Drug Interactions between fluvoxamine and RCK

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.

MONITOR: Coadministration with potent inhibitors of CYP450 1A2 may increase the plasma concentrations of ropivacaine, which has been shown to be primarily metabolized by the isoenzyme. In twelve healthy volunteers, pretreatment with the potent CYP450 1A2 inhibitor fluvoxamine (25 mg twice daily for 2 days) increased the mean total plasma clearance of ropivacaine (40 mg IV over 20 minutes) by 68% compared to administration of ropivacaine alone. In eight healthy volunteers, fluvoxamine (100 mg daily for 5 days) increased the area under the plasma concentration-time curve (AUC) of a single dose of ropivacaine (0.6 mg/kg IV over 30 minutes) by 3.7-fold compared to placebo. The ropivacaine AUC was further increased by 50% when fluvoxamine was given in combination with erythromycin (500 mg three times a day), presumably due to the additional inhibition of ropivacaine metabolism via CYP450 3A4. Fluvoxamine alone prolonged the elimination half-life of ropivacaine from 2.3 to 7.4 hours, while the addition of erythromycin further increased the half-life to 11.9 hours.

MANAGEMENT: Clinicians should recognize the potential for increased toxicity of ropivacaine during coadministration with potent CYP450 1A2 inhibitors. The risk may be further increased by concomitant use of CYP450 3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, ketolide and certain macrolide antibiotics). Cardiovascular and respiratory vital signs and the patient's state of consciousness should be closely monitored. Restlessness, anxiety, incoherent speech, light-headedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, and drowsiness may be early warning signs of central nervous system toxicity.