Drug Interactions between Gilenya 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 of fingolimod with antineoplastic, immunosuppressive, or other immune-modulating therapies is expected to increase the risk of immunosuppression and infection. Life-threatening and sometimes fatal infections have been reported. Fingolimod causes reversible sequestration of lymphocytes in lymphoid tissues. When administered daily, fingolimod produces a dose-dependent reduction in peripheral lymphocyte count to 20-30% of baseline values, which may increase the risk of infections. In Phase III clinical trials, short courses of corticosteroids (up to 5 days) to treat relapses did not increase the overall rate of infection and so is generally considered acceptable during treatment with fingolimod. A small study of 12 subjects receiving fingolimod 0.5 mg daily found that the lymphocyte count decreased to approximately 60% of baseline within 4 to 6 hours after the first dose. The lymphocyte count continued to decrease over a 2-week period, reaching a nadir count of approximately 500 cells/mcL (30% of baseline). In a placebo-controlled study of 1272 multiple sclerosis (MS) patients, 18% of patients on fingolimod 0.5 mg daily (n = 425) reached a nadir of less than 200 cells/mcL on at least one occasion, compared to no patient on placebo (n = 418). Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline but does not affect monocytes. Decreased lymphocyte counts persist during daily dosing, then generally return to baseline within 1 to 2 months after stopping the medication.

MANAGEMENT: The safety and efficacy of fingolimod in combination with antineoplastic, immunosuppressive, or immune-modulating agents have not been evaluated. Concomitant use is considered contraindicated by some authorities; however, short courses of corticosteroids (up to 5 days) are generally considered acceptable during treatment with fingolimod. A complete blood count is recommended prior to starting fingolimod if a recent one (i.e., within the last 6 months or after discontinuation of prior therapy) is not available. Treatment suspension should be considered in patients who develop a serious infection, and the benefits and risks reassessed prior to restarting treatment. Patients should be instructed to immediately report any signs or symptoms of an infection (e.g., fever, body aches, chills, nausea, vomiting, headache with neck stiffness or confusion) to their doctor. Because fingolimod remains in the blood for up to two months after the last dose, continued monitoring is recommended throughout this period, and initiating other drugs during this period warrants the same considerations needed for concomitant administration. Consult the manufacturer's product labeling for specific recommendations regarding the timing of use of fingolimod in relation to other agents used in the treatment of MS, including beta interferon, glatiramer acetate, dimethyl fumarate, alemtuzumab, teriflunomide, and mitoxantrone.

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