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Drug Interactions Pharm 560 2 October 2002. Philip D. Hansten, PharmD Professor, School of Pharmacy University of Washington. Drugs Removed from the Market Due to Drug-Drug Interactions. Cerivastatin (Baycol): Rhabdomyolysis when combined with gemfibrozil

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drug interactions pharm 560 2 october 2002
Drug InteractionsPharm 5602 October 2002

Philip D. Hansten, PharmD

Professor, School of Pharmacy

University of Washington

drugs removed from the market due to drug drug interactions
Drugs Removed from the Market Due to Drug-Drug Interactions
  • Cerivastatin (Baycol): Rhabdomyolysis when combined with gemfibrozil
  • Terfenadine (Seldane): Ventricular arrhythmias with CYP3A4 inhibitors
  • Astemizole (Hismanal): Ventricular arrhythmias with CYP3A4 inhibitors
  • Cisapride (Propulsid): Ventricular arrhythmias with CYP3A4 inhibitors
  • Mebefradil (Posicor): Rhabdomyolysis when combined with simvastatin
hospital admissions due to drug interactions in elderly france
Hospital Admissions due to Drug Interactions in Elderly (France)
  • Prospective study of 1000 patients > 70 yo admitted to geriatric unit
  • 538 patients exposed to DDIs
  • 130 patients developed ADIs
  • Most common drugs involved were cardiovascular and psychotropic

Doucet J et al. J Am Geriatr Soc. 1996;44:944-948.

severe cimetidine adverse drug interactions are rare
Severe Cimetidine Adverse Drug Interactions Are Rare
  • VA Hospital switched from ranitidine to cimetidine as cost-saving measure
  • Retrospective study of 4570 patients on cimetidine (10% got interacting drugs)
  • Only 4 patients had adverse interactions
    • 2 theophylline (nausea, vomiting, arrhythmia)
    • 1 procainamide (arrhythmia)
    • 1 warfarin (fatal intracerebral hemorrhage)

Scott MA et al. Am J Health-Syst Pharm. 1999;56:1890-91.

uncommon adverse drug interactions

Uncommon Adverse Drug Interactions

For an adverse drug interaction that occurs once in 1000 cases, one would have to study 3000 cases to have a 95% chance of observing the event.

david hume 1711 1776
David Hume (1711-1776)
  • Scientific certainty is not possible using induction
    • “All swans are white.”
  • Absence of proof is not proof of absence
    • “Bigfoot does not exist.”
    • “Those drugs do not interact.”
slide7

Assessing Drug Interactions Using Induction

Drug A + Drug B

25 Patients

NO ADR OBSERVED

Usual Conclusion: This interaction is not clinically important.

slide8

Assessing Drug Interactions Using Induction

Drug A + Drug B

25 Patients

NO ADR OBSERVED

Correct Conclusion: Available information is insufficient to determine clinical importance.

slide9

Drug Interaction Defenses

Drug A +Drug B

Prescriber’s Knowledge

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Pharmacogenetics

Drug Administration

Patient Education

Monitoring

Defenses

ADR

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

slide10

Drug Interactions: “When the Holes Line Up”

A + B

Prescriber’s Knowledge

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Drug Administration

Patient Education

Monitoring

Defenses

ADR

Latent Failures

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

slide11

Drug Interaction Errors

Prescriber’s Knowledge

A + B

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Drug Administration

Patient Education

Monitoring

NO ADR

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

nsaids ssris increased risk of bleeding
NSAIDs + SSRIs: Increased Risk of Bleeding?
  • Case-control study of 1651 incident cases compared to 10,000 matched controls
  • “The concurrent use of NSAIDs with SSRIs greatly increases risk of upper GI bleeding”
  • SSRIs  platelet uptake of serotonin

1

De Abajo FJ et al. Br Med J 1999;319:1106-1109.

clarithromycin biaxin induced digoxin toxicity
Clarithromycin (Biaxin)-Induced Digoxin Toxicity
  • 70 YO woman on digoxin 0.25 mg/day for 4 years started on clarithromycin
  • After 4 days, hospitalized with nausea, vomiting, weakness, brown spots in vision, ECG abnormalities
  • Serum digoxin = 5.4 ng/mL

