Drug interaction resources: mind the gaps

Drug interactions can lead to significant toxicity or loss of clinical effect. The risks increase with the number of drugs the patient takes.

General and specialised drug interaction resources are available. Access to up-to-date electronic resources is encouraged.

There are gaps in the information on interactions for new drugs, those with complicated metabolism and drugs with limited use. It may be necessary to use multiple resources to find the information.

When assessing information about interactions, clinicians should evaluate the relevance for each patient. In high-risk situations, expert advice can be valuable. Clinicians should report new or unusual drug interactions to the Therapeutic Goods Administration.

Treatment regimens are becoming increasingly complex, with a greater risk of drug interactions. Drug–drug interactions can cause significant patient harm. This is either due to drug toxicity or loss of efficacy. For example, voriconazole¹ and clarithromycin increase simvastatin concentrations risking rhabdomyolysis, while rifampicin decreases the anticoagulant effect of warfarin. Sometimes interacting drugs are intentionally co-prescribed, for example diltiazem can be used to increase ciclosporin concentrations. Drug–drug interactions can also occur with complementary medicines.

Clinicians should use the available drug–drug interaction resources, but be aware that, although advice may be similar from each resource, discrepancies also occur. It is important that potential drug–drug interactions are evaluated for their clinical significance and relevance to each patient. To identify interactions it is first necessary to have an accurate list of the patient’s prescription, complementary and over-the-counter medicines. Drugs given by other routes, such as topical and inhaled, should also be considered.

The mechanisms of drug–drug interactions vary.^2,3 Clinicians need to understand the drug’s pharmacology including metabolic pathways to determine both pharmacodynamic (altered effect) and pharmacokinetic (altered concentration) interactions. It can be particularly complex to assess the clinical significance of interactions from multiple drugs which each have a potentially additive effect on a shared action, such as QT prolongation,⁴ increasing serotonin, or lowering of the seizure threshold. Patient factors, such as organ dysfunction, age, concurrent
medical conditions, electrolyte disturbances and genetic factors, may influence the risk or severity of the interaction.

Toxicity from drug–drug interactions can occur not only when starting or changing doses, but also when ceasing treatment, for example the strong induction effect of carbamazepine on cytochrome enzymes takes at least two weeks to reverse. Some drugs take a long time to be completely cleared such as amiodarone.⁵ Patients should be monitored accordingly.⁶

General and specialised resources are available to help assess the clinical impact of drug interactions. These include dedicated drug–drug interaction resources for antiretroviral drugs, hepatitis C therapies, antifungals, anticancer drugs and complementary medicines (Table 1). A subscription may be needed.

The Australian Medicines Handbook (AMH) provides practical information on drug interactions considered likely to be clinically important. When appropriate it gives specific information on drug metabolism, but does not include primary references.

MIMS and the Australian Drug Information (AusDI) interaction checkers, Stockley’s Drug Interactions and Lexicomp assign their own ‘severity/risk rating’ or ‘importance’ for interactions. They give the probable mechanism of interaction, advise on actions to be taken and include clinical evidence and supporting, or in some cases disputing, references.

Some of the information used to develop drug–drug interaction resources includes:

• Australian and international product information
• primary literature (case reports and clinical papers)
• guidance from international regulatory bodies, such as the Therapeutic Goods Administration (TGA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Gaps

Depending on the information used and their editorial criteria, resources may give different advice about interactions especially when assigning clinical significance. In some cases, interaction advice may be lacking entirely. These gaps can occur due to variations in product information, or when the metabolism of a drug is not well defined. A particularly challenging area for advice about drug–drug interactions is with new drugs, such as enzalutamide (Table 2), and older re-purposed drugs, such as pristinamycin. Clinical experience of these drugs in combination with other drugs is limited. Sometimes interaction information is extrapolated from other drugs in the same class or those with similar metabolism. Interactions may not be included in the resources until they have been reported to the TGA or published as case reports.

The available resources usually provide information about interactions between two drugs, however patients may be taking multiple drugs with many potential interactions. There is no resource currently available that can provide information about the overall risk of interactions with different combinations of drugs. Medicines information pharmacists may be able to provide advice in these cases.

An A3 single-page version of this table is available.

When looking for information, clinicians are strongly encouraged to have access to the online interaction checking tool in the AMH. Similar tools in MIMS or AusDI are also valuable. For newer drugs, those with complex metabolism or for unusual drug–drug combinations, there may be a need to refer to multiple resources. 

In order to predict the potential for a drug–drug interaction, cytochrome tables, such as in the AMH or Flockhart, are useful, along with the mechanism of action given in the product information. For specific drug classes, free access to specialised resources is available (Table 1). Electronic resources should be used to improve the currency of information. However, clinicans are reminded that not even electronic resources can be considered completely up to date, due to the speed of publication of medical literature.

Hospital and medicines information pharmacists have access to specialised resources, such as Stockley’s or Lexicomp, along with locally researched drug–drug interaction resources. However, access to medicines information services and clinical pharmacologists varies by state. Pharmacists working in general practice are also a valuable resource, but are not widely available.⁷

Drug interaction alerts are included as decision support at the point of care in electronic prescribing and dispensing systems. For example, some interaction alerts in general practice software are referenced to the MIMS interaction checker.

There are concerns that systems generate so many warnings that there is a risk of alert fatigue. This has led to calls in the USA, particularly in the hospital environment, to standardise the information in electronic systems, with the development of methods to filter out unimportant drug–drug interaction alerts.⁸ However, an international or local consensus on standardisation has not yet been reached.^8,9

For new drugs there may be few clinical trials or case reports of drug–drug interactions in ‘real-world’ conditions involving patients with multiple comorbidities taking many drugs. For example, many resources about antiretroviral drug–drug interactions are based on theoretical information, so the clinical relevance in everyday practice is unknown. A Spanish group has therefore established a website that allows clinicians to submit cases of antiretroviral drug–drug interactions.¹⁰

Clinicians are encouraged to publish case reports of new or unusual drug–drug interactions, as these are valuable in informing clinical practice. Reporting suspected drug and vaccine interactions to the Therapeutic Goods Administration is also encouraged via the TGA Adverse Event Management System.

Clinicians should consult drug–drug interaction information, evaluate it and consider its relevance for their patient. For new drugs or when information is inconsistent or absent, it may be necessary to refer to multiple interaction resources or seek expert advice, for example from a medicines information pharmacist.

Conflict of interest: none declared