutic index)

2. Systemic corticosteroids instead of inhaled corticosteroids for maintenance therapy in moderate to severe COPD (unnecessary exposure to long-term side-effects of systemic steroids).

3. Nebulized ipratropium with glaucoma (may exacerbate glaucoma).

E. Musculoskeletal System

1. Non-steroidal anti-inflammatory drug (NSAID):• with history of peptic ulcer disease or gastrointestinal bleeding, unless with

concurrent histamine H2 receptor antagonist, PPI or misoprostol (risk of peptic ulcer relapse).

• with moderate-severe hypertension (moderate: 160/100mmHg – 179/109mmHg; severe: ≥180/110mmHg) (risk of exacerbation of hypertension).

• with heart failure (risk of exacerbation of heart failure). • long-term use of NSAID (>3 months) for relief of mild joint pain in osteoarthritis

(simple analgesics preferable and usually as effective for pain relief) • warfarin and NSAID together (risk of gastrointestinal bleeding). • with chronic renal failure * (risk of deterioration in renal function). * estimated GFR

20-50ml/min.2. Long-term corticosteroids (>3 months) as monotherapy for rheumatoid arthritis

or osteoarthritis (risk of major systemic corticosteroid side-effects).

3. Long-term NSAID or colchicine for chronic treatment of gout where there is no contraindication to allopurinol (allopurinol first choice prophylactic drug in gout)

F. Urogenital System

1. Bladder antimuscarinic drugs: • with dementia (risk of increased confusion, agitation).

• with chronic glaucoma (risk of acute exacerbation of glaucoma).

• with chronic constipation (risk of exacerbation of constipation).

• with chronic prostatism (risk of urinary retention).

2. Alpha-blockers:• in males with frequent incontinence i.e. one or more episodes

of incontinence daily (risk of urinary frequency and worsening of incontinence).

• with long-term urinary catheter in situ i.e. more than 2 months (drug not indicated).

G. Endocrine System

1. Glibenclamide or chlorpropamide with type 2 diabetes mellitus (risk of prolonged hypoglycemia).

2. Beta-blockers in those with diabetes mellitus and frequent hypoglycaemic episodes i.e. ≥ 1 episode per month (risk of masking hypoglycemic symptoms).

3. Estrogens:• with a history of breast cancer or venous thromboembolism

(increased risk of recurrence)

• without progestogen in patients with intact uterus (risk of endometrial cancer).

H. Drugs that adversely affect those prone to falls (≥ 1 fall in past three months)

1. Benzodiazepines (sedative, may cause reduced sensorium, impair balance).

2. Neuroleptic drugs (may cause gait dyspraxia, Parkinsonism).

3. First generation antihistamines (sedative, may impair sensorium).

4. Vasodilator drugs known to cause hypotension in those with persistent postural hypotension i.e. recurrent > 20mmHg drop in systolic blood pressure (risk of syncope, falls).

5. Long-term opiates in those with recurrent falls (risk of drowsiness, postural hypotension, vertigo).

I. Analgesic Drugs

1. Use of long-term powerful opiates e.g. morphine or fentanyl as first line therapy for mild-moderate pain (WHO analgesic ladder not observed).

2. Regular opiates for more than 2 weeks in those with chronic constipation without concurrent use of laxatives (risk of severe constipation).

3. Long-term opiates in those with dementia unless indicted for palliative care or management of moderate/severe chronic pain syndrome (risk of exacerbation of cognitive impairment).

J. Duplicate Drug Classes

Any duplicate drug class prescription e.g. two concurrent opiates, NSAID’s, SSRI’s, loop diuretics, ACE inhibitors (optimisation of monotherapy within a single drug class should be observed prior to considering a new class of drug).

Medication Appropriateness Index

1. Is there an indication for the drug?

2. Is the medication effective for the condition?

3. Is the dosage correct?

4. Are the directions correct?

5. Are the directions practical?

6. Are there clinically significant drug-drug interactions?

7. Are there clinically significant drug-disease/condition interactions?

8. Is there unnecessary duplication with other drugs?

9. Is the duration of therapy acceptable?

10. Is this drug the least expensive alternative compared with others of equal usefulness?

Arch Intern Med. Vol 166, March 27, 2006

What about targeting the most dangerous drug?

