97

A study published in 2016 examined DDIs observed in patients treated with

imatinib.

112 The investigators performed two observational studies to identify the

medications that were most frequently dispensed simultaneously with imatinib

through the French health insurance reimbursement database SNIIRAM (Systeme

National d’Information Inter-Regimes Assurance Maladie), as well as the

p. 48

p. 49

ADRs related to DDIs involving imatinib using the French Pharmacovigilance

Database. A sample of 544 patients from SNIIRAM with at least 1 reimbursement for

imatinib were identified between January 2012 through August 2015. Of this cohort

of 544 patients, 89.3% (486) of patients had at least 1 prescription medication that

could potentially interact with imatinib based on mechanism of action (e.g.,

metabolism pathways). The results of the study also found that the most frequent DDI

was with paracetamol (acetaminophen), (77.4%), which resulted in an increased risk

of paracetamol toxicity. Other study findings with greater than 10% of patients with

potential DDIs were with proton pumps inhibitors (33.3% for omeprazole) or

dexamethasone (23.7%) that could reduce imatinib’s effectiveness, and with

levothyroxine (18.5%) that could decrease levothyroxine’s effectiveness. The

suspected mechanisms of this drug interaction with levothyroxine are an induction by

imatinib of nondeiodination clearance or induction by imatinib of uridine

diphosphate glucuronyl transferases.

113,114 Study results also found that the most

frequently used drugs that could increase imatinib toxicity were ketoconazole and

clarithromycin (respectively, 5.1% and 4.7%).

112 The overall findings of this study

suggest that at least 40% of patients who are receiving imatinib are at risk of DDIs

and may reach an even higher rate according to the results of the study performed in

SNIIRAM. The highest rate of potential DDIs in this study with imatinib was with the

following agents: paracetamol, PPIs, dexamethasone, or levothyroxine. Based on the

study findings, the investigators provided recommendations regarding the use of

imatinib with specific agents. It is recommended that the reader refers to the package

insert of imatinib for drug interactions and dosing guidelines. Further study regarding

DDIs with imatinib, as well as other TKIs, is warranted.

With regard to selection of an antimalarial agent for D.T., chloroquine,

mefloquine, and atovaquone-proguanil (Malarone) may have potential interactions

with imatinib. The proguanil component is metabolized via the 2C19 pathway. Given

the options that can be used for malaria prophylaxis in D.T., doxycycline would be

an appropriate antimalarial agent used for malaria prophylaxis that does not interact

with imatinib or D.T.’s other medications (Refer to Chapter 81 Parasitic Infections

for malaria prophylaxis options). The most commonly reported adverse effects with

doxycycline are GI effects, including nausea, vomiting, abdominal pain, and diarrhea.

Esophageal ulceration associated with doxycycline is a rare but well-described

adverse event. D.T. should be counseled to take doxycycline with food and plentiful

fluids, in an upright position in order to minimize GI adverse effects. Because

doxycycline can cause photosensitivity and D.T. will be on a safari, the risk of

photosensitivity can be reduced by the use of an appropriate sunscreen and wearing

protective clothing, including a hat. D.T. should also be counseled regarding the use

of paracetamol (acetaminophen) and also to check in advance with his pharmacist

before taking any natural products that may be metabolized via cytochrome P450.

RESOURCES AND EVIDENCE FOR CLINICAL

DECISION SUPPORT

Healthcare providers have become increasingly challenged on devising optimal

approaches to managing drug interactions. Patient safety initiatives have expanded in

efforts to improve the healthcare delivery system with medication error prevention as

a high-priority area. The consensus recommendations published by the expert group

in 2015 have provided a road map for addressing the key concerns to improve the

approach to evaluating DDI evidence for clinical decision-making.

5 As part of this

process, it was important to review existing methods for evaluating DDIs. The Drug

Interaction Probability Scale (DIPS), a 10-item scale, was developed to evaluate

individual case reports for DDIs by assessing an adverse event for causality by a

DDI.

