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Clinically Important Drug-Drug Interactions and How To Manage Them
Clinically Important Drug-Drug Interactions and How To Manage Them
Clinically Important Drug-Drug Interactions and How To Manage Them
practical pointers
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This article is designed to be read in conjunction with the A3 table of drug interactions provided as
an insert in this issue of the Journal of Primary Health Care and also available on the journal website.
Background
–– An antihypertensive + tricyclic anti-depressants
The more medicines a person requires, the in- –– An antihypertensive + isosorbide mononitrate
creased risk of a drug–drug interaction. Unfortu-
nately it is not possible to simply stop potentially • Increasing renal impairment with:
offending medicines, but the medicines interac- –– ACE inhibitor, diuretic and NSAID.
tions need to be managed as safely as possible.
Pharmacodynamic interactions are more complex
There are two types of medicine interactions— and usually involve interference with absorption,
pharmacodynamic and pharmacokinetic. Pharma- e.g. tetracycline and food, calcium or metabo-
cokinetic interactions are relatively straightfor- lism by enzymes such as the cytochrome P450
CORRESPONDENCE TO:
ward and are relatively predictable if the actions enzymes, p-glycoprotein and other less common
Linda Bryant
Department of General of the medicine are known. These involve the enzyme systems.
Practice and Primary additive effect of similar medicines, or a cancel-
Health Care, The ling effect, for example: Twenty years ago we talked of ‘liver enzymes’
University of Auckland,
and competition through protein binding. This
Private Bag 92019,
Auckland, New Zealand • Increasing risk of hypotension with: has become more sophisticated now, with many
l.bryant@auckland.ac.nz –– Two antihypertensives types of enzymes, but the main ones are a large
Warfarin
Managing interactions
• Erythromycin, clarithromycin and roxithromycin Questions to ask when about to prescribe a potentially interacting medicine:
–– Increasing reports of high INR results, some resulting in hospitalisation • Is the combination really necessary—what are the alternatives?
–– If the combination is really necessary, monitor the INR in 3 days. • What are the likely adverse effects of high dosages of the target medicine (how hazardous)?
• Tramadol • What clinical monitoring does the patient need to know about to report back to you?
–– Increasing reports • What objective monitoring needs to be done, and when?
–– If tramadol is used, it should be used consistently and monitor INR in 3 days, then 1 week if there was no change.
The Red Alert drugs and interactions
• Amiodarone
–– 20–60% increase in warfarin The following medicines should ‘ring alarm bells’ as having important interactions:
–– Monitor INR weekly for 4 weeks (onset usually seen in 2 weeks). • Warfarin
• Statins particularly simvastatin (not pravastatin)
• Macrolide antibiotics particularly erythromycin, clarithromycin (less with roxithromycin, minimal with azithromycin)
SSRIs • Calcium channel blockers particularly diltiazem and verapamil
–– May get 40-fold increase in tricyclic antidepressant • SSRIs particularly fluoxetine, paroxetine; less so citalopram
Diltiazem and Diltiazem Not reported, but 200–500% increase. Expected additive Expected additive Expected additive Unlikely interaction Case reports of up to 150–300% increase 150–300% increase 200–300% increase. No apparent clinical
potential increase. Monitor ALT (6 weeks) action. Effect may action. Effect may action. Effect may be 200% increase. Monitor cyclosporin, possible. Warn about sedation effect.
verapamil are potent Monitor muscle and muscle aches. be greater due to be greater due to greater due to enzyme Monitor for increased renal function, BP. Monitor digoxin in and risk of driving.
inhibitors. Amlodipine, aches. enzyme inhibition. enzyme inhibition. inhibition. sedation, blurred vision, 7–10 days.
felodipine and postural hypotension.
nifedipine less so.
Verapamil 400% increase. 400–600% increase. Expected additive Not a rational Expected additive Unlikely interaction Case reports of up to 150–300% increase 150–300% increase Unlikely interaction. No apparent clinical
Monitor ALT (6 Monitor ALT (6 weeks) action. Effect may combination. action. Effect may 200% increase. Monitor cyclosporin, possible. effect.
weeks) and muscle and muscle aches. be greater due to be greater due to Monitor for increased renal function, BP. Monitor digoxin in
aches. enzyme inhibition. enzyme inhibition. sedation, blurred vision, 7–10 days.
postural hypotension.