N Engl J Med 2011;365:2002-12

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

100,000 admissions annually due to adverse drug events occurred during the study period

N Engl J Med 2011;365:2002-2012.

Emergency Hospitalizations for Adverse Drug Events in Older Americans

Four drug classes caused 67% of admissions Warfarin 33%, Insulins 13.9%, Oral antiplatelet drugs 13.3% Oral hypoglycemics 10.7%.

Potentially inappropriate medications were implicated in only 3.6% of emergency department visits

N Engl J Med 2011;365:2002-2012.

Warfarin Interactions

Case 3

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) Amoxicillinb) Codeinec) Cefiximed) Azithromycine) TMP/Sulfa

Warfarin InteractionsDecrease 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

104 patients on stable warfarin therapy. Effect on INR of Terazosin (control), Azithromycin (32 patients), Levofloxacin (27) and TMP/Sulfa (16)

Mean change in INR: Terazosin -.15, Azithromycin +.51 , Levofloxacin + .85, Sulfa +1.76

Percent patients having a INR > 4: Terazosin 5%, Azithromycin 31%, Levofloxacin 33%, TMP/Sulfa 69%

JGIM 2005;20 (7);653-6.

Risk of UGI Hemorrhage in Warfarin Treated Patients Receiving Antibiotics

Antibiotic Odds Ratio TMP-Sulfa 3.84 (CI 2.33-6.33) Ciprofloxacin 1.94 (CI 1.28-2.95) Amoxicillin 1.37 (CI .92-2.05) Nitrofurantoin 1.40 (CI .71-2.75)

Arch Intern Med 2010; 170(7):617-621)

JAMA Intern Med. 2014;():. doi:10.1001/jamainternmed.2013.13957

Thirty-Day Outcomes by Antibiotic and Interaction Mechanism

Warfarin Interactions With Antibiotics in the Ambulatory Care Setting

Antibiotics for UTI in Patients on Warfarin

Penicillins/cephalosporins ok Nitrofurantoin ok Quinolones be worried TMP/Sulfa don’t use

Case 4

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 > 61

In double blind crossover trial patients on Warfarin + 4 g/d of Acetaminophen had PT 1.75 x control2

Patients received 2 gm or 4 gm acetaminophen or placebo with warfarin, 54% of those receiving acetaminophen overshot INR goal vs 17% of placebo3

1. JAMA 1998;279:657-6622. Clin Res 1984;32:698a3. Pharmacotherapy 2007; 27 (5):675-83.

Case 5

A 76 yo man is admitted with increasing SOB. He hasa 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) PrednisoneB) AmoxicillinC) CodeineD) Amoxicillin + Pantoprazole

Effect of Oral Corticosteroids OnWarfarin 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.

Warfarin –Simvastatin Interaction

Study looking at average warfarin dose needed in patients on simvastatin and warfarin, compared to warfarin alone.

56 patients in each group, matched by age, body size, and gender.

Mean warfarin dose was 3.3 for those taking simvastatin vs 4.0 for those not taking simvastatin

Etiology of the need for less warfarin was likely P450 inhibition of CYP3A4 and CYP2C9 subunits

J Thromb Heamost 2006;4 (6): 1422-4.

Dabigatran: Safer???

In 2011, the FDA received more adverse event reports related to dabigatran than for any other drug.

3,800 serious adverse events, 542 deaths, 2,367 reports of hemorrhage, 291 acute renal failure and 644 strokes

Warfarin #2: 1,106 serious adverse events, 72 deaths.