Trevedi S et al. Ann Intern Med 1998;128:604. Letter

p glycoprotein p gp
P-glycoprotein (P-gp)
  • Efflux pump:  exposure to xenobiotics
  • Found in numerous tissues:
    • Intestinal Epithelium
    • Biliary canaliculi
    • Renal proximal tubules
    • Blood-brain barrier
    • Tumor cells
  • Promiscuous: interacts with wide variety of chemical structures

Kovarik JM et al. Clin Pharmacol Ther 1999;66:391-400.

p glycoprotein actively transports drugs out of cell wall
P-Glycoprotein Actively Transports Drugs Out of Cell Wall

Entry via passive diffusion

Outside Cell

Cell Wall

PGP

Inside Cell

= Lipophilic Drug

p glycoprotein involved in digoxin pharmacokinetics
P-glycoprotein Involved in Digoxin Pharmacokinetics

P-glycoprotein protects against digoxin toxicity by:

  • Decreasing G.I. absorption
  • Increasing biliary excretion
  • Increasing renal tubular secretion
  • Decreasing access to the brain

Tanigawara Y. Ther Drug Monit 2000;22:137-140.

itraconazole increases levels of methylprednisolone
Itraconazole Increases Levels of Methylprednisolone
  • Randomized crossover study of 14 subjects, 4 days of itraconazole, then single dose of:
    • Methylpred. 48mg
    • Prednisolone 60 mg
  • Marked effect on methylprednisolone, but not prednisolone

Lebrun-Vignes B. Br J Clin Pharmacol. 2001;51:443-450.

slide18

Drug Interaction Errors

Prescriber’s Knowledge

A + B

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Drug Administration

Patient Education

Monitoring

NO ADR

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

asthma sufferer wins 28 6 million award seattle times 9 3 94
“Asthma Sufferer Wins $28.6 Million Award”(Seattle Times 9/3/94)
  • 24-year-old man on theophylline went into ER with infection, and the ER physician gave him ciprofloxacin
  • Theophylline levels doubled, and he was left with permanent brain damage
  • Physician was awarded $22.5 million for “damage to his reputation”
st john s wort reduces simvastatin zocor levels
St. John’s Wort Reduces Simvastatin (Zocor) Levels

Simvastatin Acid AUC

  • 16 subjects took 10mg simvastatin alone and after St. John’s Wort 900 mg/day X 14 days
  • AUC of Simvastatin & its active metabolite substantially reduced
  • Induction of CYP3A4 and P-glycoprotein?
  • No effect on Pravastatin

Sugimoto K et al. Clin Pharmacol Ther 2001;70:518-24.

st john s wort increases cyp3a4 activity
St. John’s Wort Increases CYP3A4 Activity
  • 12 subjects took probe drugs with St. John’s Wort 900mg/d X 14d
    • Caffeine (1A2)
    • Tolbutamide (2C9)
    • Dextromethorphan (2D6)
    • Midazolam (3A4)
  • Only midazolam was affected (PO > IV)

Wang Z et al. Clin Pharmacol 2001;70:317-26.

garlic supplements decrease saquinavir invirase levels
Garlic Supplements Decrease Saquinavir (Invirase) Levels
  • 9 subjects took 1200 mg saquinavir TID alone and after garlic capsules BID X 20 days
  • Allicin content of garlic capsules confirmed
  • Garlic associated with 51% decrease in AUC of saquinavir

Piscitelli SC et al. 8th Conf. On Retroviruses, 2001, Abst. 743

ibuprofen advil inhibits the antiplatelet effects of aspirin
Ibuprofen (Advil) Inhibits the Antiplatelet Effects of Aspirin
  • Subjects took 81 mg ASA in AM for 6 days with 3 ibuprofen dosing schedules:
    • 400 mg 2 hours before ASA ( platelet effect)
    • 400 mg 2 hours after ASA (No effect on ASA)
    • 400 mg 2, 7 & 12 h after ASA ( platelet effect)
  • Other agents did not reduce platelet effect:
    • Rofecoxib (Vioxx) 25 mg before or after ASA
    • Diclofenac DR 75 mg BID (2 & 10 h after ASA)
    • Acetaminophen 1000 mg before or after ASA