Azole Fluconazole Potential for an Potential for an Unlikely to be Unlikely to be clinically Unlikely to be Unlikely to be clinically Contradictory Limited reports. Monitor 200–300% increase. Potential interaction. 200% increase in Increased INR in a
interaction. Be alert interaction (has been clinically important. important. Be alert for clinically important. important. Be alert for information. High for TCA adverse effects. Reduce dosage Monitor digoxin in some cases. number of people.
antifungals for muscle aches. reported). Be alert for Be alert for swollen swollen ankles. Be alert for swollen swollen ankles. consequences. Use 70–80% and monitor. 7–10 days. Warn about sedation, Monitor INR after
muscle aches. ankles. ankles. extra precautions. driving. 3–5 days.
Itraconazole is a
particularly potent Itraconazole 200–300% increase. 1000–2000% increase. An interaction is Significant increase Significant increase An interaction is likely. Isolated cases of Limited reports. Monitor 200–300% increase. 200–400% increase Potential interaction 200–300% increase in Only isolated cases
inhibitor. Monitor ALT (6 Avoid combination. likely. Also negative plus negative inotropic plus negative Also negative inotropic contraceptive failure. for TCA adverse effects. Reduce dosage but unpredictable. – may increase tramadol some cases. reported.
Fluconazole is a less weeks) and muscle inotropic effect noted, effect. Reduce inotropic effect. effect. Avoid or use extra 70–80% and monitor. Monitor digoxin in concentrations. Monitor Warn about sedation, Monitor INR after
aches. Monitor BP, swollen diltiazem. Monitor BP, Monitor BP, swollen Monitor BP, swollen precautions. 7–10 days. for ↑ ADRs, including driving. 3–5 days.
potent inhibitor.
ankles and cardiac swollen ankles, and ankles and cardiac ankles and cardiac serotonin toxicity.
function. cardiac function. function. function.
SSRIs Fluoxetine Unlikely interaction. Small potential for an Isolated cases of Isolated cases of Isolated cases of Isolated cases of Unlikely interaction. 400%+ increase. Isolated reports of Isolated reports. May increase seizure No apparent Unpredictable increase
interaction. Monitor for interaction. interaction. interaction. interaction. Dose dependent. interactions. Monitor for any risk and reduce interactions. in INR. Monitor INR.
Fluoxetine and muscle aches. Be alert for swollen Be alert for swollen Be alert for swollen Be alert for swollen Warn about serotonin Avoid and use gastrointestinal analgesia. Potential additive
paroxetine are the ankles. ankles. ankles. ankles. toxicity, increased seizure an alternative disturbances. Warn about serotonin antiplatelet effect.
most potent inhibitors. risk. antidepressant. toxicity.
Citalopram is less Care if also on a TCA.
likely to interaction, Paroxetine Unlikely interaction. Unlikely interaction. Unlikely interaction. Unlikely interaction. Unlikely interaction. Unlikely interaction. Unlikely interaction. 400%+ increase. Dose May increase seizure No apparent Isolated reports of
although there have dependent. risk and reduce interaction. increased INR. Monitor.
been cases. Warn about serotonin analgesia. Potential additive
toxicity, increased seizure Warn about serotonin antiplatelet effect.
risk. toxicity.
Care if also on a TCA.
Antiepileptics Carbamazepine Probable reduction Potential reduction 40–400% increase in Felodipine 40%+ increase in Pregnancy risk. Concentration of the Concentration of Unlikely interaction. Interaction unlikely but No apparent clinical INR is reduced. Dose
in simvastatin in amlodipine carbamazepine and concentrations carbamazepine and Spotting occurs in tricyclic antidepressant cyclosporin reduced. tramadol can lower effect. increase of warfarin
Carbamazepine and concentration. concentration. phenytoin possible. reduced. phenytoin possible. > 60%. Estimate can be reduced but May need a 2- to 5-fold seizure threshold. often required.