ISMP Quarterwatch Oct 2013

CYP450 enzyme CYP3A4

CYP3A4 metabolizes about half of all drugs on the market

many other common drugs are moderate-to-potent inhibitors of CYP3A4

a number of drugs are known to be CYP3A4 inducers

http://www.pharmacytimes.com/publications/issue/2008/2008-09/2008-09-8687#sthash.uQjlfuF1.dpuf

http://www.pharmacytimes.com/publications/issue/2008/2008-09/2008-09-8687




CYP3A4 Inhibitors

Clarithromycin Erythromycin Conazole’s—Flu, Itra,

Keto, Mi, Vori Diltiazem Verapamil

Amiodarone Fluoxetine Grapefruit juice Nefazodone Tamoxifen Cyclosporine

CYP3A4 Inducers

Carbamazepine Dexamethasone Efavirenz Fosphenytoin Griseofulvin Modafinil

Nafcillin Phenobarbital Phenytoin Primidone Rifampin St. John's wort

CYP3A4 and Statins

Case 6

A 70 yo man with atrial fibrillation presents for followup after an MI. He reports that he has medicare part D and is concerned about the cost of his meds. Current medications : Metoprolol, amiodarone, nitroglycerin, ASA. His lipid panel shows an LDL cholesterol of 120. What would you recommend?A) No treatmentB) AtorvastatinC) SimvastatinD) LovastatinE) Pravastatin

Simvastatin and Amiodarone

Amiodarone is a potent inhbitor of CYP3A subunit of the P450 system, which metabolizes simvastatin.

Multiple case reports of severe rhabdomyolysis in patients treated with simvastatin and amiodarone

In the SEARCH trial, those receiving amiodarone and 80 mg of simvastatin had an 8.8 RR of myopathy

Lovastatin shares the same metabolism, so would avoid it

Disposition Kinetics with Amiodarone /Simvastatin vs Pravastatin Prospective, cross over, randomized , open label

study in 12 healthy volunteers All received Simvastatin alone and after 3 days of 400

mg amiodarone, and pravastatin alone and after 3 days of amiodarone

Amiodarone increased simvastatin AUC by 73%, peak plasma concentration by 100%, and t ½ by 48%.

There was no effect on pravastatin.

Clin Pharmacol Ther 2007; 81 (5): 679-684

Case 7

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 ofStatin Toxicity

Fibrates (Gemfibrozil 15X >> Fenofibrate) Azole antifungals Amiodarone Erythromycin/Clarithromycin Protease inhibitors Verapamil/Diltiazem Least drug interactions with pravastatin,

most with simvastatin and lovastatin

What Should You Worry About When Prescribing Simvastatin?

Mild interaction with warfarin Major interaction with grapefruit juice 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

Previous lovastatin label New lovastatin labelAvoid lovastatin with:•Itraconazole •Ketoconazole •Erythromycin •Clarithromycin •Telithromycin •HIV protease inhibitors •Nefazodone

Contraindicated with lovastatin:•Itraconazole /Ketoconazole •Posaconazole •Erythromycin /Clarithromycin /Telithromycin •HIV protease inhibitors •Boceprevir •Telaprevir •Nefazodone

Do not exceed 20 mg lovastatin daily with:•Gemfibrozil /Other fibrates •Lipid-lowering doses (≥1 g/day) of niacin •Cyclosporine •Danazol

Avoid with lovastatin:•Cyclosporine •Gemfibrozil

Do not exceed 20 mg lovastatin daily with:•Danazol •Diltiazem •Verapamil

Do not exceed 40 mg lovastatin daily with:•Amiodarone •Verapamil

Do not exceed 40 mg lovastatin daily with:•Amiodarone

Avoid large quantities of grapefruit juice (>1 quart daily)

Avoid large quantities of grapefruit juice (>1 quart daily)

Lovastatin Dose Limitations 2/28/12

Case 10

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) AzithromycinB) ClarithromycinC) LevofloxacinD) ErythromycinE) Chloramphenicol

Colchicine Drug Interactions

Higher risk in patients with renal insufficiency

Many (over 100) reports of death with interaction with clarithromycin, a strong CYP3A4 inhibitor

Avoid clarithromycin, protease inhibitors, itraconazole and ketoconazole

Case 12

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 interactionB) Lisinopril-clarithromycin interactionC) Diltiazem-clarithromycin interactionD) Linezolid- clarithromycin interactionE) Linezolid- isosorbide interaction

Hypotension Related to Macrolide-Ca 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 admitted 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.

