Drug Interactions between dexamethasone / ketorolac / moxifloxacin and vandetanib

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.

GENERALLY AVOID: Vandetanib can cause concentration-dependent 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 a phase 3 clinical trial where 231 medullary thyroid cancer patients were randomized to receive vandetanib 300 mg once daily, mean change in QTcF (Fridericia-corrected QT interval) from baseline based on the exposure-response relationship was 35 ms for the 300 mg dose. The QTcF increase remained above 30 ms for the duration of the trial (up to 2 years). In addition, 36% of patients experienced greater than 60 ms QTcF increases from baseline and 4.3% had QTcF greater than 500 ms. Vandetanib treatment alone has been associated with reported cases of torsade de pointes, ventricular tachycardia, and sudden death. 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, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The use of vandetanib in combination with other medications that can prolong the QT interval should generally be avoided. Should treatment with other QT-prolonging drugs be required, the manufacturer recommends more frequent monitoring of the ECG as well as serum potassium, magnesium, and calcium levels. Given vandetanib's half-life of 19 days, ECGs and serum electrolytes should typically be obtained at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment, and every 3 months thereafter. Vandetanib should not be started if baseline QTcF is greater than 450 ms, and treatment should be interrupted if QTcF is greater than 500 ms. Treatment may resume when QTcF returns to less than 450 ms, but at a reduced dosage. In addition, hypokalemia, hypomagnesemia, and/or hypocalcemia must be corrected prior to vandetanib administration. Since diarrhea is a common side effect of vandetanib and may cause electrolyte imbalances, ECG and electrolyte levels should also be monitored more frequently when diarrhea develops. Vandetanib treatment should be stopped in the presence of severe diarrhea. Treatment may resume when diarrhea improves, but at a reduced dosage. Following any dosage reduction, or any interruption of treatment greater than 2 weeks, QT assessment and serum electrolytes should be conducted as described previously. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope. Because of the drug's long half-life, adverse reactions including a prolonged QT interval may not resolve quickly, thus appropriate monitoring is necessary.

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.

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may decrease the plasma concentrations of vandetanib, which is a substrate of the isoenzyme. In 16 healthy male subjects, coadministration of rifampin (600 mg/day on days 1 to 31) and vandetanib (single 300 mg oral dose on day 10) resulted in an approximately 40% decrease in vandetanib exposure (AUC) and almost 50% decrease in half-life (from 217.6 hours to 116.3 hours) compared to vandetanib administered alone. There was no significant change in the peak plasma concentration (Cmax) of vandetanib. In the presence of rifampin, the Cmax and AUC of a metabolite, N-desmethylvandetanib, increased by 414% and 266%, respectively. Rifampin also increased the Cmax and AUC of another metabolite, vandetanib N-oxide, by approximately 179% and 126%, respectively. However, the plasma concentrations of vandetanib N-oxide were very low throughout, thus the change in absolute plasma levels induced by rifampin was actually quite small. The clinical implications of these changes are unknown. The two metabolites have shown in vitro pharmacologic activity in cellular assays against vascular endothelial growth factor and epidermal growth factor, with N-desmethylvandetanib exhibiting similar potency to parent drug and vandetanib N-oxide exhibiting less than 1/50 the activity of the parent drug.

MANAGEMENT: Concomitant use of vandetanib with potent CYP450 3A4 inducers should generally be avoided.

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.