Drug Interactions between dexamethasone / ketorolac / moxifloxacin and erlotinib

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: 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 inducers of CYP450 3A4 may decrease the plasma concentrations of erlotinib, which has been shown in vitro to be primarily metabolized by CYP450 3A4 (approximately 80% to 95%) and to a lesser extent by CYP450 1A2. According to the product labeling, erlotinib systemic exposure (AUC) was reduced in the presence of the potent inducer rifampin by 58% to 80%, which is equivalent to a dose of about 30 to 63 mg in lung cancer patients. In one study, pretreatment with rifampin 600 mg daily for 7 days prior to administration of a single 150 mg erlotinib dose increased clearance of erlotinib by 3-fold and reduced median AUC by 69% compared to erlotinib administered alone. In another study, pretreatment with rifampin for 11 days followed by a single 450 mg dose of erlotinib on day 8 resulted in a mean erlotinib AUC that was just 58% of that observed following a single 150 mg dose of erlotinib in the absence of rifampin treatment. Systemic exposure of the active metabolites of erlotinib (OSI-413 and OSI-420) was largely unaffected by rifampin. Consequently, the active metabolites represented 18% of the total erlotinib exposure following coadministration with rifampin relative to only 5% when erlotinib was given alone. No data are available for use with other, less potent CYP450 3A4 inducers.

MANAGEMENT: The potential for diminished pharmacologic effects of erlotinib should be considered during coadministration with CYP450 3A4 inducers. Pharmacologic response to erlotinib should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the erlotinib dosage adjusted as necessary.

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.

MONITOR: Coadministration of erlotinib with anti-angiogenic agents, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or taxane-based chemotherapy may increase the risk of gastrointestinal (GI) perforation. Erlotinib treatment has been associated with an increased risk of developing gastrointestinal (GI) perforation, including fatal cases. Patients with a prior history of peptic ulceration or diverticular disease may also have an increased risk. In three lung cancer studies with erlotinib monotherapy and a pancreatic cancer study with erlotinib plus gemcitabine, the incidence of gastrointestinal perforation in patients treated with erlotinib was 0.2% and 0.4%, respectively, compared to 0.1% and 0% in the control arms. Cases of GI bleeding have also been reported with concomitant administration of NSAIDs.

MANAGEMENT: Caution is recommended when using erlotinib in patients with a history of peptic ulceration or diverticular disease and in patients receiving concomitant treatment with drugs associated with an increased risk of GI perforation such as anti-angiogenic agents, corticosteroids, NSAIDs, and taxane-based chemotherapy. Patients should be advised to contact their healthcare provider if they experience signs and symptoms of GI perforation such as severe abdominal pain, fever, chills, nausea, or vomiting. The manufacturer recommends that erlotinib should be permanently discontinued in patients who develop gastrointestinal perforation.