JAMA. 2013;310(23):2544-2553. doi:10.1001/jama.2013.282426Published online November 9, 2013.

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!

Miscellaneous Effects of Common Drugs

Case 11

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 insufficiencyB) CarvedilolC) TMP/SulfaD) VerapamilE) Digoxin

Trimethoprim-Sulfamethoxazole and Hyperkalemia

Population based, nested case-control study of patients 66 or older who were receiving and ACEI or ARB (14 years)

Case patients were those who had hyperkalemia within 14 days of receiving TMP-sulfa, amoxicillin,ciprofloxacin, norfloxacin or nitrofurantoin. For each case patient 4 controls were matched.

4148 admissions due to hyperkalemia, 371 within 14 days of antibiotic exposure. Compared to amoxicillin the relative risk for hyperkalemia with TMP-sulfa was 6.7 (CI 4.5-10) . No other antibiotic posed a significant risk for hyperkalemia.

Arch Intern Med 2010; 170(12): 1045-1049.

Effect of Standard Dose TMP-Sulfa on Potassium in Elderly Men Thirty-three patients who received standard-dose

TMP/SMX for 3 or more days comprised the study group. Twenty patients who received oral cephradine or

amoxicillin for 3 or more days comprised the control group.

Patients taking ACEI, NSAIDS,B Blockers or who had CRI were excluded

The serum potassium concentration in the study group was 4.22 ± 0.40 mmol/L and increased by 0.31 ± 0.38 mmol/L at the end of therapy (p < 0.001).

Ann of Pharm 1996;30(4):347-350.

Trimethoprim InducedHyperkalemia

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 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

Case 14

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.Which has the strongest association with UGI bleeding?A) FluoxetineB) BenazaprilC) HydrochlorothiazideD) AcetaminophenE) 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 NSAID

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;163:59-64BMJ 1999; 319 (7217):1106-9.Aliment Pharmacol Ther 2008; 27: 31-40. Meta-analysisClin Gastroenterol Hepatol. 2009 Dec;7(12):1314-21.

Case 15

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 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

FDA Drug Safety Communication: Recognize that if citalopram must be used in patients with certain conditions

because of the risk of QT prolongation, ECG monitoring and/or electrolyte monitoring should be performed.

Patients with congenital long QT syndrome are at particular risk of Torsade de Pointes, ventricular tachycardia, and sudden death when given drugs that prolong the QT interval. Nevertheless, the labeling recommendation for patients with congenital long QT syndrome has been changed from “contraindicated” to “not recommended,” because it is recognized that there may be some patients with this condition who could benefit from a low dose of citalopram and who lack viable alternatives.

The maximum recommended dose of citalopram is 20 mg per day for patients older than 60 years of age.

Citalopram should be discontinued in patients who are found to have persistent QTc measurements greater than 500 ms.

Think Before Putting SSRI’Sin the Drinking Water

Probable increased risk of UGI bleed Often overlooked cause of hyponatremia Sexual dysfunction (20-50%) QT prolongation with citalopram

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 Safety Communication

• A diagnosis of CDAD should be considered for PPI users with diarrhea that does not improve.

• Advise patients to seek immediate care from a healthcare professional if they experience watery stool that does not go away, abdominal pain, and fever while taking PPIs.

• Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Problems With PPI’s

Decreased Ca absorption Increased fracture risk Decreased iron absorption 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)

What To Remember From ThisTalk

Beers criteria are commonly used to identify dangerous drugs, but may not be accurate

STOPP criteria have been tested to reduce numbers of drugs

CYP3A4 interactions are a common source of neurotoxicity

Watch carefully for side effects from TMP/Sulfa, PPIs and SSRIs.

Dangerous Drugs and How to Minimize the Dangers

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