115 This tool was developed to address limitations of previous assessment

instruments, such as the Naranjo scale. The reader is referred to Appendix C of the

consensus recommendations for further information regarding DIPS and other

available instruments.

5 The expert group also discussed the current systematic

approaches using clinical decision support (CDS) systems, their limitations, and the

need for a new assessment instrument to objectively evaluate a body of evidence to

establish the existence of a DDI. One of the key challenges of CDS systems is to

determine what evidence is required for a DDI to be applicable to an entire drug

class. Pharmacokinetic interactions are rarely generalizable to all agents within a

drug class, and if there is class effect, the magnitude of the effect can often vary,

which typically necessitates that each drug is reviewed individually. In some cases,

pharmacokinetic interaction data may be extrapolated from one agent to other agents

in the small class if the purported mechanism of interaction involves common

pharmacologic effects.

To advance this important initiative, recently another group of experts convened to

address the following: (1) to outline the process to use for developing and maintain a

standard set of DDIs; (2) to determine the information that should be included in a

knowledge base of standard DDIs; (3) to determine whether a list of contraindicated

drug pairs can or should be established; and (4) to determine how to more

intelligently filter DDI alerts.

116 Their recommendations for selecting drug–drug

interactions for CDS were released in 2016. The reader is referred to both the 2015

and the 2016 recommendations.

5,116

Because various avenues are examined to reduce the risk of drug interactions

within society, it is essential as healthcare providers that we improve patient

education regarding medication information. This strategy includes our

communications with patients both verbal instructions and patient instruction leaflets

given with the prescription. It is important to consider translation of information into

different languages and to also promote culturally competent communication within

every healthcare setting. The use of auxiliary warning labels placed on the

medication package, books, and referring patients to quality health information on the

internet. Pharmacists are uniquely positioned to provide important information

regarding OTC medications, including herbal products when patients receive

prescription information, and when they are seeking recommendations for OTC

products.

117

CONCLUSION

Given the complexities of data on drug interactions and the complexities within the

healthcare systems, healthcare providers have become increasingly challenged on

devising optimal approaches to managing drug interactions.

3 Patient safety initiatives

have expanded in efforts to improve the healthcare delivery system with medication

error prevention as a high-priority area. Medication errors may be related to

professional practice, healthcare products, procedures, and systems, including

prescribing, order communication, product labeling, packaging, nomenclature,

compounding, dispensing, distribution, administration, education, monitoring, and

use.

2,4 Because exposure to drug–drug interactions is a significant source of

preventable drug-related harm, appropriate medication use, including drug

interaction management, will avoid medication errors.

5

Although the majority of drug interactions are clinically insignificant, in certain

circumstances drug interactions are considered to be highly significant and can cause

harm. Patients should be informed of the importance of maintaining a complete

medication

p. 49

p. 50

profile including over-the-counter medications, herbs, and dietary supplements.

The incorporation of pharmacogenetic information into risk assessment of patients

will improve our ability to prevent DDIs and to better evaluate interactions with

biologic drugs.

More well-controlled studies are needed after drug approvals. Population-based

studies are useful to determine the severity of, incidence of, and clinical importance

of drug interactions. Pharmacogenetic research can further improve the precision of

DDE evidence and CDS by identifying patient-specific predisposing factors. Future

directives will identify the most appropriate process to rate the quality of DDI

evidence and provided graded recommendations to reduce the risk of adverse

consequences.

5

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Baxter K, Preston CL. Stockley’s Drug Interactions. 10th ed London, Pharmaceutical Press, 2013.[Preston CL.

Stockley’s Drug Interactions Pocket Companion. Pharmaceutical press, 2015.] (61).

