Drug Interactions between deferasirox and Symbyax

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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MONITOR: Serotonin reuptake inhibitors (SRIs) may potentiate the risk of bleeding in patients treated with ulcerogenic agents and agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. The tricyclic antidepressant, clomipramine, is also a strong SRI and may interact similarly. Serotonin release by platelets plays an important role in hemostasis, thus SRIs may alter platelet function and induce bleeding. Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Bleeding events related to SRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Additional epidemiological studies have confirmed the association between use of these agents and the occurrence of upper gastrointestinal bleeding, and concurrent use of NSAIDs or aspirin was found to potentiate the risk. Preliminary data also suggest that there may be a pharmacodynamic interaction between SSRIs and oral anticoagulants that can cause an increased bleeding diathesis. Concomitant administration of paroxetine and warfarin, specifically, has been associated with an increased frequency of bleeding without apparent changes in the disposition of either drug or changes in the prothrombin time. Bleeding has also been reported with fluoxetine and warfarin, while citalopram and sertraline have been reported to prolong the prothrombin time of patients taking warfarin by about 5% to 8%. In the RE-LY study (Randomized Evaluation of Long-term anticoagulant therapy), SRIs were associated with an increased risk of bleeding in all treatment groups.

MANAGEMENT: Caution is advised if SRIs or clomipramine are used in combination with other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic complications is recommended. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

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MONITOR: Coadministration with inhibitors of CYP450 1A2 may increase the plasma concentrations of olanzapine. Data from available studies indicate that olanzapine is primarily metabolized by CYP450 1A2 and, to a lesser extent, by CYP450 2D6. When coadministered with fluvoxamine, a potent CYP450 1A2 inhibitor that also inhibits CYP450 2D6, olanzapine peak plasma concentration (Cmax) increased by an average of 54% in female nonsmokers and 77% in male smokers, while systemic exposure (AUC) increased by an average of 52% and 108%, respectively. The greater degree of interaction in smokers is likely due to induction of CYP450 1A2 by polycyclic aromatic hydrocarbons in cigarette smoke, resulting in increased expression of the isoenzyme. Similar results have been reported in several other pharmacokinetic studies. In 12 healthy male volunteers, administration of a single 10 mg dose of olanzapine during treatment with fluvoxamine 100 mg/day increased mean olanzapine Cmax, AUC and elimination half-life (T1/2) by 49%, 76% and 40%, respectively, compared to administration of olanzapine alone. In 10 male smokers with schizophrenia, olanzapine Cmax, AUC, and T1/2 increased by 12% to 64%, 30% to 55%, and 25% to 32%, respectively, when a single 10 mg dose of olanzapine was administered on day 10 of treatment with fluvoxamine 50 mg/day and 100 mg/day, each for 2 weeks. In 8 patients with schizophrenia who had been treated with olanzapine 10 to 20 mg/day for at least 3 months, the addition of fluvoxamine 100 mg/day for 8 weeks increased olanzapine plasma concentrations by 12% to 112%, with a mean of 81%, from baseline. In an analysis of data from a therapeutic drug monitoring service, patients treated concomitantly with fluvoxamine had olanzapine plasma concentration to daily dose (C/D) ratios that were on average 2.3-fold higher than those of patients receiving olanzapine alone. The difference was as high as 4.2-fold in some patients. In contrast, coadministration with sertraline was not associated with increased C/D ratios compared to olanzapine alone, and a pharmacokinetic study involving 15 healthy volunteers also demonstrated no significant interaction with fluoxetine. Another similar study conducted in a group of 250 patients receiving olanzapine daily doses ranging from 2.5 to 30 mg found that coadministration with fluvoxamine increased median C/D ratios by 74%. In an investigation to test the hypothesis that coadministration of a low subclinical dose of fluvoxamine (25 mg/day) can help reduce olanzapine therapeutic dose requirements, a 26% reduction in the mean olanzapine dosage taken by 10 male smokers with stable psychotic illness resulted in no significant changes in olanzapine plasma concentration, antipsychotic response, or metabolic indices (e.g., serum glucose, lipids) during treatment with fluvoxamine for up to 6 weeks. Clinical toxicity has been cited in a case report of a patient treated with fluvoxamine 150 mg/day and olanzapine 15 mg/day for several months. The patient had mydriasis, hand tremors, and muscle rigidity in association with toxic olanzapine plasma levels. Subsequent reduction of the olanzapine dosage to 5 mg/day resolved the toxicity but did not produce adequate therapeutic response, and the patient was switched to paroxetine with no further problems. The interaction has also been reported with ciprofloxacin, another CYP450 1A2 inhibitor. Doubling of olanzapine concentrations, akathisia, and QT prolongation have been described in various case reports.

MANAGEMENT: Pharmacologic response and olanzapine plasma levels should be monitored more closely whenever CYP450 1A2 inhibitors are added to or withdrawn from therapy in patients stabilized on their antipsychotic regimen, and the dosage adjusted as necessary.

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