Phenytoin Monitor lipid profile. Monitor blood Monitor serum Check blood Monitor serum failure rate 3.1 / 100 not usually clinically increase in dosage. Monitor INR in 5–7
phenytoin are potent
enzyme inducers. pressure. concentrations in pressure control. concentrations in 7 women years. significant. Monitor serum days.
Valproate, gabapentin 7 days. days. Avoid or increase (NB TCAs increase cyclosporin or use
and lamotrigine are Effect of diltiazem can Effect of verapamil can contraceptive dosage. seizure risk) alternative antiepileptic.
be reduced. Check be reduced. Check
less likely to cause an
blood pressure. blood pressure.
interaction.
Amiodarone Potential interaction. Cases of No reported Possible additive No reported Possible additive Unlikely interaction. Unlikely interaction. Significant increase. Double digoxin Potential interaction. Increase in INR seen in
Monitor for muscle rhabdomyolysis interactions, but effect on myocardial interaction, but effect on myocardial Monitor cyclosporin. concentration. May prolong sedation. most patients.
aches. reported. Statin-dose be alert for swollen contractility. be alert for swollen contractility. Be aware of long half- Monitor digoxin in Avoid combination Monitor INR weekly for
dependent. ankles. ankles. life of amiodarone. 2 weeks. (temazepam likely to 4 weeks (onset seen in
Monitor for muscle be less problematic). ~2 weeks).
aches, and ALT in 6
weeks.
Grapefruit juice 150–250% increase. 1500% increase. Can increase Can increase Up to 1200% 150% increase. Unlikely to be Unlikely interaction. Up to 150% increase. Unlikely interaction. 150% increase. Unlikely interaction.
Avoid combination. Avoid combination. concentrations. concentrations. increase. Avoid combination. important but spotting Avoid combination. Avoid combination.
Avoid combination. Avoid combination. Avoid combination. has been reported.
Rifampicin Probable reduction Potential interaction. Diltiazem Limited information, Verapamil Spotting occurs Isolated reported Cyclosporin Serum digoxin Triazolam INR can be reduced
in simvastatin Monitor blood concentrations but possible concentrations and 50–70% of decreased TCA concentrations likely to concentration can be concentration may and a dose increase of
concentration. pressure. markedly reduced. interaction. markedly reduced. have menstrual concentrations. be reduced. reduced by 50%. be decreased but not warfarin required.
Monitor lipid profile. Monitor blood Monitor blood Monitor blood disturbances. Use Monitor cyclosporin. Monitor digoxin temazepam. Monitor INR in 5–7
pressure and pulse pressure. pressure and pulse extra precautions concentration in days.
rate. rate. for 4–8 weeks after 7–10 days.
stopping rifampicin.
St Johns Wort Probable reduction Potential interaction. Potential interaction. Potential interaction. Potential interaction. Interactions reported. Serotonin toxicity risk. Reduced cyclosporin Digoxin may be Potential risk of Limited cases of
in concentration – Monitor blood Monitor blood Monitor blood Monitor blood Avoid combination. Avoid combination. concentrations. reduced by up to a serotonin toxicity and reduced INR.
monitor lipid profile. pressure. pressure. pressure. pressure. Avoid combination. third. increased seizure risk. Avoid combination.
Avoid combination.
The coloured text in the table relates Potential interactions not in the table: ‘Dangerous Trio’ – Diuretics, ACE inhibitor (or Angiotensin II antagonist) plus NSAID (or COX-2 inhibitor). Increased risk of renal failure. Avoid or monitor renal function in 7–10 days, then in 1 month.
to the importance of the interaction: Warfarin and tramadol Increased INR is reported. Avoid combination. Monitor INR in 3–5 days. Regular tramadol is preferable to prn.
RED=Major
Lithium and ACE inhibitors or diuretics or NSAIDs Increased lithium concentrations possible. Monitor lithium weekly for 2 weeks (NSAID), 6 weeks (ACE Inhibitor), 4 weeks (NSAID).
BLUE=Moderate
GREEN=Minor, if at all Allopurinol and azathioprine Increased azathioprine concentrations. Avoid combination.
BLACK=To be aware of Antibiotics and oral contraceptives This interaction is very unlikely but due to the consequences using extra precautions is suggested (equates to 7-day rule). Probably more risk with broad spectrum.