Caterina P, Antonello DP, Chiara G, et al. Pharmacokinetic drug-drug interaction and their implication in clinical

management. J Res Med Sci. 2013;18:600-609.(3)

Scheife RT, et al. Consensus Recommendations for Systematic Evaluation of Drug-Drug Interaction Evidence for

Clinical Decision Support. Drug Saf. 2015;38:197–206. (5)

Tilson H, Hines LE, McEvoy G, Weinstein DM, et al. Recommendations for selecting drug-drug interactions for

clinical decision support. Am J Health-System Pharm. 2016;73(8):576-585.(116)

Key Websites

Hartshorn EA TD. Principles of drug interactions. Facts & Comparisons eAnswers Web site.

http://online.factsandcomparisons.com.ezproxymcp.flo.org/Viewer.aspx?book=DIF&monoID=fandcdif5444. Updated 2015. Accessed March 10, 2017.(60)

COMPLETE REFERENCES CHAPTER 3 DRUG

INTERACTIONS

Robertson S et al. Chapter 15, Drug Interactions. In: Atkinson AJ et al, eds. Principles of Clinical Pharmacology.

3rd ed. Waltham, MA: Elsevier Academic Press; 2012:239–257.

Magro L et al. Epidemiology and characteristics of adverse reactions caused by drug-drug interactions. Expert

Opin Drug Saf. 2012;11(1):83–94.

Caterina P et al. Pharmacokinetic drug-drug interaction and their implication in clinical management. J Res Med

Sci. 2013;18:600–609.

Rowland M et al. Chapter 12: Variability. In: Rowland M et al, eds. Clinical Pharmacokinetics and

Pharmacodynamics Concepts and Applications. 4th ed. Philadelphia, PA: Wolters Kluwer Lippincott Williams

& Wilkins; 2011: 483–525.

Scheife RT et al. Consensus recommendations for systematic evaluation of drug-drug interaction evidence for

clinical decision support. Drug Saf. 2015;38:197–206.

Rowland M et al. Chapter 17: Drug Interactions. In: Rowland M et al, eds. Clinical Pharmacokinetics and

Pharmacodynamics Concepts and Applications. 4th ed. Philadelphia, PA: Wolters Kluwer Lippincott Williams

& Wilkins; 2011:483–525.

Oates JA. Chapter 5. The science of drug therapy. In: Brunton LL, ed. Goodman & Gilman’s The

Pharmacological Basis of Therapeutics. 11th ed. McGraw-Hill, Medical Publishing Division; 2006.

Hines LE et al. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother.

2011;9(6):364–377.

Sharifi H et al. Polypharmacy-induced drug-drug interaction; threat to patient safety. Drug Res. 2014;64:633–637.

Wallace J et al. Appropriate prescribing and important drug interactions in older adults. Med Clin N Am.

2015;99:295–310.

Gnjidic D et al. Clinical implications from drug-drug and drug-disease interactions in older people. Clin Exp

Pharmacol Physiol. 2013;40:320–325.

Shi S et al. Age-related changes in pharmacokinetics. Curr Drug Metab. 2011;12:601–610.

Maeda K. Systematic review of the effects of improvement of prescription to reduce the number of medications

in the elderly with polypharmacy. Yakugaku Zasshi. 2009;129(5):631–645.

Pizzuti R et al. Gruppo ARGENTO. Prescription drugs and the elderly: results of the Agrento study. Ig Sanita

Pubbl. 2006;62(1):11–26.

Kalula SZ. Drugs and the older person. CME. 2007;25(9):422–425.

Shapiro LE et al. Drug interactions: Proteins, pumps, and P-450s. J Am Acad Dermatol. 2002;47:467–484.

Sitar DS. Aging issues in drug disposition and efficacy. Poc West Pharmacol Soc. 2007;50:16–20.

Polidoro A et al. Frailty and disability in the elderly: a diagnostic dilemma. Arch Gerontol Geriatr. 2011;52(2):e75–

e78.

Hubbard RE et al. Frailty, inflammation and the elderly. Biogerontology. 2010;11(5):635–641.

Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol.

2003;38:843–853.

Costa AJ. Potential drug interactions in an ambulatory geriatric population. Fam Pract. 1991;8:234–236.

Gorski JC et al. The contribution of intestinal and hepatic CYHP3A4 to the interaction between midazolam and

clarithromycin. Clin Pharmacol Ther. 1998;64:133–143.

