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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

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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

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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

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

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