Catella-Lawson F et al. New Engl J Med. 2001;345:1809-17.

slide24

Drug Interaction Errors

Prescriber’s Knowledge

A + B

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Drug Administration

Patient Education

Monitoring

NO ADR

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

rifampin markedly reduces simvastatin plasma levels
Rifampin Markedly Reduces Simvastatin Plasma Levels
  • 10 subjects took 40 mg simvastatin alone & after rifampin 600 mg/day for 5 days
  • Simvastatin acid AUC decreased by 93%
  • No effect on half-life of simvastatin; primary effect on first pass metabolism

Kyrklund et al. Clin Pharmacol Ther 2000;68:592-597..

sertraline zoloft levels reduced by enzyme inducers pht cbz
Sertraline (Zoloft) Levels Reduced by Enzyme Inducers (PHT, CBZ)

Sertraline C/D Ratio

  • Sertraline serum levels compared in 9 patients on phenytoin (PHT) or carbamazepine (CBZ) versus 54 patients on just sertraline
  • Concentration/daily dose ratios considerably lower with enzyme inducers

Pihlsgard M, Eliasson E. Eur J Clin Pharmacol 2002;57:915-916.

cushing s syndrome with ritonavir nasal fluticasone
Cushing’s Syndrome with Ritonavir + Nasal Fluticasone
  • 30 YO HIV (+) man on ritonavir and nasal fluticasone developed Cushingoid facies
  • Positive dechallenge and rechallenge
  • Similar case reported by Chen (1998)

Hillebrand-Haverkort et al. AIDS 1999;13:1803.

fluticazone susceptible to cyp3a4 inhibitors
Fluticazone Susceptible to CYP3A4 Inhibitors?
  • Fluticasone metabolized by CYP3A4 to inactive metabolite
  • Bioavailability of fluticasone after inhalation = 12 to 26%
  • CYP3A4 inhibitors theoretically would increase systemic effects of fluticasone
slide29

Drug Interaction Errors

Prescriber’s Knowledge

A + B

Computer Screening

Pharmacist’s Knowledge

Patient Risk Factors

Drug Administration

Patient Education

Monitoring

NO ADR

Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

factors influencing drug interaction outcomes
Factors Influencing Drug Interaction Outcomes

PATIENT

FACTORS

DRUG

ADMINISTRATION

Dose

Duration

Dosing Times

Sequence

Route

Dosage Form

Genetics

Diseases

Diet/Nutrition

Environment

Smoking

Alcohol

CLINICAL

OUTCOME

OF DRUG

INTERACTIONS

HIGH VARIABILITY

Adapted from Hansten. Science & Medicine. 1998;5:16-25.

fluconazole diflucan warfarin coumadin
Fluconazole (Diflucan) + Warfarin (Coumadin)
  • 7 people on warfarin given fluconazole 100 mg daily X 7 d
  • Marked increase in the PT response (but high variability)
  • No bleeding occurred

Crussell-Porter LL et al. Arch Intern Med 1993;153:102-104.

fatal hyperkalemia after amiloride ace inhibitors
Fatal Hyperkalemia After Amiloride + ACE Inhibitors
  • 5 patients presented to ER with severe hyperkalemia (on ACE inhibitor with amiloride added 8 to 18 days earlier)
  • All 5 were over 50 & had diabetes and 4 had renal impairment
  • Potassium levels = 9.4 to 11 mEq/L
  • 2 patients died (authors recommend avoiding combination)

Chiu T-F et al. Ann Emerg Med 1997;30:612-615.

hyperkalemia risk estimates with various combinations of drugs
Hyperkalemia Risk Estimates With Various Combinations of Drugs

Patients Predisposed to Hyperkalemia*

* e.g., Diabetes, Renal impairment, High dietary potassium, etc.