Tolterodine (Detrol®, Detrol® LA) Interactions
- Amantadine
- Amoxapine
Antacids
Anti-retroviral protease inhibitors
Antimuscarinics
- Bosentan
- Caffeine
- Cisapride
- Citalopram
- Clarithromycin
- Clozapine
- Cyclobenzaprine
- Delavirdine
- Diltiazem
- Disopyramide
Diuretics
- Efavirenz
- Erythromycin
- Ethanol
- Fluconazole
- Fluoxetine
- Fluvoxamine
- food
- grapefruit juice
- Green Tea
- Guarana
- Imatinib, STI-571
- Itraconazole
- Ketoconazole
- Maprotiline
- Memantine
- Metoclopramide
- Nefazodone
- Norfloxacin
- Olanzapine
- Omeprazole
Opiate agonists
- Orphenadrine
- Paroxetine
Phenothiazines
- Quinidine
- Quinine
Sedating H1-blockers
- Sertraline
- Tegaserod
- Topiramate
Tricyclic antidepressants
- Troleandomycin
- Venlafaxine
- Verapamil
- Voriconazole
- Warfarin
- Zafirlukast
Tolterodine (Detrol®, Detrol® LA) Interactions
NOTE: Tolterodine is metabolized primarily by CYP2D6 and alternatively, CYP3A4 in those patients who are poor metabolizers of tolterodine via CYP2D6. In vitro data show that tolterodine is a competitive inhibitor of CYP2D6 at high concentrations; the drug shows no significant inhibition of other CYP isoenzymes. However, tolterodine does not result in clinically relevant drug interactions from the in vivo inhibition of CYP2D6.
Depending on the specific agent, additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly with other antimuscarinics. Other commonly used drugs with moderate to significant anticholinergic effects include amantadine, amoxapine, bupropion, clozapine, cyclobenzaprine, disopyramide, maprotiline, olanzapine, orphenadrine, the sedating H1-blockers, most phenothiazines, and most tricyclic antidepressants. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Beverages containing caffeine or ethanol may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas) and alcoholic beverages.
Diuretics can increase urinary frequency, which may aggravate bladder symptoms. However, tolterodine does not adversely affect the diuretics. No adverse electrocardiographic effects occurred when tolterodine was co-administered with diuretic agents in clinical studies.
Tolterodine 2 mg twice daily had no effect on the pharmacokinetics oral contraceptives (e.g., ethinyl estradiol; levonorgestrel) as evidenced by the monitoring of ethinyl estradiol and levonorgestrel over a 2-month cycle in healthy female volunteers.
In healthy volunteers, coadministration of tolterodine 2 mg twice daily for 7 days and a single 25-mg dose of warfarin on day 4 had no effect on prothrombin time, Factor VII suppression, or on the pharmacokinetics of warfarin. The use of only a single dose of warfarin decreases the relevance of these results. Increased INR values have been reported in patients receiving concurrent warfarin and tolterodine. Two patients stabilized on warfarin experienced elevated INR values 10-14 days after beginning tolterodine treatment. The mechanism of the interaction is not known. Tolterodine is metabolized primarily by cytochrome P450 (CYP) 2D6 and alternatively, CYP3A4 in those patients who are poor metabolizers of tolterodine via CYP2D6. Since neither warfarin nor tolterodine are inducers or inhibitors of hepatic enzymes, competitive inhibition of warfarin metabolism may be a possible mechanism. Careful monitoring of the INR should be considered in patients receiving the combination of tolterodine and warfarin. Significant dosage reductions of warfarin may be required.
Clinicians should be aware that a food interaction is possible with tolterodine. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Grapefruit and grapefruit juice inhibit CYP3A4 metabolism in gut enterocytes. Patients should not significantly adjust their intake of grapefruit or grapefruit juice while taking tolterodine. As with drugs that significantly inhibit the CYP3A4 pathway, consideration should be given to limiting tolterodine dosage to 2 mg/day in some patients.
Ketoconazole requires an acidic pH for oral absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect include antimuscarinics. Antimuscarinics have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be considered if antimuscarinic medications are required. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed; CYP3A4 inhibitors include systemically-administered azole antifungals (e.g., fluconazole itraconazole, ketoconazole, voriconazole). Because it is difficult to assess which patients will be poor metabolizers of tolterodine via CYP2D6, those patients receiving CYP3A4 inhibitors should not receive > 2 mg/day of tolterodine.
