Drug Interactions

DRUG INTERACTIONS
Case 1:
Mrs C is a 62-year-old woman with a history of hypertension, atrial fibrillation and type 2
diabetes. She is a non-smoker and obese. Her current medication comprises flecainide 100 mg
twice a day, aspirin 75 mg daily, simvastatin 40 mg and diltiazem 180 mg daily. Mrs C is
suffering from a respiratory tract infection and her primary care doctor has prescribed a 5-day
course of clarithromycin.
Questions
1. Are there likely to be any clinically significant drug interactions?
Answer: There is potential for interaction between simvastatin and diltiazem and between
simvastatin and clarithromycin. Some statins, particularly simvastatin and atorvastatin, are
metabolized by cytochrome P450 (CYP3A4) and co-administration of potent inhibitors of this
enzyme may particularly increase plasma levels of these statins and so increase the risk of dose-
related side effects, including rhabdomyolysis. Clarithromycin is a potent inhibitor of CYP3A4
and diltiazem is a less potent inhibitor.
2. What advice do you give?
Answer: Current advice is that diltiazem and simvastatin may be given together provided the
simvastatin dose does not exceed 40 mg daily, so it is reasonable for this therapy to be continued.
However, clarithromycin should not be given together with simvastatin. Myopathy and
rhabdomyolysis have been reported in patients taking the combination. Mrs C should be advised
not to take her simvastatin while she is taking clarithromycin and to start taking it again after she
has completed the course of antibiotic.
Case 2:
A 19-year-old woman is on long-term treatment with minocycline 100 mg daily for acne.
She wishes to start using the combined oral contraceptive and her doctor has prescribed a low-
strength pill (containing ethinyloestradiol 20 µcg with norethisterone 1 mg). The doctor contacts
the pharmacist for advice on whether the tetracycline will interfere with the efficacy of the oral
contraceptive
Question
Is there a clinically significant interaction in this situation?
Answer: Contraceptive failure has been attributed to doxycycline, lymecycline, oxytetracycline,
minocycline and tetracycline in about 40 reported cases, seven of which specified long-term
antibacterial use. There is controversy about whether or not a drug interaction occurs but if there
is one it appears to be very rare. Controlled trials have not shown any effect of tetracycline or
doxycycline on contraceptive steroid levels. The postulated mechanism is suppression of
intestinal bacteria resulting in a fall in enterohepatic recirculation of ethinyloestradiol. Overall,
there is no evidence that this is clinically important.
In the case of long-term use of tetracyclines for acne, a small number of cases of
contraceptive failure have been reported. Nevertheless, the only well-designed, case–control
study in dermatological practice indicated that the incidence of contraceptive failure due to this
interaction could not be distinguished from the general and recognized failure rate of oral
contraceptives. The UK Family Planning Association advises that women on long-term antibiotic
therapy need only take extra precautions for the first 3 weeks of oral contraceptive use because,
after about 2 weeks, the gut flora becomes resistant to the antibiotic. In addition, there is some
evidence that ethinyloestradiol may accentuate the facial pigmentation that can be caused by
minocycline.
Case 3:
A 48-year-old man with a history of epilepsy is admitted to hospital with tremor, ataxia,
headache, abnormal thinking and increased partial seizure activity. His prescribed medicines are
phenytoin 300 mg daily, clonazepam 6 mg daily and fluoxetine 20 mg daily. It transpires that
fluoxetine therapy had been initiated 2 weeks previously. The patient's phenytoin level is found
to be 35 mg/L; at the last outpatient clinic visit 4 months ago, it was 18 mg/L.
Question
What is the proposed mechanism of interaction between fluoxetine and phenytoin and how
should it be managed?
Answer: Fluoxetine is believed to inhibit the metabolism of phenytoin by the cytochrome P450
isoenzyme CYP2C9, potentially leading to increased plasma phenytoin levels. There are a
number of published case reports and anecdotal observations of phenytoin toxicity occurring
with the combination, but the available evidence s conflicting. A review by the U.S. Food and
Drug Administration suggested that a marked increase in plasma phenytoin levels, with
accompanying toxicity, can occur within 1–42 days (mean onset time of 2 weeks) after starting
fluoxetine. If fluoxetine is added to treatment with phenytoin, the patient should be closely
monitored. Ideally the phenytoin plasma levels should be monitored and there may be a need to
reduce the phenytoin dosage.

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