Drug Interactions between codeine / phenylephrine / promethazine and metoclopramide

CONTRAINDICATED: Coadministration of metoclopramide with phenothiazines, neuroleptics, or other antidopaminergic agents (e.g., tetrabenazine) may increase the frequency and severity of extrapyramidal reactions (i.e., acute dystonic reactions, tardive dyskinesia, akathisia, Parkinson-like symptoms) due to additive antidopaminergic effects. By itself, metoclopramide can cause acute dystonic reactions in approximately 0.2% of patients treated with the usual adult dosages of 30 to 40 mg/day. These reactions are typically seen during the first 24 to 48 hours of treatment, occur more frequently in pediatric and adult patients less than 30 years of age, and are increased with higher dosages. Symptoms may include involuntary movements of limbs, facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, opisthotonus (tetanus-like reactions), and rarely, stridor and dyspnea due to laryngospasm. Dystonic reactions usually respond to treatment with anticholinergic agents such as diphenhydramine or benztropine. Tardive dyskinesia (TD) is a potentially irreversible and disfiguring disorder characterized most frequently by involuntary movements of the tongue, face, mouth, or jaw, and less frequently by involuntary movements of the trunk and/or extremities. Movements may be choreoathetotic in appearance. Although the risk of TD with metoclopramide has not been extensively studied, a prevalence of 20% has been reported in one study among patients treated for at least 12 weeks. The risk is increased in the elderly, women, and diabetic populations; however, it is not possible to predict which patients will develop TD. Both the risk of developing TD and the likelihood that TD will become irreversible increase with duration of treatment and total cumulative dose. There is no known effective treatment. In some patients, TD may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn. Akathisia, or motor restlessness, consist of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, and foot tapping. Symptoms may disappear spontaneously or respond to a reduction in dosage. Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, and mask-like facies. These symptoms most commonly occur within the first 6 months of metoclopramide therapy and subside within 2 to 3 months following drug discontinuation.

MANAGEMENT: Due to the potential for increased risk of serious and potentially irreversible extrapyramidal reactions, metoclopramide should not be prescribed in combination with other antidopaminergic agents. In addition, metoclopramide should not be used for longer than 12 weeks except in rare cases where therapeutic benefit is anticipated to outweigh the risk of developing tardive dyskinesia.

MONITOR: By diminishing gastrointestinal motility, narcotic analgesics may antagonize the pharmacologic effects of gastrointestinal prokinetic agents. In addition, concomitant use may increase central nervous system effects such as sedation, dizziness, confusion, and mental depression.

MONITOR: Gastrointestinal prokinetic agents may alter the absorption characteristics of some controlled release narcotic analgesic preparations. In a study of 20 patients undergoing surgery, peak plasma concentration (Cmax) of morphine was reached more quickly in patients who received a 20 mg dose of sustained-release morphine with 20 mg metoclopramide compared to patients who received morphine alone, although the actual Cmax and systemic exposure (AUC) were not significantly altered. Both the degree and the rate of onset of sedation were also increased in the metoclopramide group, which may have been partially due to additive pharmacodynamic effects of the drugs. During chronic administration, however, the clinical relevance of this interaction may be diminished due to tolerance.

MANAGEMENT: The potential for reduced efficacy of gastrokinetic agents should be considered during coadministration with opioid analgesics. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring 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.