In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed. CYP3A4 inhibitors include systemically-administered azole antifungals (e.g., fluconazole itraconazole, ketoconazole, voriconazole), anti-retroviral protease inhibitors, delavirdine, diltiazem, efavirenz, fluvoxamine, grapefruit, nefazodone, norfloxacin, omeprazole, some macrolide antibiotics (erythromycin, clarithromycin and troleandomycin), quinine, verapamil, and zafirlukast. In addition, ritonavir and delavirdine inhibit CYP2D6. This paragraph may not completely list all significant CYP3A4 inhibitors. Because it is difficult to assess which patients will be poor metabolizers of tolterodine via CYP2D6, those patients receiving CYP3A4 inhibitors should not receive > 2 mg/day of tolterodine.
No dosage adjustment is required for tolterodine when administered concomitantly with fluoxetine, although a pharmacokinetic interaction does occur. Fluoxetine is a potent inhibitor of CYP2D6 and significantly inhibits the metabolism of tolterodine in extensive metabolizers. In a pharmacokinetic interaction study, there was a 4.8 fold increase in tolterodine AUC following concomitant administration with fluoxetine. The sums of unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite of tolterodine are only 25% higher during the interaction, however. Other SSRI-type antidepressants that inhibit CYP2D6 metabolism include citalopram, paroxetine, sertraline, and the SSRI-like antidepressant venlafaxine (weak inhibitor of CYP2D6).
Quinidine can inhibit the hepatic CYP2D6 isoenzyme, which may decrease the metabolism of tolterodine. It is not known if dosage adjustments in tolterodine would be needed as the result of this interaction.
Imatinib, STI-571 is a potent inhibitor of cytochrome P450 (CYP) 2D6 and 3A4. Tolterodine is metabolized primarily by CYP2D6 and alternatively, CYP3A4 in those patients who are poor metabolizers of tolterodine via CYP2D6. It is not known if dosage adjustments are required in patients requiring concurrent therapy, but patients should be monitored for increased anticholinergic effects.
Through an additive effect, the use of topiramate (a weak carbonic anhydrase inhibitor) with agents that may increase the risk for heat-related disorders, such as antimuscarinics, may lead to oligohidrosis, hyperthermia and/or heat stroke.
Bosentan is a significant inducer of CYP2C9 and CYP3A4 hepatic isoenzymes. Theoretically, bosentan can increase the hepatic clearance of tolterodine (CYP2C9 and CYP3A4 substrate). However, this interaction has not been studied.
Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use.
Antacids may inhibit the oral absorption of the antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Tolterodine is an antagonist at muscarinic cholinergic receptors; the anticholinergic actions of the drug are most potent on the urinary bladder, with less activity on GI and salivary muscarinic cholinergic receptors. Tolterodine, as an antimuscarinic, may slow GI motility and thus may potentially antagonize the actions of drugs that enhance gastrointestinal motility, like cisapride, metoclopramide, or tegaserod. However, the clinical significance of this potential interaction is uncertain.
The adverse effects of antimuscarinics, such as dry mouth, urinary hesitancy or blurred vision may be enhanced with use of memantine; dosage adjustments of the anticholinergic drug may be required when memantine is coadministered.
[ Last revised: 3/30/2005 2:55:00 PM ]
References
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. Ben-Zeev B, Watemberg N, Augarten A, et al. Oligohydrosis and hyperthermia: a pilot study of a novel topiramate adverse effect. J Child Neurol 2003;18:254-7.
. Ketoconazole package insert. Schaumburg, IL: Novopharm USA Inc.; 1997 Oct.
. Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein and footnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2005 Edition. Edmonds, WA: H&H Publications; 2005:157-170.
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. Zyprexa® (olanzapine) package insert. Indianapolis IN: Eli Lilly and Company; 2004 March.
. Food and Drug Administration (FDA). NDA Safety Review: NDA 21-487, Memantine, Forest Laboratories, Inc.;August 20, 2003. Retrieved July 12, 2004. Available on the World Wide Web at http://www.fda.gov/ohrms/dockets/ac/03/briefing/3979B1_04_FDA-Safety%20Review.pdf.
. Hoffman BB, Lefkowitz RJ. Atropine, scopolamine, and related antimuscarinic drugs. Gilman AG, Rall TW, Nies AS, Taylor P, (eds.) In: Goodman and Gilman’s Pharmacological Basis of Therapeutics. 8th ed., New York, Pergamon Press. 1990. 150-61.
. Detrol® (tolterodine tartrate) tablets package insert. Kalamazoo, MI: Pharmacia & Upjohn Co.; 2002 Jul.
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