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Drug Interactions between Coartem and tolterodine

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

tolterodine lumefantrine

Applies to: tolterodine and Coartem (artemether / lumefantrine)

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of tolterodine, which is primarily metabolized by this isoenzyme in most patients (referred to as "extensive metabolizers") to an active metabolite that is equipotent to tolterodine. A subset of the population (about 7%) is devoid of CYP450 2D6 (referred to as "poor metabolizers" or PMs) and uses CYP450 3A4 to metabolize tolterodine to an inactive metabolite instead. In a study to assess this interaction, fluoxetine (a potent CYP450 2D6 inhibitor) was administered concurrently with immediate release tolterodine. It was observed that fluoxetine significantly inhibited the metabolism of tolterodine immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine systemic exposure (AUC). There was a 52% decrease in the peak plasma concentration (Cmax) and a 20% decrease in the AUC of tolterodine's active metabolite. During this interaction the sums of unbound serum concentrations of tolterodine and its active metabolite are about 25% higher, meaning little alteration in the overall pharmacological activity of tolterodine is expected. However, increased plasma concentrations may increase the risk of adverse effects associated with tolterodine, including QT prolongation and anticholinergic effects.

MANAGEMENT: During concomitant therapy with drugs that inhibit CYP450 2D6 activity, the possibility of prolonged and/or increased pharmacologic effects of tolterodine should be considered. Increased monitoring may be particularly important when the CYP450 2D6 inhibitor has a similar adverse effect profile to that of tolterodine or when its inhibitory effects are long lasting (e.g., rolapitant can increase the plasma concentrations and risk of adverse effects of CYP450 2D6 substrates for at least 28 days). Patients should be counseled to report any increases in side effects or changes in condition.

References (6)
  1. (2001) "Product Information. Detrol (tolterodine)." Pharmacia and Upjohn
  2. Brynne N, Svanstrom C, AbergWistedt A, Hallen B, Bertilsson L (1999) "Fluoxetine inhibits the metabolism of tolterodin-pharmacokinetic implications and proposed clinical relevance." Br J Clin Pharmacol, 48, p. 553-63
  3. (2015) "Product Information. Varubi (rolapitant)." Tesaro Inc.
  4. (2021) "Product Information. Tolterodine Tartrate ER (tolterodine)." Ajanta Pharma USA
  5. (2014) "Product Information. Tolterodine Tartrate (tolterodine)." Greenstone LLC
  6. (2023) "Product Information. Detrusitol XL (tolterodine)." Viatris UK Healthcare Ltd

Drug and food interactions

Moderate

lumefantrine food

Applies to: Coartem (artemether / lumefantrine)

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of artemether and lumefantrine. The mechanism is decreased clearance due to inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. High plasma levels of artemether and lumefantrine may increase the risk of QT interval prolongation and ventricular arrhythmias including torsade de pointes. In clinical trials, asymptomatic prolongation of the Fridericia-corrected QT interval (QTcF) by more than 30 msec from baseline was reported in approximately one-third of patients treated with artemether-lumefantrine, and prolongation by more than 60 msec was reported in more than 5% of patients. A few patients (0.4%) in the adult/adolescent population and no patient in the infant/children population experienced a QTcF greater than 500 msec. However, the possibility that these increases were disease-related cannot be ruled out. In a study of healthy adult volunteers, administration of the six-dose regimen of artemether-lumefantrine was associated with mean changes in QTcF from baseline of 7.45, 7.29, 6.12 and 6.84 msec at 68, 72, 96, and 108 hours after the first dose, respectively. There was a concentration-dependent increase in QTcF for lumefantrine. No subject had a greater than 30 msec increase from baseline nor an absolute increase to more than 500 msec.

ADJUST DOSING INTERVAL: Food enhances the oral absorption of artemether and lumefantrine. In healthy volunteers, the relative bioavailability of artemether increased by two- to threefold and that of lumefantrine by sixteenfold when administered after a high-fat meal as opposed to under fasted conditions.

MANAGEMENT: Patients receiving artemether-lumefantrine therapy should avoid the consumption of grapefruits and grapefruit juice. To ensure maximal oral absorption, artemether-lumefantrine should be taken with food. Inadequate food intake can increase the risk for recrudescence of malaria. Patients who are averse to food during treatment should be closely monitored and encouraged to resume normal eating as soon as food can be tolerated.

References (3)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2009) "Product Information. Coartem (artemether-lumefantrine)." Novartis Pharmaceuticals

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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