Drug Interactions between Larapam SR and Symbyax

GENERALLY AVOID: Due to its serotonergic activity, coadministration of tramadol with selective serotonin reuptake inhibitors (SSRIs) may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea. Patients receiving tramadol with SSRIs may also have an increased risk of seizures due to additive epileptogenic effects of these agents. Pharmacokinetically, coadministration with certain SSRIs, namely fluoxetine, paroxetine and possibly sertraline, may decrease the plasma concentrations of the active O-demethylated (M1) metabolite of tramadol due to inhibition of CYP450 2D6, the isoenzyme responsible for the formation of the metabolite. The clinical significance of this potential interaction is unknown. However, M1 is thought to possess up to 6 times the analgesic effect of tramadol, thus diminished therapeutic response to tramadol should be considered.

MANAGEMENT: In general, the use of tramadol in combination with SSRIs should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when initiating or increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life (e.g., fluoxetine, vortioxetine).

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GENERALLY AVOID: Concomitant use of opioids with central nervous system (CNS) depressants (e.g., benzodiazepines, sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may result in profound sedation, respiratory depression, coma, and death. The risk of hypotension may also be increased with some CNS depressants (e.g., alcohol, benzodiazepines, antipsychotics).

MANAGEMENT: The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect, with cautious titration and dosage adjustments when needed. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. Cough medications containing opioids (e.g., codeine, hydrocodone) should not be prescribed to patients using benzodiazepines or other CNS depressants including alcohol. For patients who have been receiving extended therapy with both an opioid and a benzodiazepine or antipsychotic and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms.

MONITOR CLOSELY: Concomitant use of some antipsychotics with other agents that can reduce gastrointestinal motility, such as opioids, may increase the risk of ileus and constipation. Certain antipsychotic agents, including phenothiazines, thioxanthenes, clozapine, olanzapine and quetiapine, can cause gastrointestinal adverse effects in association with their anticholinergic activity. Potential complications may include paralytic ileus, intestinal obstruction, fecal impaction, megacolon, and intestinal ischemia or infarction, particularly with agents that have potent anticholinergic effects such as clozapine and quetiapine.

MANAGEMENT: Close monitoring of bowel function is recommended during concomitant use of opioids with antipsychotic agents that exhibit anticholinergic effects, particularly in the elderly. Delayed diagnosis and treatment of constipation may increase the risk of severe complications, which can result in hospitalization, surgery, and death. Patients should be advised to maintain adequate hydration, physical activity and fiber intake, and to report any changes in the frequency or character of bowel movements as well as signs and symptoms of potential complications of ileus such as nausea, vomiting, abdominal distension, and abdominal pain. If constipation or gastrointestinal hypomotility is identified, monitor closely and treat promptly with appropriate laxatives to prevent severe complications. Consider prophylactic laxatives in high risk patients, such as those with a history of constipation, colonic disease, or lower abdominal surgery.

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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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