Bhardwaj S et al. Muscular effects of statins in the elderly female; a review. Clin Intervent Aging. 2013;8:47–59.

Blouin RA et al. Chapter 11: Special pharmacokinetic considerations in the obese. In: Burton ME et al, eds.

Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring. 3rd ed. Philadelphia, PA: Lippincott

Williams & Wilkins; 232–240.

McCabe BJ. Prevention of food-drug interactions with a special emphasis on older adults Curr Opin Clin Nutr

Metabol Care. 2004;7:21–26.

Zevin S et al. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet. 1999;36(6):425–438.

Samer CF et al. Applications of CYP450 testing in the clinicalsettings. Mol Diagn Ther. 2013;17:165–84.

Grattagliano I et al. Avoiding drug interactions: Here’s help. J Fam Pract. 2010;59(6):322–329.

Corsonello A et al. The impact of drug interactions and polypharmacy on antimicrobial therapy in the elderly. Clin

Microbiol Infect. 2015;21(a): 20–26.

Zhou J et al. The effect of therapeutic hypothermia on drug metabolism and drug response: Cellular mechanisms

to organ function. Expert Opin Drug Metab Toxicol. 2011;7(7):803–816.

Thelen K et al. Cytochrome P450-mediated metabolism in the human gut. J Pharm Pharmacol. 2009;61:541–558.

Finch A et al. P-glycoprotein and its role in drug-drug interactions. Aust Prescr. 2014;37:137–139.

Doligalski CT et al. Drug interactions: A primer for the gastroenterologist. Gastroenterol Hepatol. 2012;8(6):376–

383.

Andrus MR. Oral anticoagulant drug interactions with statins: case report of fluvastatin and review of the

literature. Pharmacotherapy. 2004;24:285–290.

Barry M. Rosuvastatin–warfarin drug interaction. Lancet. 2004;363:328.

Olsson GO et al. Rosuvastatin–warfarin drug interaction. Lancet. 2004;363:897.

Manzi SF et al. Drug Interactions-A Review. Clin Ped Emerg Med. 2005;6:93–102.

Middleton RK. Drug Interactions. In: Quan H et al, eds. Textbook of Therapeutics Drug and Disease

Management. 8th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Benet LZ et al. Changes in plasma protein binding have little clinical relevance. Clin Pharmcol Ther. 2002;71:115–

121.

Boobis A et al. Drug interactions. Drug Metab Rev. 2009;41(3):486–527.

Zhou SF et al. Clinically important drug interactions potentially involving mechanism-based inhibition of

cytochrome P450A and the role of therapeutic drug monitoring. Ther Drug Moni. 2007;29(6):687–710.

Lynch T et al. Ther effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects.

Am Fam Physician. 2007;76(3):391–396.

Ladda MA et al. The effects of CKD on cytochrome P450-mediated drug metabolism. Adv Chronic Kidney Dis.

2016;23(2):67–75.

Anaisi N. Drug interactions involving immunosuppressive agents. Graft. 2001;4(4):232–247.

Bailey DG et al. Grapefruit juice-drug interactions. Br J Clin Pharmacol. 1998;46(2):101–110.

Evans AM. Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Ther Drug

Monit. 2000;22(1):131–136.

Thummel KE et al. Metabolically-based drug-drug interactions. Principles and mechanisms. In: Levy RH et al,

eds. Metabolic Drug Interactions. Philadelphia, PA: Lippincott Williams & Wilkins; 2000: 3–47.

Bachmann KA et al. Drug-drug interactions and the cytochromes P450. In: Lee JS et al, eds. Drug Metabolizing

Enzymes: CYP450 and Other Enzymes in Drug Discovery and Development. New York, NY: Marcel Dekker,

Inc.; 2003: 311–336.

Obach RS. Drug-drug interactions: an important negative attribute in drugs. Drugs Today. 2003;39:301–338.

Weaver RJ. Assessment of drug-drug interactions: concepts and approaches. Xeobiotica. 2001;31:499–538.

