Drug Interactions between Ascomp with Codeine and tirzepatide

GENERALLY AVOID: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine 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, phenothiazines).

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 and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms. Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

MONITOR: Tirzepatide can delay gastric emptying, which may impact the absorption of concomitantly administered oral medications and cause a decrease in the peak plasma concentration (Cmax) and a delay in the time to reach peak plasma concentration (Tmax). The impact of tirzepatide on gastric emptying has been reported to be dose- and time-dependent, with the greatest effect observed after a single 5 mg dose but diminished after subsequent doses. When acetaminophen was administered following a single 5 mg dose of tirzepatide, acetaminophen Cmax was decreased by 50% and its median Tmax delayed by 1 hour. However, no significant impact on acetaminophen Cmax and Tmax was observed after 4 consecutive weekly doses of tirzepatide (5 mg/5 mg/8 mg/10 mg), and the overall exposure (AUC) of acetaminophen was unaffected. Tirzepatide at lower doses of 0.5 mg and 1.5 mg also had minimal effects on acetaminophen exposure.

MANAGEMENT: Although no specific dosage adjustment of concomitant medications is generally recommended based on available data, potential clinical impact on some oral medications cannot be ruled out, particularly those with a narrow therapeutic index or low bioavailability, those that depend on threshold concentrations for efficacy (e.g., antibiotics), and those that require rapid gastrointestinal absorption (e.g., hypnotics, analgesics). Oral medications with a narrow therapeutic index may require additional monitoring when used in combination with tirzepatide, especially at initiation of tirzepatide and following any dose adjustments. The risk of delayed effects due to delayed gastric emptying should also be considered for any oral medications that require a rapid onset of action.

MONITOR: Additive increases in heart rate may occur when tirzepatide is coadministered with other drugs that can also increase heart rate. The mechanism by which tirzepatide may affect heart rate is unknown. In placebo-controlled trials, treatment with tirzepatide resulted in an average increase in heart rate of 2 to 4 beats per minute (bpm) compared to an average increase of 1 bpm in patients receiving placebo. The incidence of patients who had a change in heart rate of greater than 20 bpm from baseline for 2 or more consecutive visits was 2.1%, 3.8% and 2.9% for tirzepatide 5 mg, 10 mg and 15 mg, respectively, compared with 2.1% for placebo. Episodes of sinus tachycardia, associated with a concomitant increase in heart rate of greater than or equal to 15 bpm from baseline, were reported in 4.3%, 4.6%, 5.9% and 10% of subjects treated with placebo or tirzepatide 5 mg, 10 mg and 15 mg, respectively. For patients enrolled in Japan, the reported frequencies of these episodes were 7% (3/43), 7.1% (3/42), 9.3% (4/43) and 23% (10/43), respectively.

MANAGEMENT: Although the clinical relevance of the effects on heart rate is not currently known, some authorities suggest observing caution when tirzepatide is coadministered with other drugs that can increase heart rate such as those with sympathomimetic or anticholinergic activity. Advise patients of the potential risk of tachycardia and to contact their healthcare provider if it occurs in the absence of a known cause (i.e., at rest).

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.