Drug Interactions between dexamethasone / ketorolac / moxifloxacin and ziprasidone

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.

CONTRAINDICATED: Ziprasidone can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In placebo-controlled trials in adults, oral ziprasidone increased the QTc interval by approximately 10 msec at the highest recommended daily dosage of 160 mg compared to placebo. In a study comparing the QT prolonging effect of several antipsychotic drugs at the maximum plasma concentration following administration alone in patient volunteers, the mean increase in QTc (QT interval corrected for heart rate) from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (haloperidol, olanzapine, quetiapine, and risperidone), but was approximately 14 msec less than the prolongation observed for thioridazine. In another study evaluating the QT prolonging effect of intramuscular ziprasidone versus intramuscular haloperidol (control) at the maximum plasma concentration following administration in patient volunteers, the mean increase in QTc from baseline for ziprasidone (20 mg and 30 mg doses given 4 hours apart) was 4.6 msec after the first injection and 12.8 msec after the second injection, which at 30 mg is 1.5 times the highest recommended dose. The mean increase in QTc from baseline for haloperidol (7.5 mg and 10 mg doses given 4 hours apart) was 6.0 msec following the first injection and 14.7 msec following the second injection. No patients had a QTc interval exceeding 500 msec. 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).

MONITOR CLOSELY: Central nervous system depressant or toxic effects may be additively or synergistically increased in patients taking ziprasidone with certain other drugs (such as other CNS-active agents or efavirenz) that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: Coadministration of ziprasidone with other drugs that can prolong the QT interval is considered contraindicated. Additionally, patients treated with any medication that can cause CNS toxicity symptoms should be advised to seek prompt medical attention if they experience symptoms. Patients should be advised to avoid driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how the medications affect them.

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.

Coadministration with drugs that are inducers of the CYP450 3A4 isoenzyme may only modestly decrease the plasma concentrations of ziprasidone, as less than 1/3 of ziprasidone metabolic clearance occurs via oxidation mediated by CYP450 3A4. In nine healthy subjects, pretreatment with the potent CYP450 3A4 inducer carbamazepine (100 mg/day titrated to 400 mg/day over 5 days) for 25 days decreased the mean peak plasma concentration (Cmax) and 12-hour area under the concentration-time curve (AUC) of ziprasidone (20 mg orally twice a day for 3 days) by 27% and 36%, respectively, compared to when ziprasidone was administered alone. The half-life was decreased by 1 hour. These changes, although statistically significant, were not considered clinically important. There were also no serious adverse events or clinically significant alterations in ECG or vital signs throughout the study. These findings suggest that ziprasidone dose modifications are unlikely to be necessary in patients receiving potent CYP450 3A4 inducers.