Drug Interaction Report

ADJUST DOSE: Bupropion is a centrally-acting norepinephrine/dopamine reuptake inhibitor and may potentiate the central nervous system effects of dopamine agonists. Limited clinical data suggest a higher incidence of adverse effects in patients receiving bupropion concurrently with either levodopa or amantadine, including nausea, vomiting, dizziness, vertigo, restlessness, agitation, confusion, delirium, tremor, ataxia, and gait disturbance. In a published case report, neurotoxic effects developed in 3 elderly patients following addition of amantadine to bupropion therapy and resolved within 72 hours after discontinuation of both drugs. The authors theorize that additive central dopaminergic effects of the drugs may have caused the apparent interaction.

MANAGEMENT: Caution is advised when bupropion is used concomitantly with dopaminergic drugs. Some manufacturers recommend a lower initial dosage of bupropion when possible and gradual dosage increments.

MONITOR: When catechol-O-methyltransferase (COMT) inhibitors are administered together with levodopa/carbidopa, they may increase the relative bioavailability (AUC) of levodopa. This is due to a decrease in levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa (from approximately 2 hours to 3.5 hours). Adverse effects such as dyskinesia, somnolence, and orthostatic hypotension may be potentiated. In the presence of the decarboxylase inhibitor carbidopa, COMT is the major metabolizing enzyme for levodopa. In clinical trials of COMT inhibitors administered concomitantly with levodopa, patients required a dosage reduction in levodopa if their daily dose of levodopa was greater than 600 mg with tolcapone or 800 mg with entacapone, or if they had moderate or severe dyskinesia before beginning COMT inhibitor treatment. In patients receiving once daily opicapone at bedtime with levodopa/carbidopa administered every three or four hours, levodopa peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 43% to 44% and 62% to 94%, respectively, compared to administration of levodopa/carbidopa alone.

MANAGEMENT: Although COMT inhibitors are intended for use with levodopa/carbidopa, clinicians should be aware that dose reduction of levodopa may be necessary during coadministration. This is especially true if the patient is experiencing dyskinesia induced by levodopa. Use with caution in patients with severe dyskinesia or dystonia. Likewise, when discontinuing a COMT inhibitor, monitor patients and consider adjustment of other dopaminergic therapies as needed. In addition, some authorities advise that opicapone should be administered as a once-daily dose at least one hour before or after combinations containing levodopa so as to avoid any interaction with the absorption of levodopa (AU, UK).

GENERALLY AVOID: Excessive use or abrupt discontinuation of alcohol after chronic ingestion may precipitate seizures in patients receiving bupropion. Additionally, there have been rare postmarketing reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who drank alcohol during treatment with bupropion. According to one forensic report, a patient died after taking large doses of both bupropion and alcohol. It is uncertain whether a drug interaction was involved. Single-dose studies in healthy volunteers given bupropion and alcohol failed to demonstrate either a significant pharmacokinetic or pharmacodynamic interaction.

MANAGEMENT: The manufacturer recommends that alcohol consumption be minimized or avoided during bupropion treatment. The use of bupropion is contraindicated in patients undergoing abrupt discontinuation of alcohol.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of levodopa. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MONITOR: Limited clinical data suggest that high protein content in the diet may reduce or cause fluctuations in the clinical response to oral and enteral formulations of levodopa in patients with Parkinson's disease. Proposed mechanisms include delayed gastric emptying, decreased levodopa absorption when taken with a protein rich diet, and competition with certain amino acids for transport across the gut wall and/or the blood brain barrier. Data have been conflicting. Clinical studies have variously reported no effect, reduced levodopa absorption with low-protein meals, reduced effects of oral and enteral formulations of levodopa with high daily protein intake, and no differences compared to fasting with high-protein meals. Neuroleptic malignant-like symptoms were reported in a patient with Parkinson's disease who was receiving pramipexole, entacapone, and immediate-release levodopa/carbidopa, after the protein content of his enteral feedings via nasogastric tube was increased from 0.88 g/kg/day to 1.8 g/kg/day; symptoms improved after the protein was reduced to 1 g/kg/day and bromocriptine was administered. Another patient receiving immediate-release carbidopa/levodopa, pramipexole, and entacapone experienced severe rigidity after initiation of continuous enteral nutrition via oral gastric tube containing 1.4 g/kg/day of protein; his Parkinsonian symptoms improved after the protein content was reduced to 0.9 g/kg/day, the feeding was changed to bolus feedings, and the levodopa was administered between boluses.

MANAGEMENT: In general, alcohol consumption should be avoided or limited during treatment with CNS-depressant agents. Until more data are available, it is advisable to avoid large fluctuations in daily protein intake and to monitor patients for altered effects of oral and enteral levodopa formulations if the protein content of the diet is increased.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

ADJUST DOSING INTERVAL: The oral bioavailability and pharmacologic effects of levodopa and carbidopa may be decreased during concurrent administration with iron-containing products. The proposed mechanism is chelation of levodopa and carbidopa by the iron cation, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract. In nine patients with Parkinson's disease, administration of levodopa-carbidopa 100 mg-25 mg with ferrous sulfate 325 mg decreased levodopa peak plasma concentration (Cmax) and systemic exposure (AUC) by 47% and 30%, respectively, and carbidopa Cmax and AUC by 77% and 82%, respectively, compared to administration with placebo. There was also evidence of reduced efficacy of levodopa in some patients. In another study consisting of eight healthy subjects, coadministration of levodopa 250 mg with ferrous sulfate 325 mg resulted in greater than 50% reductions in the Cmax and AUC of levodopa compared to administration of levodopa alone. The magnitude of the interaction was the greatest in patients whose plasma levels of levodopa were the highest following administration of levodopa alone.

MANAGEMENT: Until more information is available, patients receiving levodopa and/or carbidopa in combination with iron-containing products should be advised to separate the times of administration by as much as possible. Patients should be monitored for reduced efficacy of levodopa, and the dosage adjusted as necessary.

MONITOR: Additive or synergistic effects on blood pressure may occur when bupropion is combined with sympathomimetic agents such as nasal decongestants, adrenergic bronchodilators, ophthalmic vasoconstrictors, and systemic vasopressors. Treatment with bupropion can result in elevated blood pressure and hypertension. In clinical practice, hypertension, in some cases severe and requiring acute treatment, has been observed in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have occurred in both patients with and without evidence of preexisting hypertension. Furthermore, postmarketing cases of hypertensive crisis have been reported during the initial titration phase with bupropion-naltrexone treatment.

MANAGEMENT: Caution is advised when bupropion is used with other drugs that increase dopaminergic or noradrenergic activity due to an increased risk of hypertension. Blood pressure and heart rate should be measured prior to initiating bupropion therapy and monitored at regular intervals consistent with usual clinical practice, particularly in patients with preexisting hypertension. Dose reduction or discontinuation of bupropion should be considered in patients who experience clinically significant and sustained increases in blood pressure or heart rate.

MONITOR: The concomitant use of bupropion and nicotine replacement for smoking cessation may increase the risk of hypertension. In a clinical study (n=250), 6.1% of patients who used sustained-release bupropion with nicotine transdermal system developed treatment-emergent hypertension, compared to 2.5% of patients treated with bupropion alone, 1.6% treated with nicotine alone, and 3.1% treated with placebo. Three patients in the bupropion plus nicotine group and one patient in the nicotine-only group discontinued treatment due to hypertension. The majority had evidence of preexisting hypertension.

MANAGEMENT: Blood pressure monitoring is recommended for patients concomitantly using bupropion and nicotine replacement for smoking cessation.