Cheng JW et al. Updates of cytochrome P450-mediated cardiovascular drug interactions. Am J Ther.

2009;16:155–163.

Sabol BJ et al. Malabsorption-associated warfarin resistance. Am J Health Syst Pharm. 2009;66:1548–1553.

Gugler R et al. Phenytoin: Pharmacokinetics and Bioavailability. Clin Pharm Ther. 1976;19:135–142.

Maynard GA et al. Phenytoin absorption from tube feedings. Arch Intern Med. 1987;147:1821.

Jung D et al. Effect of dose on phenytoin absorption. Clin Pharmacol Ther. 1980;28:479–485.

Martin E et al. The pharmacokinetics of phenytoin. J Pharmacokinet Biopharm. 1977;5:579–596.

Gubbins PO et al. Drug absorption in gastrointestinal disease and surgery. Clin Pharmacokinet. 1991;21:431–447.

Gulseth MP et al. Pharmacogenomics of warfarin: Uncovering a piece of the warfarin mystery. Am J HealthSyst Pharm. 2009;66:123–133.

Gorbach SL. Chapter 95 microbiology of the gastrointestinal tract. In: Baron S, ed. Medical Microbiology. 4th ed.

Galveston, TX: University of Texas Medical Branch at Galveston; 1996.

http://www.ncbi.nlm.nih.gov/books/NBK7670/. Accessed February 10, 2016.

Hartshorn EA et al. Principles of drug interactions. Facts & Comparisons. eAnswers Web site.

http://online.factsandcomparisons.com.ezproxymcp.flo.org/Viewer.aspx?book=DIF&monoID=fandcdif5444. Updated 2015. Accessed March 10, 2016.

Baxter K et al, ed. Stockley’s Drug Interactions. 10th ed. London, UK: Pharmaceutical Press; 2013.

Foinard A et al. Impact of physical incompatibility on drug mass flow rates: example of furosemide-midazolam

incompatibility. Ann Intensive Care. 2012;2:28.

Bungard TJ et al. Drug interactions involving warfarin: Practice tool and practical management tips. CPJ/RPC.

2011;144(1):21–25. e9.

Horn JR et al. Time course for enzyme induction and deinduction. Pharmacy Times. 2011.

Pleuvry BJ. Pharmacodynamic and pharmacokinetic drug interactions. Anaesth Intensive Care Med.

2005;6(4):129–133.

Hylek EM et al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA.

1998;276:657–662.

Lopes RD et al. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility.

Blood. 2011;118:6269–6273.

Yue Q et al. Safety of St John’s wort. Lancet. 2000;355:576–577.

Henderson L et al. St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin

Pharmacol. 2002;54:349–356.

Pharmacist’s Letter/Prescriber’s Letter, “Clinically Significant Statin Drug Interactions”, August 2009, Volume

25, Number 250812 and Pharmacist’s Letter/Prescriber’s Letter, “Characteristics of the Various Statins”, June

2010, Volume 26, Number 260611.

McGrath CD et al. Monitoring of neuromuscular block. Cont Educ Anaesth Crit Care Pain. 2006;6(1):7–12.

Warr J et al. Current therapeutic uses, pharmacology, and clinical considerations of neuromuscular blocking

agents for critically ill adults. Ann Pharmacother. 2011:45:1116–1126.

Roberts DJ et al. Drug absorption, distribution, metabolism and excretion considerations in critically ill adults.

Expert Opin Drug Metab Toxicol. 2013;9(9):1067–1084.

Smith BS et al. Introduction to drug pharmacokinetics in the critically ill patient. Chest. 2012;141(5):1327–1336.

Cawley MJ. Mechanical ventilation: a tutorial for pharmacists. Pharmacotherapy. 2007;27(2):250–266.

Hraiech S et al. The Role of Neuromuscular blockers in ARDS: benefits and risks. Curr Opin Crit Care.

2012;18:495–502.

DeJonghe B. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA. 2002;288:2859–

2867.