Interactions between Samsca and Tacrolimus

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the plasma concentrations of tacrolimus. The proposed mechanism for the interaction is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. Although clinical data are lacking, this interaction may result in increased risk of serious adverse reactions such as nephro- and neurotoxicity, as well as other adverse effects associated with tacrolimus such as malignancies, infections, diabetes, hyperkalemia, hypertension, and QT prolongation.

GENERALLY AVOID: Alcohol may modify the rate of tacrolimus release from extended release formulations, thereby potentially increasing the risk of serious adverse reactions.

ADJUST DOSING INTERVAL: Coadministration with food decreases the rate and extent of tacrolimus absorption. This effect is greatest after a high-fat meal.

MANAGEMENT: Patients should avoid consumption of food or drink containing grapefruit during treatment with tacrolimus. Concomitant use of tacrolimus, especially extended release formulations, with alcohol should also be avoided. Tacrolimus extended release formulations should be administered on an empty stomach, at least 1 hour before or 2 hours after a meal, and tacrolimus immediate release formulations should be taken consistently every day with or without food.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of tolvaptan. 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 of tolvaptan with grapefruit juice resulted in a 1.8-fold increase in tolvaptan systemic exposure. The clinical significance is unknown, although increased pharmacologic effects may be expected. Too rapid correction of hyponatremia increases the risk of osmotic demyelination syndrome, which is associated with dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death.

MANAGEMENT: Patients treated with tolvaptan should avoid consumption of grapefruits and grapefruit juice.

Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes. It is recommended to avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider monitoring of tacrolimus whole blood concentrations and obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes. It is recommended to avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider monitoring of tacrolimus whole blood concentrations and obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

Tacrolimus can induce post-transplant insulin-dependent diabetes mellitus (PTDM). Temporary insulin therapy has been required in some patients, while long-term insulin use has been necessary in others. Reversible insulin dependence has occurred in kidney and liver transplant patients. PTDM has occurred in a greater percentage of tacrolimus-treated (20%) versus cyclosporine-treated (4%) kidney transplant patients. Black and Hispanic patients are at increased risk for PTDM. Therapy with tacrolimus should be administered cautiously in patients with pre-transplant diabetes mellitus.

Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes. It is recommended to avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider monitoring of tacrolimus whole blood concentrations and obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

Due to immunosuppression, patients receiving tacrolimus are at increased risk for infections, including polyoma virus infections, post-transplant lymphoproliferative disorder (PTLD) and CMV viremia and CMV disease. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML). Cases of PML have been reported in patients treated with tacrolimus. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. PTLD associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. Patients that are Epstein-Barr Virus (EBV) seronegative appears to have the greatest risk of developing PTLD. It is recommended to monitor EBV serology during tacrolimus therapy. Caution and patient monitoring is recommended when using this drug in immunosuppressed patients.

Due to immunosuppression, patients receiving tacrolimus are at increased risk for infections, including polyoma virus infections, post-transplant lymphoproliferative disorder (PTLD) and CMV viremia and CMV disease. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML). Cases of PML have been reported in patients treated with tacrolimus. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. PTLD associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. Patients that are Epstein-Barr Virus (EBV) seronegative appears to have the greatest risk of developing PTLD. It is recommended to monitor EBV serology during tacrolimus therapy. Caution and patient monitoring is recommended when using this drug in immunosuppressed patients.

Tacrolimus undergoes significant hepatic metabolism, primarily by CYP450 3A enzymes. Less than 5% of tacrolimus is eliminated unchanged in the bile and <1% is eliminated unchanged in the urine. Moderate or severe hepatic dysfunction or impaired post-transplant hepatic function may alter the metabolic and therapeutic activity of tacrolimus and increase the whole blood tacrolimus concentration. Therapy with tacrolimus should be administered cautiously and dosage adjustments considered in the presence of moderate or severe hepatic impairment.

Tolvaptan can cause serious and potentially fatal liver injury. Patients with symptoms that indicate liver injury such as fatigue, anorexia, right upper abdominal pain, dark urine or jaundice should discontinue treatment right away. Therapy duration should be limited to 30 days. The use of tolvaptan should be avoided in patients with underlying liver disease, including cirrhosis, because the ability to recover from liver injury may be impaired.

Nephrotoxicity has been reported in 52% of kidney and 40% of liver transplant patients. Renal toxicity includes increasing serum creatinine and blood urea nitrogen, and renal failure sometimes requiring hemodialysis. Oliguria and hematuria also have been reported. The mechanism of tacrolimus-induced renal dysfunction is not well established. Renal toxicity appears to be dose-related, although toxicity may still occur even at suggested therapeutic concentrations. Therapy with tacrolimus should be administered cautiously and dosage reductions may be necessary in patients with compromised renal function. Alternative immunosuppressive therapy should be considered in the presence of persistent or worsening renal dysfunction.

There are no clinical trials of tolvaptan in patients with CrCl < 10 mL/min, and because drug effects on serum sodium levels are likely lost at very low levels of renal function, use in these patients is not recommended. Additionally, no benefit can be expected in anuric patients, so the use of tolvaptan is contraindicated in these patients.

Osmotic demyelination syndrome is a risk associated with overly rapid correction of hyponatremia (> 12 mEq/L/24 hours). This syndrome can result in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizure, coma or death. Patients with advanced liver disease, alcoholism or severe malnutrition are at increased risk and require slower rates of correction. Serum sodium concentration and neurological status should be monitored appropriately during treatment administration. Vasopressin antagonists should be initiated and re- initiated in patients only in hospital settings were sodium levels can be monitored closely.

The use of tacrolimus has been associated with hyperkalemia. Therapy with tacrolimus should be administered cautiously in patients with elevated serum potassium levels. Close monitoring of potassium levels is recommended. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during tacrolimus therapy.

The use of tacrolimus has been associated with hypertension. Therapy with tacrolimus should be administered cautiously in patients with elevated blood pressure. Close monitoring of blood pressure is recommended.

Osmotic demyelination syndrome is a risk associated with overly rapid correction of hyponatremia (> 12 mEq/L/24 hours). This syndrome can result in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizure, coma or death. Patients with advanced liver disease, alcoholism or severe malnutrition are at increased risk and require slower rates of correction. Serum sodium concentration and neurological status should be monitored appropriately during treatment administration. Vasopressin antagonists should be initiated and re- initiated in patients only in hospital settings were sodium levels can be monitored closely.