Drug Interactions between dexamethasone / ketorolac / moxifloxacin and ponesimod

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

MONITOR CLOSELY: Coadministration of ponesimod with antineoplastic, immunosuppressive, or other immune-modulating therapies may increase the risk of unintended additive immunosuppressive effects. Ponesimod causes reversible sequestration of lymphocytes in lymphoid tissues. When administered daily, ponesimod produces a dose-dependent reduction in peripheral lymphocyte count to 30% to 40% of baseline values, which may increase the risk of infections. Life-threatening and rare fatal infections have been reported in association with sphingosine 1-phosphate (S1P) receptor modulators. Decreased lymphocyte counts persist during chronic daily dosing and generally return to normal within 1 week after stopping the medication. Because residual pharmacodynamic effects, such as decreased peripheral lymphocytes, may persist for 1 to 2 weeks after the last dose, use of immunosuppressants during this time may also lead to additive immune effects.

MANAGEMENT: The safety and efficacy of ponesimod in combination with antineoplastic, immunosuppressive, or immune-modulating agents have not been evaluated. Caution is advised during coadministration and for 1 to 2 weeks after the last dose of ponesimod. When switching from drugs with prolonged immune effects to ponesimod, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation.

GENERALLY AVOID: Due to its significant bradycardic effects, the risk of QT prolongation and torsade de pointes arrhythmia may be increased during initiation of ponesimod treatment in patients receiving drugs that prolong the QT interval. Posenimod can cause a transient decrease in heart rate during initiation of therapy that is usually apparent within an hour of the first dose and reaches its nadir within 2 to 4 hours. The heart rate typically recovers to baseline levels 4 to 5 hours after administration, and the effect diminishes with repeated dosing on subsequent days, indicating tolerance. In an active-controlled clinical study, bradycardia at treatment initiation and sinus bradycardia on ECG (defined as heart rate less than 50 bpm) occurred in 5.8% of ponesimod-treated patients compared to 1.6% of patients receiving teriflunomide. The mean decrease in heart rate on day 1 of ponesimod dosing was 6 bpm. Following day 1, decreases in heart rate were less pronounced. Post-dose heart rates below or equal to 40 bpm were rarely observed. However, decreases in heart rate induced by ponesimod can be reversed by atropine if necessary. Initiation of ponesimod treatment has also resulted in transient AV conduction delays that follow a similar temporal pattern as that observed for decreases in heart rate during dose titration. In the same study, first-degree AV block (prolonged PR interval on ECG) occurred in 3.4% of ponesimod-treated patients and 1.2% of patients receiving teriflunomide. Second- and third-degree AV blocks were not reported in patients treated with ponesimod. Overall, bradycardia and conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours without intervention or discontinuation of ponesimod treatment. In a study evaluating the effect on QT interval of ponesimod 40 mg and 100 mg (respectively 2- and 5-fold the recommended maintenance dose) administered until steady-state, ponesimod treatment resulted in maximum mean prolongations of the QTcF of 11.8 ms (40 mg) and 16.2 ms (100 mg). No subject had absolute QTcF greater than 480 ms or change in QTcF from baseline greater than 90 ms following ponesimod treatment. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Ponesimod has not been studied in patients receiving drugs that can prolong the QT interval. Because bradycardia and AV block are recognized risk factors for QT prolongation and torsade de pointes arrhythmia, treatment with ponesimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties. Advice from a cardiologist should be sought if treatment with ponesimod is considered in patients on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes or drugs that slow heart rate or AV conduction.

MONITOR: The combined use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. In a large, case-control study of elderly patients, those who used corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease and GI hemorrhage of 14.6 compared to those who used neither. Corticosteroid use was associated with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the GI mucosa during coadministration. Some investigators have also suggested that the primary effect of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than cause de novo ulcerations.

MANAGEMENT: Caution is advised if corticosteroids and NSAIDs are used together, especially in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.

MONITOR: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of central nervous system toxicity sometimes associated with fluoroquinolone use. The interaction has been reported most often with enoxacin. It may occur with other fluoroquinolones as well, but is poorly documented. The exact mechanism of interaction is unknown. Some investigators suggest that the piperazine ring of fluoroquinolones may inhibit the binding of gamma-aminobutyric acid (GABA) to brain receptors and that NSAIDs may synergistically add to this effect. Patients with a history of seizures may be at greater risk.

MANAGEMENT: Clinical monitoring for signs of CNS stimulation such as tremors, involuntary muscle movements, hallucinations, or seizures is recommended if fluoroquinolone antibiotics are prescribed in combination with NSAIDs.