Drug Interactions between atazanavir / cobicistat and MLK F2

GENERALLY AVOID: Additive toxicities may occur when bupivacaine is coadministered with other local anesthetics. The potential for increased risk of systemic toxicities such as methemoglobinemia and central nervous system and cardiovascular adverse reactions should be recognized.

MANAGEMENT: Additional use of local anesthetics should generally be avoided within 96 hours following administration of bupivacaine. If coadministration cannot be avoided, overall local anesthetic exposure through 72 hours must be considered in addition to monitoring for the development of methemoglobinemia as well as central nervous system and cardiovascular adverse reactions. Signs and symptoms of methemoglobinemia may be delayed some hours after drug exposure. Patients or their caregivers should be advised to seek medical attention if they notice signs and symptoms of methemoglobinemia such as slate-grey cyanosis in buccal mucous membranes, lips, and nail beds; nausea; headache; dizziness; lightheadedness; lethargy; fatigue; dyspnea; tachypnea; tachycardia; palpitation; anxiety; and confusion. In severe cases, patients may progress to central nervous system depression, stupor, seizures, acidosis, cardiac arrhythmias, syncope, shock, coma, and death. Early warning signs of central nervous system toxicity may include restlessness, anxiety, incoherent speech, dizziness, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, blurred vision, tremors, twitching, depression, and drowsiness. Cardiovascular toxicity may include atrioventricular block, ventricular arrhythmias, cardiac arrest, and decreased cardiac output and arterial blood pressure due to depressed cardiac conductivity, excitability, and myocardial contractility. Patients should have cardiovascular and respiratory vital signs and state of consciousness constantly monitored while under treatment.

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MONITOR CLOSELY: Coadministration with atazanavir may increase the plasma concentrations of amiodarone, systemic lidocaine, and quinidine. The proposed mechanism is atazanavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these antiarrhythmic agents. The interaction has not been studied but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities.

MANAGEMENT: Caution is advised if atazanavir must be used with amiodarone, systemic lidocaine, or quinidine. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever atazanavir is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary. According to some authorities, use of the fixed combination atazanavir-cobicistat or atazanavir-ritonavir with amiodarone or quinidine is considered contraindicated.

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MONITOR CLOSELY: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of triamcinolone. No pharmacokinetic data are available. However, there have been numerous published case reports of Cushing's syndrome and adrenal suppression associated with concomitant use of triamcinolone with various ritonavir-containing antiretroviral regimens and one case report with nefazodone.

MANAGEMENT: The possibility of increased corticosteroid effects should be considered when triamcinolone is used with potent CYP450 3A4 inhibitors. Some authorities advise against concomitant use unless the potential benefit outweighs the risk. If coadministration is necessary, a lower dosage of triamcinolone may be appropriate. Patients should be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and menstrual disorders. Other systemic glucocorticoid effects may include adrenal suppression, immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents. Following extensive use with a potent CYP450 3A4 inhibitor, a progressive dosage reduction may be required over a longer period if triamcinolone is to be withdrawn from therapy, as there may be a significant risk of adrenal suppression. Signs and symptoms of adrenal insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting, fatigue, weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as inability to respond to stress (e.g., illness, infection, surgery, trauma).

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MONITOR CLOSELY: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of triamcinolone. No pharmacokinetic data are available. However, there have been numerous published case reports of Cushing's syndrome and adrenal suppression associated with concomitant use of triamcinolone with various ritonavir-containing antiretroviral regimens and one case report with nefazodone.

MANAGEMENT: The possibility of increased corticosteroid effects should be considered when triamcinolone is used with potent CYP450 3A4 inhibitors. Some authorities advise against concomitant use unless the potential benefit outweighs the risk. If coadministration is necessary, a lower dosage of triamcinolone may be appropriate. Patients should be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and menstrual disorders. Other systemic glucocorticoid effects may include adrenal suppression, immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents. Following extensive use with a potent CYP450 3A4 inhibitor, a progressive dosage reduction may be required over a longer period if triamcinolone is to be withdrawn from therapy, as there may be a significant risk of adrenal suppression. Signs and symptoms of adrenal insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting, fatigue, weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as inability to respond to stress (e.g., illness, infection, surgery, trauma).

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MONITOR: Coadministration with cobicistat may increase the plasma concentrations of lidocaine. The proposed mechanism involves cobicistat inhibition of CYP450 3A4-mediated metabolism of lidocaine. The interaction has not been specifically studied, but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities if levels are significantly increased.

MANAGEMENT: Caution is advised if cobicistat must be used concomitantly with lidocaine. Pharmacologic response and plasma lidocaine levels should be monitored more closely whenever cobicistat is added to or withdrawn from therapy, and the lidocaine dosage adjusted as necessary.

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