Drug Interactions between Effervescent Pain Relief and Nuedexta

GENERALLY AVOID: Coadministration with potent CYP450 2D6 inhibitors (e.g., quinidine, terbinafine) may significantly increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Studies in humans have shown an increase in systemic exposure of dextromethorphan of up to 43-fold when given concurrently with quinidine. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. However, this interaction has also been used clinically, with dextromethorphan in combination with quinidine indicated by some authorities for the treatment of pseudobulbar affect. Data evaluating the impact of this interaction in patients who are poor metabolizers of CYP450 2D6 are limited; most studies include extensive metabolizers of this isoenzyme. It is expected that poor metabolizers would have elevated dextromethorphan levels without concurrent quinidine

MANAGEMENT: The combination of dextromethorphan with potent CYP450 2D6 inhibitors should be generally avoided. Some manufacturers consider the concomitant use of dextromethorphan and selective serotonin reuptake inhibitors contraindicated. If use is considered necessary, the patient should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.

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MONITOR: One study has suggested that the antiplatelet effects of quinidine and aspirin may be additive. The risk of bleeding could be increased.

MANAGEMENT: Patients' bleeding times should be monitored and they 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. Patients should also be counseled to avoid any other over-the-counter salicylate products.

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MONITOR: Coadministration with drugs that can increase urinary pH such as antacids, carbonic anhydrase inhibitors, or urinary alkalinizers may decrease the urinary excretion of quinidine. The proposed mechanism is increased renal tubular reabsorption due to reduced ionization of quinidine in alkaline urine. In four healthy subjects given quinidine 200 mg every 6 hours, renal clearance of quinidine was reduced by an average of 50% during coadministration with sodium bicarbonate and acetazolamide 500 mg twice a day. Average urinary quinidine level was 115 mg/L at urinary pH below 6, but fell to 13 mg/L at urinary pH above 7.5. Likewise, average quinidine urinary excretion rate fell from 103 to 31 mcg/minute with increasing pH. In another six healthy subjects studied under the same conditions, increased serum quinidine levels were observed in five subjects during urine alkalinization, and prolongations of the QT interval were reported in three of the five. Since only about 20% of a quinidine dose is typically eliminated unchanged by the kidney, the clinical significance of this interaction is unknown. A case report describes a woman who developed toxicity in association with a threefold increase in serum quinidine levels after taking eight Mylanta antacid tablets (each containing 200 mg aluminum hydroxide gel, 200 mg magnesium hydroxide, and 20 mg simethicone) everyday for a week. However, the patient also drank over a liter of orange and grapefruit juice daily, the latter of which can inhibit quinidine metabolism and may have contributed to the toxic drug levels. In pharmacokinetic studies, single doses of aluminum hydroxide alone had no significant effect on quinidine pharmacokinetics or urinary pH, although the possibility of a significant interaction in occasional patients cannot be ruled out.

MANAGEMENT: Caution is advised if quinidine is used with agents that can increase urinary pH. Quinidine levels may need to be monitored more closely following addition or discontinuation of these agents, and the quinidine dosage adjusted as necessary. Patients should be advised to seek medical attention if they experience symptoms that could indicate quinidine toxicity such as tinnitus, hearing loss, visual disturbances, diarrhea, headache, dizziness, palpitations, syncope, or irregular heartbeats.

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MONITOR: Agents that cause urinary alkalinization can reduce serum salicylate concentrations in patients receiving anti-inflammatory dosages of aspirin or other salicylates. The mechanism involves reduction in salicylate renal tubular reabsorption due to increased urinary pH, resulting in increased renal salicylate clearance especially above urine pH of 7. This interaction is sometimes exploited in the treatment of salicylate toxicity.

MANAGEMENT: Patients treated chronically with urinary alkalinizers and large doses of salicylates (i.e. 3 g/day or more) should be monitored for potentially diminished or inadequate analgesic and anti-inflammatory effects, and the salicylate dosage adjusted if necessary.

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