Drug Interactions between Embeda and Uni Serp

MONITOR CLOSELY: Coadministration with P-glycoprotein (P-gp) inhibitors may increase the plasma concentrations of morphine and its risk of adverse effects, including hypotension, respiratory and CNS depression, profound sedation, coma, and death. The proposed mechanism may involve inhibition of the intestinal P-gp efflux transporter, resulting in enhanced oral bioavailability of morphine, a P-gp substrate. The interaction may be more significant for orally administered morphine. According to some authorities, the concomitant use of a P-gp inhibitor with oral morphine may increase the systemic exposure of morphine by approximately 2-fold. However, in a pharmacokinetic study involving 12 healthy subjects, itraconazole (200 mg daily for 4 days), a strong P-gp inhibitor, increased the morphine (0.3 mg/kg as a single oral dose) peak plasma concentration (Cmax) and systemic exposure (AUC) by 28% and 22%, respectively. Plasma concentrations of intravenously administered morphine appear less affected. In a crossover study involving 14 healthy volunteers, intravenous administration of P-gp inhibitor cyclosporine followed by an intravenous infusion of morphine 0.1 mg/kg led to a minimal increase of morphine AUC to 100 ng/mL*h compared to 85 ng/mL*h when administered after control (no infusion). In the same study, cyclosporine appeared to prolong morphine-induced miosis.

MANAGEMENT: Caution is recommended whenever morphine, particularly orally administered morphine, is used concomitantly with a P-gp inhibitor. Close clinical and laboratory monitoring should be considered whenever a P-gp inhibitor is added to or withdrawn from therapy, and the morphine dosage adjusted as necessary. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation that may be greater than otherwise expected. In addition, patients should be advised to avoid driving or operating hazardous machinery until they know how these medications affect them.

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CONTRAINDICATED: Naltrexone can antagonize the effects of opioids via competitive inhibition of opioid receptors. Patients receiving naltrexone may not benefit from opioid-containing medications such as cough and cold products, antidiarrheal preparations, and narcotic analgesics. Likewise, patients dependent on opioids may experience withdrawal symptoms when given naltrexone. Following use of naltrexone, patients may have increased sensitivity to opioids.

**Note: This warning does not apply to opioid products that are specifically formulated with naltrexone to deter abuse via snorting or intravenous injection when crushed.**

MANAGEMENT: The use of naltrexone is considered contraindicated in patients receiving opioids or dependent on opioids, including those maintained on opiate agonists (e.g., methadone) or partial agonists (e.g., buprenorphine). Naltrexone should also not be given to patients in acute opioid withdrawal. In an urgent situation when analgesia may be required in a patient who has received full blocking doses of naltrexone, consideration should be given to regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid analgesics, or general anesthesia. If opioid analgesia is required, the amount of opioid needed may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged. A rapidly-acting opioid analgesic that minimizes the duration of respiratory depression is preferred. Clinicians should be aware that reversal of full naltrexone blockade by administration of large doses of opiates can cause histamine release. Therefore, patients may experience non-opioid receptor-mediated effects such as facial swelling, itching, generalized erythema, and bronchoconstriction. Irrespective of the drug chosen to reverse naltrexone blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.

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MONITOR: Concomitant treatment with other antihypertensive agents or vasodilators, including alpha-adrenoreceptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-adrenergic blockers, calcium channel blockers, diuretics and nitrates, may potentiate the hypotensive effects of hydralazine and dihydralazine.

MANAGEMENT: Blood pressure and heart rate should be closely monitored when hydralazine or dihydralazine is used with other agents that can induce hypotension.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Concomitant treatment with other antihypertensive agents or vasodilators, including alpha-adrenoreceptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-adrenergic blockers, calcium channel blockers, diuretics and nitrates, may potentiate the hypotensive effects of hydralazine and dihydralazine.

MANAGEMENT: Blood pressure and heart rate should be closely monitored when hydralazine or dihydralazine is used with other agents that can induce hypotension.

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MONITOR: The hypotensive effects of thiazide diuretics and alpha-adrenergic blockers may be additive. Postural hypotension may occur.

MANAGEMENT: Hemodynamic responses should be monitored during coadministration, especially during the first few weeks of therapy. Patients should be advised to take the alpha-blocker at bedtime and to notify their physician if they experience dizziness or syncope while awake.

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