Interactions between Multaq and Temsirolimus

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of dronedarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the product labeling, administration with grapefruit juice resulted in a 2.5-fold increase in dronedarone peak plasma concentration and a 3-fold increase in systemic exposure. Because dronedarone is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of dronedarone. The mechanism of interaction is unknown. According to the product labeling, the absolute bioavailability of dronedarone increases from about 4% when administered in the fasted state to approximately 15% when administered with a high-fat meal.

MANAGEMENT: Patients treated with dronedarone should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Dronedarone should be taken twice daily with the morning and evening meals.

GENERALLY AVOID: Coadministration of temsirolimus with grapefruit juice may increase the plasma concentrations of sirolimus, a major active metabolite of temsirolimus and known substrate of CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism by certain compounds present in grapefruits.

MANAGEMENT: Patients treated with temsirolimus should preferably avoid the consumption of grapefruit or grapefruit juice.

Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. Caution should be exercised during the infusion and appropriate supportive care should be available. For patients who develop hypersensitivity reaction during the infusion, it is recommended to stop the infusion and close observation with the possibility of resuming therapy at a slower rate should be contemplated at the discretion of the physician. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered. A benefit-risk assessment should be done prior to the continuation of therapy in patients with severe or life-threatening reactions.

Dronedarone has shown to double the risk of death in patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure. It has also shown to double the risk of stroke and death and hospitalization due to heart failure in patients with atrial fibrillation. Other patients at risk include patients with second or third degree AV block, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), patients with bradycardia < 50 bpm, and patients with QT interval prolongation. The use of dronedarone is contraindicated in these patients.

Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. Caution should be exercised during the infusion and appropriate supportive care should be available. For patients who develop hypersensitivity reaction during the infusion, it is recommended to stop the infusion and close observation with the possibility of resuming therapy at a slower rate should be contemplated at the discretion of the physician. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered. A benefit-risk assessment should be done prior to the continuation of therapy in patients with severe or life-threatening reactions.

Cases of fatal bowel perforation occurred in patients who received temsirolimus. Therapy with temsirolimus should be administered with caution in patients who may be at increased risk for gastrointestinal perforation, such as those with a history of diverticulitis. Patients presenting with new onset or worsening of abdominal symptoms or blood in the stools should be evaluated promptly for early identification of gastrointestinal perforation.

Dronedarone has shown to double the risk of death in patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure. It has also shown to double the risk of stroke and death and hospitalization due to heart failure in patients with atrial fibrillation. Other patients at risk include patients with second or third degree AV block, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), patients with bradycardia < 50 bpm, and patients with QT interval prolongation. The use of dronedarone is contraindicated in these patients.

Dronedarone is extensively metabolized by the liver. There is little clinical experience with moderate hepatic impairment and none in patients with severe hepatic impairment. No dosage adjustment is recommended for patients with moderate hepatic impairment, however its use is contraindicated in patients with severe hepatic impairment. Additionally hepatocellular liver injury, including acute liver failure has been reported in patients using dronedarone in the postmarketing setting. Patients should be advised to report immediately any symptoms suggesting hepatic injury, such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine or itching.

Temsirolimus is contraindicated in patients with bilirubin >1.5×ULN. Caution is recommended when treating patients with mild hepatic impairment and a dose reduction may be needed depending on AST and bilirubin levels. Dosage adjustment is needed based on hepatic function; therefore, assessment of AST and bilirubin levels is recommended before initiation of therapy and periodically thereafter.

Dronedarone has shown to double the risk of death in patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure. It has also shown to double the risk of stroke and death and hospitalization due to heart failure in patients with atrial fibrillation. Other patients at risk include patients with second or third degree AV block, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), patients with bradycardia < 50 bpm, and patients with QT interval prolongation. The use of dronedarone is contraindicated in these patients.

Cases of renal failure, including acute renal failure and elevations of serum creatinine and proteinuria, some with a fatal outcome, have been observed in patients treated with inhibitors of mTOR (mammalian target of rapamycin). Therapy with these agents should be administered cautiously in patients with renal dysfunction, in particularly where patients have additional risk factors that may further impair renal function. Renal impairment is not expected to influence drug exposure, and no dosage adjustment is recommended in patients with renal impairment. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of therapy and periodically thereafter.

The administration of live vaccines should be avoided during therapy with inhibitor of mTOR (mammalian target of rapamycin). It is recommended that close contact with individuals who have received live vaccines should be avoided because of the potential risk for shedding from the household contact and transmission to patient. It is recommended to be up-to-date with all required immunizations, as recommended by current immunization guidelines, before initiating therapy with these agents.

Inhibition of mTOR activity results in delays of wound healing and increases the occurrence of wound-related complications, which might require surgical intervention. Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes). Caution is recommended when using these agents, particularly in the perioperative period.

Inhibition of mTOR activity results in delays of wound healing and increases the occurrence of wound-related complications, which might require surgical intervention. Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes). Caution is recommended when using these agents, particularly in the perioperative period.

Elevations in serum blood glucose levels have been reported in patients taking inhibitors of mTOR (mammalian target of rapamycin). Monitoring of fasting serum glucose levels is recommended prior to the start of therapy and periodically thereafter. Clinicians should achieve control of glucose levels before initiating therapy with these agents.

Elevations in cholesterol and triglyceride levels have been reported in patients taking inhibitors of mTOR (mammalian target of rapamycin). Monitoring of fasting lipid profile is recommended prior to the start of therapy and periodically thereafter. Clinicians should achieve control of lipid levels before initiating therapy with these agents.

The immunosuppressant effect of inhibitors of mTOR (mammalian target of rapamycin) may decrease host resistance to infectious agents and may predispose patients to bacterial, fungal, viral, or protozoal infections, infections with opportunistic pathogens, and reactivation of viral infections. Therapy with these agents should be administered with caution in patients with an infection, particularly active infections or any untreated systemic fungal, bacterial, parasitic, or viral infection. It is recommended to complete the treatment of preexisting invasive fungal infections prior to starting treatment and if a diagnosis of invasive systemic fungal infection is made during treatment, discontinue and treat with appropriate antifungal therapy.

Cases of interstitial lung disease, some resulting in death, occurred in patients who received temsirolimus. It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of therapy. Close monitoring for the occurrence of any new or worsening respiratory symptoms is advisable and if clinically significant respiratory symptoms develop, consider withholding administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis.

Cases of interstitial lung disease, some resulting in death, occurred in patients who received temsirolimus. It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of therapy. Close monitoring for the occurrence of any new or worsening respiratory symptoms is advisable and if clinically significant respiratory symptoms develop, consider withholding administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis.