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    Vasopressin Antagonists

    BOXED WARNING

    Alcoholism, malnutrition, osmotic demyelination syndrome, requires a specialized care setting

    An overly rapid increase in serum sodium concentration during drug administration (more than 12 mEq/L/24 hours) can result in serious neurologic sequelae such as osmotic demyelination syndrome that can result in dysarthria, mutism, dysphagia, lethargy, change in affect, spastic quadriparesis, seizures, coma, or death. In controlled clinical trials, 7% of patients with serum sodium less than 130 mEq/L receiving tolvaptan at doses starting at 15 mg/day had an increase of serum sodium more than 8 mEq/L at 8 hours (compared to 1% for placebo) and 2% had an increase of serum sodium more than 12 mEq/L at 24 hours (compared to none for placebo). No patients had evidence of osmotic demyelination syndrome or neurologic sequelae. Although not observed in tolvaptan clinical studies, osmotic demyelination syndrome has been reported following the rapid correction of low serum sodium concentrations. The initiation and re-initiation of tolvaptan requires a specialized care setting where serum sodium concentrations and neurological status can be closely monitored during therapy. Slower rates of serum sodium correction should be considered in patients more susceptible to the deleterious effects of too rapid a rise in serum sodium concentrations such as patients with severe malnutrition, alcoholism, advanced liver disease, SIADH, very low baseline serum sodium concentrations (hyponatremia), or those receiving a diuretic concomitantly. Tolvaptan should be discontinued or interrupted if the patient develops too rapid a rise in serum sodium concentrations; the administration of hypotonic fluid should be considered. Fluid restriction during the first 24 hours of tolvaptan therapy should be avoided as this may increase the possibility of rapid correction of serum sodium.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral V2 vasopressin receptor antagonist.
    For treatment of hypervolemic and euvolemic hyponatremia, including in patients with heart failure and SIADH
    Must be initiated and re-initiated in a hospital.
    Do not use in patients with hepatic disease, including cirrhosis;use in other patients limited to 30 days due to risk of hepatic injury.

    COMMON BRAND NAMES

    Samsca

    HOW SUPPLIED

    Samsca Oral Tab: 15mg, 30mg

    DOSAGE & INDICATIONS

    For the treatment of clinically significant hypervolemic and euvolemic hyponatremia (i.e., serum sodium < 125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including in patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).
    NOTE: Only initiate or re-initiate tolvaptan in a hospital where serum sodium concentrations can be closely monitored. Too rapid correction can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, changes in affect, spastic quadriparesis, seizures, coma, and death.
    NOTE: Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with tolvaptan.
    NOTE: A clear symptomatic or survival benefit with tolvaptan therapy has not been established.
    Oral dosage
    Adults

    The recommended starting dose is 15 mg PO once daily. After 24 hours, the dose may be increased to 30 mg PO once daily. A minimum of 24 hours should lapse between dose adjustments. Maximum: 60 mg/day PO. Do not administer tolvaptan for more than 30 days to minimize the risk of liver injury.
    Serum sodium and volume status should be closely monitored during initiation and titration. During tolvaptan therapy, patients should be advised to continue to ingest fluid in response to thirst. Fluid restriction should be avoided during the first 24 hours of therapy. Fluid restriction during tolvaptan therapy may increase the risk for hypovolemia and dehydration. However, upon discontinuation of tolvaptan therapy, patients should continue fluid restriction and be monitored for serum sodium and volume status. Results from the EVEREST trials (randomized, double-blind, placebo-controlled trial of 4133 patients) demonstrated that initiation of tolvaptan (30 mg/day) as adjunct therapy to standard treatment for acute heart failure within 48 hours of hospital admission improved many acute signs and symptoms of heart failure including dyspnea, edema, and body weight, as well as correction of serum sodium in the presence of hyponatremia. However, compared to placebo, continued administration of tolvaptan (minimum 60 days, mean 0.75 years) had no effect on the composite of cardiovascular death or hospitalization for heart failure (42% for tolvaptan compared to 40.2% for placebo, HR 1.04; 95% CI, 0.95—1.14; P = 0.55).

    MAXIMUM DOSAGE

    Adults

    60 mg/day PO for up to 30 days.

    Geriatric

    60 mg/day PO for up to 30 days.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Administration of tolvaptan should be avoided in patients with underlying hepatic disease.

    Renal Impairment

    CrCl 10—79 ml/min: No dosage adjustment needed.
    CrCl < 10 ml/min and patients requiring hemodialysis: No information is available; tolvaptan is contraindicated in anuric patients.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.
     
    Only initiate and re-initiate treatment in a hospital where serum sodium concentrations and volume status can be closely monitored.
    Monitor for neurologic changes associated with rapid correction of serum sodium concentrations (> 12 mEq/L over 24 hours).
    Do not administer for longer than 30 days due to the risk of hepatic injury.

    Oral Administration

    Administer tolvaptan with or without food.
    Avoid fluid restriction during the first 24 hours of therapy. Advise patients to drink fluid in response to thirst.

    STORAGE

    Samsca:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Tolvaptan is contraindicated in patients requiring urgent intervention to raise serum sodium acutely, as tolvaptan has not been studied in this clinical setting.
     
    Tolvaptan is contraindicated in patients who have experienced hypersensitivity (e.g., generalized rash, anaphylactic shock) to tolvaptan or any component of the product.
     
    Concomitant use with hypertonic saline is not recommended.

    Alcoholism, malnutrition, osmotic demyelination syndrome, requires a specialized care setting

    An overly rapid increase in serum sodium concentration during drug administration (more than 12 mEq/L/24 hours) can result in serious neurologic sequelae such as osmotic demyelination syndrome that can result in dysarthria, mutism, dysphagia, lethargy, change in affect, spastic quadriparesis, seizures, coma, or death. In controlled clinical trials, 7% of patients with serum sodium less than 130 mEq/L receiving tolvaptan at doses starting at 15 mg/day had an increase of serum sodium more than 8 mEq/L at 8 hours (compared to 1% for placebo) and 2% had an increase of serum sodium more than 12 mEq/L at 24 hours (compared to none for placebo). No patients had evidence of osmotic demyelination syndrome or neurologic sequelae. Although not observed in tolvaptan clinical studies, osmotic demyelination syndrome has been reported following the rapid correction of low serum sodium concentrations. The initiation and re-initiation of tolvaptan requires a specialized care setting where serum sodium concentrations and neurological status can be closely monitored during therapy. Slower rates of serum sodium correction should be considered in patients more susceptible to the deleterious effects of too rapid a rise in serum sodium concentrations such as patients with severe malnutrition, alcoholism, advanced liver disease, SIADH, very low baseline serum sodium concentrations (hyponatremia), or those receiving a diuretic concomitantly. Tolvaptan should be discontinued or interrupted if the patient develops too rapid a rise in serum sodium concentrations; the administration of hypotonic fluid should be considered. Fluid restriction during the first 24 hours of tolvaptan therapy should be avoided as this may increase the possibility of rapid correction of serum sodium.

    Hypovolemia

    Tolvaptan is contraindicated in patients with hyponatremia associated with hypovolemia (hypovolemic hyponatremia). The risks of developing hypotension and renal failure from worsening hypovolemia outweigh the possible benefits of therapy with tolvaptan in this population. Additionally, tolvaptan is contraindicated in patients who are unable to sense and respond appropriately to thirst as these patients are at an increased risk of developing an overly rapid correction of serum sodium (i.e., hypernatremia) and hypovolemia.

    Anuria

    Tolvaptan is contraindicated in patients with anuria since no clinical benefit is expected in patients unable to make urine.

    Hepatic disease

    Avoid use of tolvaptan in patients with underlying hepatic disease, including cirrhosis. Serious and life-threatening hepatic injury has been reported with use of tolvaptan and the ability of the liver to recover from hepatic injury may be impaired in patients with pre-existing hepatic impairment. In clinical trials of patients with cirrhosis treated with tolvaptan, gastrointestinal bleeding occurred in 10% (n=6) of tolvaptan patients compared to 2% (n=1) of patients treated with placebo. Furthermore, a slower rate of serum sodium correction should be considered in patients with advanced hepatic disease, as these patients are more susceptible to the serious neurological sequelae (e.g., osmotic demyelination syndrome) that is possible when too rapid a rise in serum sodium concentrations occurs.

    Dehydration

    Dehydration or hypovolemia may occur during the course of tolvaptan therapy, particularly in susceptible patients such as those who are fluid-restricted or those who are volume-depleted and receiving diuretics. Fluid restriction should be avoided during the first 24 hours of therapy as this may increase the risk of dehydration and hypovolemia. Patients should be encouraged to ingest fluid in response to thirst and should be monitored for signs of dehydration and hypovolemia. If clinically significant dehydration or hypovolemia occurs, tolvaptan should be discontinued or interrupted and vital signs and fluid and electrolyte balance should be closely monitored.

    Hyperkalemia

    Tolvaptan should be used cautiously in patients with hyperkalemia. Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume that could result in increased serum potassium. Serum potassium levels should be monitored after initiation of tolvaptan treatment in patients with a serum potassium > 5 mEq/L as well as those who are receiving drugs known to increase serum potassium levels.

    Geriatric

    Results of clinical trials of tolvaptan, showed that 42% were >= 65 years and 19% were >= 75 years. No differences in safety or efficacy were noted between geriatric patients when compared to the general study population; however, greater sensitivity of some elderly patients to tolvaptan therapy cannot be ruled out.

    Pregnancy

    Tolvaptan is classified as FDA pregnancy risk category C. It is not known whether tolvaptan can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Tolvaptan has been shown to have adverse effects on the fetus when given to pregnant animals (e.g., cleft palate, brachymelia, microphthyalmia, skeletal malformations, decreased fetal weight, delayed fetal ossification, and embryo-fetal death). The effect of tolvaptan use on labor and obstetric delivery in humans has not been studied. Tolvaptan should be used during pregnancy only if the potential benefit justifies any possible risk to the fetus.

    Breast-feeding

    It is unknown if tolvaptan is excreted into human breast milk. It is excreted into the milk of lactating rats. According to the manufacturer, because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or tolvaptan, taking into consideration the importance of the drug to the mother. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Safety and effectiveness of tolvaptan have not been established in neonates, infants, children and adolescents less than 18 years of age.

    Autosomal dominant polycystic kidney disease

    Significantly elevated hepatic enzymes with concomitant, clinically significant hyperbilirubinemia were observed in 3 tolvaptan-treated patients in a clinical trial of about 1400 patients with autosomal dominant polycystic kidney disease (ADPKD) and its open-label extension trial. The maximum daily dose of tolvaptan administered in the trials was higher than the maximum daily dose approved for the treatment of hyponatremia (120mg/day vs. 60 mg/day); tolvaptan is not FDA-approved in patients with ADPKD. The data are insufficient to determine if the possibility of hepatic injury is limited to patients with ADPKD. Therefore, carefully evaluate any patient presenting with symptoms that may indicate hepatic injury. If hepatic injury is suspected, discontinue tolvaptan, institute appropriate treatment, and investigate the probable cause. Do not reinitiate tolvaptan unless the cause for the observed liver injury is definitively established to be unrelated to treatment with tolvaptan.

    ADVERSE REACTIONS

    Severe

    diabetic ketoacidosis / Delayed / 0-2.0
    thrombosis / Delayed / 0-2.0
    pulmonary embolism / Delayed / 0-2.0
    stroke / Early / 0-2.0
    rhabdomyolysis / Delayed / 0-2.0
    disseminated intravascular coagulation (DIC) / Delayed / 0-2.0
    ventricular fibrillation / Early / 0-2.0
    hyperkalemia / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    osmotic demyelination syndrome / Early / Incidence not known
    anaphylactic shock / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 7.0-7.0
    hyperglycemia / Delayed / 6.0-6.0
    dehydration / Delayed / 3.3-3.3
    colitis / Delayed / 0-2.0
    prolonged bleeding time / Delayed / 0-2.0
    vaginal bleeding / Delayed / 0-2.0
    bleeding / Early / 0-2.0
    respiratory depression / Rapid / 0-2.0
    hypernatremia / Delayed / 0.8-1.7
    elevated hepatic enzymes / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    hypovolemia / Early / Incidence not known

    Mild

    polydipsia / Early / 12.0-16.0
    xerostomia / Early / 13.0-13.0
    polyuria / Early / 4.0-11.0
    asthenia / Delayed / 9.0-9.0
    fever / Early / 4.0-4.0
    anorexia / Delayed / 4.0-4.0
    nausea / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known

    DRUG INTERACTIONS

    Afatinib: (Moderate) If the concomitant use of tolvaptan and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of tolvaptan. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and tolvaptan is a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Aliskiren; Valsartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Alogliptin; Pioglitazone: (Major) Tolvaptan is metabolized by CYP3A4. Pioglitazone is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Amiloride: (Moderate) Monitor serum potassium closely if these drugs are used together. In clinical studies, tolvaptan was administered concomitantly with potassium-sparing diuretics. Hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics than when potassium-sparing diuretics were administered with placebo.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium closely if these drugs are used together. In clinical studies, tolvaptan was administered concomitantly with potassium-sparing diuretics. Hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics than when potassium-sparing diuretics were administered with placebo. (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Amiodarone: (Major) The concomitant use of tolvaptan and moderate CYP3A4 inhibitors, such as amiodarone, should be avoided, and coadministration of tolvaptan and P-gp inhibitors, such as amiodarone, may necessitate dose reduction of tolvaptan. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Amiodarone is a moderate inhibitor of CYP3A4 and P-gp. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. Furthermore, coadministration of tolvaptan with P-gp inhibitors may necessitate a dose decrease of tolvaptan.
    Amlodipine; Benazepril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Amlodipine; Olmesartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Amlodipine; Telmisartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Amlodipine; Valsartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Amoxicillin; Clarithromycin; Lansoprazole: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as clarithromycin, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Clarithromycin is a strong inhibitor of CYP3A4 and P-gp. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Amoxicillin; Clarithromycin; Omeprazole: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as clarithromycin, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Clarithromycin is a strong inhibitor of CYP3A4 and P-gp. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Amprenavir: (Major) Tolvaptan is metabolized by CYP3A4. Amprenavir is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. Concomitant use of tolvaptan with moderate CYP3A4 inhibitors, such as amprenavir, should be avoided.
    Angiotensin II receptor antagonists: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Angiotensin-converting enzyme inhibitors: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Aprepitant, Fosaprepitant: (Major) The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as aprepitant, fosaprepitant, should be avoided. If coadministration cannot be avoided, use caution and monitor for an increase in tolvaptan-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tolvaptan is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tolvaptan. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Argatroban: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Atazanavir: (Major) Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided. Tolvaptan is metabolized by CYP3A4; atazanavir is an inhibitor of CYP3A4.
    Atazanavir; Cobicistat: (Major) Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided. Tolvaptan is metabolized by CYP3A4; atazanavir is an inhibitor of CYP3A4. (Major) Coadministration may cause a marked increased in tolvaptan concentrations.The concomitant use of tolvaptan and moderate CYP3A4 inhibitors, such as cobicistat, should be avoided; coadministration of tolvaptan and P-glycoprotein (P-gp) inhibitors, such as cobicistat, may necessitate dose reduction of tolvaptan. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Cobicistat is an inhibitor of CYP3A4 and P-gp.
    Atenolol; Chlorthalidone: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Azilsartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Azilsartan; Chlorthalidone: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Azithromycin: (Major) Both tolvaptan and azithromycin are P-glycoprotein (PGP) inhibitors and substrates, so coadministration may lead to increased concentrations of either agent. Monitor patients for side effects if these drugs are given together. If tolvaptan and azithromycin are coadministered, a reduction in the dose of tolvaptan may be required. For tolvaptan, monitor serum electrolytes and clinical response.
    Barbiturates: (Major) Tolvaptan is metabolized by CYP3A4. Barbiturates induce CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Benazepril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Bendroflumethiazide; Nadolol: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Bexarotene: (Major) Tolvaptan is metabolized by CYP3A4. Bexarotene is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering tolvaptan with boceprevir due to an increased potential for tolvaptan-related adverse events. If tolvaptan dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of tolvaptan. Tolvaptan is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated tolvaptan plasma concentrations.
    Bosentan: (Major) Tolvaptan is metabolized by CYP3A4. Bosentan is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Brigatinib: (Major) Avoid coadministration of brigatinib with tolvaptan if possible due to decreased plasma exposure to tolvaptan which may result in decreased efficacy; if concomitant use is unavoidable, the dose of tolvaptan may need to be increased. Tolvaptan is a CYP3A4 substrate and brigatinib is a CYP3A4 inducer in vitro. Coadministration with a strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Bumetanide: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and loop diuretics increases the risk of too rapid correction of serum sodium.
    Cabozantinib: (Moderate) Monitor for an increase in tolvaptan-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of tolvaptan may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and tolvaptan is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Canagliflozin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Tolvaptan is a mild PGP inhibitor and PGP substrate. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Tolvaptan is a mild PGP inhibitor and PGP substrate. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions.
    Candesartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Captopril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Carbamazepine: (Major) Tolvaptan is metabolized by CYP3A4. Carbamazepine is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Carvedilol: (Moderate) Altered concentrations of tolvaptan and/or carvedilol may occur during coadministration. Carvedilol and tolvaptan are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Ceritinib: (Major) Avoid coadministration of ceritinib with tolvaptan due to increased tolvaptan exposure. Ceritinib is a CYP3A4 inhibitor and tolvaptan is metabolized by CYP3A4. Coadministration of strong CYP3A4 inhibitors is contraindicated and moderate CYP3A4 inhibitors should be avoided in combination with tolvaptan. Because the strength of inhibition of CYP3A4 by ceritinib is unknown, a specific recommendation for the safe use of ceritinib and tolvaptan cannot be provided.
    Chloramphenicol: (Major) Tolvaptan is metabolized by CYP3A4. Chloramphenicol is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Chlorothiazide: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Chlorthalidone: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Chlorthalidone; Clonidine: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Cimetidine: (Major) Avoid coadministration of cimetidine and tolvaptan due to the potential for substantial increases in tolvaptan exposure. Cimetidine is a moderate CYP3A4 inhibitor and tolvaptan is a CYP3A4 substrate. (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Clarithromycin: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as clarithromycin, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Clarithromycin is a strong inhibitor of CYP3A4 and P-gp. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Clindamycin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Cobicistat: (Major) Coadministration may cause a marked increased in tolvaptan concentrations.The concomitant use of tolvaptan and moderate CYP3A4 inhibitors, such as cobicistat, should be avoided; coadministration of tolvaptan and P-glycoprotein (P-gp) inhibitors, such as cobicistat, may necessitate dose reduction of tolvaptan. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Cobicistat is an inhibitor of CYP3A4 and P-gp.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration may cause a marked increased in tolvaptan concentrations.The concomitant use of tolvaptan and moderate CYP3A4 inhibitors, such as cobicistat, should be avoided; coadministration of tolvaptan and P-glycoprotein (P-gp) inhibitors, such as cobicistat, may necessitate dose reduction of tolvaptan. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Cobicistat is an inhibitor of CYP3A4 and P-gp.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration may cause a marked increased in tolvaptan concentrations.The concomitant use of tolvaptan and moderate CYP3A4 inhibitors, such as cobicistat, should be avoided; coadministration of tolvaptan and P-glycoprotein (P-gp) inhibitors, such as cobicistat, may necessitate dose reduction of tolvaptan. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Cobicistat is an inhibitor of CYP3A4 and P-gp. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tolvaptan. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and tolvaptan is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and tolvaptan is a weak P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Conivaptan: (Major) Tolvaptan is metabolized by CYP3A4. Conivaptan is a moderate inhibitor of CYP3A4 and in the same therapeutic class as tolvaptan. Coadministration of conivaptan with tolvaptan may cause a marked increased in tolvaptan concentrations and should be avoided. Additionally, the coadministration of tolvaptan and conivaptan would represent therapeutic duplication and could cause deleterious effects.
    Crizotinib: (Major) Avoid coadministration of tolvaptan with crizotinib due to the risk of increased tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). Crizotinib is a moderate CYP3A4 inhibitor and is also a P-gp inhibitor at clinical relevant concentrations. The effect of moderate CYP3A inhibitors on tolvaptan exposure has not been assessed, but are expected to lead to substantial increases in tolvaptan plasma concentrations. Coadministration with other P-gp inhibitors has also increased tolvaptan plasma concentrations.
    Cyclosporine: (Major) Tolvaptan is a substrate for P-gp. Cyclosporine is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan. If tolvaptan and cyclosporine are coadministered, a reduction in the dose of tolvaptan may be required.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with tolvaptan, a mild P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like tolvaptan in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with tolvaptan, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Major) The concomitant use of dabrafenib and tolvaptan may lead to decreased tolvaptan concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of tolvaptan efficacy. Dabrafenib is a moderate CYP3A4 inducer and tolvaptan is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    Daclatasvir: (Moderate) Systemic exposure of tolvaptan, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of tolvaptan; monitor patients for potential adverse effects.
    Danazol: (Major) Tolvaptan is metabolized by CYP3A4. Danazol is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Darunavir: (Major) Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Darunavir is a moderate inhibitor of CYP3A4 and P-gp.
    Darunavir; Cobicistat: (Major) Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Darunavir is a moderate inhibitor of CYP3A4 and P-gp. (Major) Coadministration may cause a marked increased in tolvaptan concentrations.The concomitant use of tolvaptan and moderate CYP3A4 inhibitors, such as cobicistat, should be avoided; coadministration of tolvaptan and P-glycoprotein (P-gp) inhibitors, such as cobicistat, may necessitate dose reduction of tolvaptan. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Cobicistat is an inhibitor of CYP3A4 and P-gp.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as ritonavir, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Ritonavir is a strong inhibitor of CYP3A4 and P-gp. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Dasatinib: (Major) Tolvaptan is metabolized by CYP3A4. Dasatinib is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Delavirdine: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as delavirdine, is contraindicated. Tolvaptan is metabolized by CYP3A4. Delavirdine is a strong inhibitor of CYP3A4. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Desmopressin: (Major) Coadministration of tolvaptan and desmopressin (DDAVP) is not recommended. Tolvaptan is a V2 receptor antagonist and may interfere with the V2 agonist activity of DDAVP. In a male subject with mild Von Willebrand (vW) disease, intravenous infusion of DDAVP 2 hours after administration of oral tolvaptan did not produce the expected increases in vW Factor Antigen or Factor VIII activity.
    Dexamethasone: (Major) Tolvaptan is metabolized by CYP3A4. Dexamethasone is an inducer of CYP3A4. Coadministration of CYP3A4 inducers, such as dexamethasone, with tolvaptan may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan. Additionally, the potassium-wasting effects of corticosteroid therapy can be exacerbated by concomitant administration of other potassium-depleting drugs including diuretics. Serum potassium levels should be monitored in patients receiving these drugs concomitantly.
    Dextran: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Dextromethorphan; Quinidine: (Major) Tolvaptan is a substrate for P-gp. Quinidine is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan; a reduction in the dose of tolvaptan may be required.
    Digoxin: (Major) Coadministration of digoxin and tolvaptan increases the serum concentration of digoxin by 30%. Digoxin is a substrate for P-glycoprotein (P-gp); tolvaptan is a substrate and inhibitor of P-gp. Measure serum digoxin concentrations before initiating tolvaptan. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
    Diltiazem: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Diltiazem is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increase in tolvaptan concentrations and should be avoided.
    Doxorubicin: (Major) Tolvaptan is a mild P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of tolvaptan and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Drospirenone; Ethinyl Estradiol: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Edoxaban: (Moderate) Coadministration of edoxaban and tolvaptan may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and tolvaptan is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of tolvaptan; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Major) Tolvaptan is metabolized by CYP3A4. Efavirenz is an inducer of CYP3A4. Coadministration of CYP3A4 inducers, such as efavirenz, with tolvaptan may result in a reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy. The concomitant use of tolvaptan and CYP3A4 inducers should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Tolvaptan is metabolized by CYP3A4. Efavirenz is an inducer of CYP3A4. Coadministration of CYP3A4 inducers, such as efavirenz, with tolvaptan may result in a reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy. The concomitant use of tolvaptan and CYP3A4 inducers should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tolvaptan. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Moderate) Administering tolvaptan with elbasvir; grazoprevir may result in elevated tolvaptan plasma concentrations. Tolvaptan is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Coadministration of tolvaptan and eliglustat may result in increased plasma concentrations of tolvaptan. Monitor patients closely for tolvaptan-related adverse effects including a rise in serum sodium concentrations, polyuria, thirst, and dehydration. The dose of tolvaptan may need to be reduced. Tolvaptan is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tolvaptan. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tolvaptan. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Enalapril, Enalaprilat: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Enalapril; Felodipine: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Enzalutamide: (Major) Avoid coadministration of tolvaptan with enzalutamide if possible due to decreased plasma concentrations of tolvaptan. If concomitant use is unavoidable, monitor for decreased efficacy of tolvaptan and increase the dose as clinically indicated. Tolvaptan is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    Eprosartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Erythromycin: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Erythromycin is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increase in tolvaptan concentrations and should be avoided.
    Erythromycin; Sulfisoxazole: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Erythromycin is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increase in tolvaptan concentrations and should be avoided.
    Eslicarbazepine: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Tolvaptan is metabolized by CYP3A4. Coadministration of eslicarbazepine with tolvaptan may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy. The concomitant use of tolvaptan and CYP3A4 inducers should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Ethacrynic Acid: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and loop diuretics increases the risk of too rapid correction of serum sodium.
    Ethinyl Estradiol: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Desogestrel: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Etonogestrel: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Levonorgestrel: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Norelgestromin: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Norethindrone: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Norgestimate: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Ethinyl Estradiol; Norgestrel: (Major) Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors, such as ethinyl estradiol, should be avoided.
    Etoposide, VP-16: (Minor) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with tolvaptan. Tolvaptan is a weak inhibitor of P-glycoprotein (P-gp) and etoposide, VP-16 is a P-gp substrate. Coadministration may increase etoposide concentrations.
    Etravirine: (Major) Tolvaptan is metabolized by CYP3A4. Etravirine is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Fluconazole: (Major) Tolvaptan is metabolized by CYP3A4. Fluconazole is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided. (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Fluoxetine: (Moderate) Administering tolvaptan with fluoxetine may result in elevated tolvaptan plasma concentrations. Tolvaptan is a substrate of CYP3A; fluoxetine is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Fluoxetine; Olanzapine: (Moderate) Administering tolvaptan with fluoxetine may result in elevated tolvaptan plasma concentrations. Tolvaptan is a substrate of CYP3A; fluoxetine is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Flutamide: (Major) Tolvaptan is metabolized by CYP3A4. Flutamide is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Fluvoxamine: (Major) Tolvaptan is metabolized by CYP3A4. Fluvoxamine is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Fosamprenavir: (Major) Tolvaptan is metabolized by CYP3A4. Fosamprenavir is a moderate inhibitor and inducer of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations; however, coadministration with CYP3A4 inducers may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy. The concomitant use of tolvaptan and moderate CYP3A4 inhibitors and inducers should be avoided. If coadministration is unavoidable, a change in the dose of tolvaptan may be necessary and patients should be monitored closely for side effects and changes in efficacy. In addition, tolvaptan is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp), while fosamprenavir is a P-gp substrate and inducer.
    Fosinopril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Fosphenytoin: (Major) Tolvaptan is metabolized by CYP3A4. Phenytoin (or fosphenytoin) is an inducer of CYP3A4. Coadministration of CYP3A4 inducers, such as phenytoin, with tolvaptan may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy. The concomitant use of tolvaptan and CYP3A4 inducers should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Furosemide: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and loop diuretics increases the risk of too rapid correction of serum sodium.
    Gentamicin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Glecaprevir; Pibrentasvir: (Moderate) A dose reduction of tolvaptan may be necessary if coadministered with glecaprevir due to increased tolvaptan exposure; glecaprevir exposure may also increase. Glecaprevir and tolvaptan are both substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) A dose reduction of tolvaptan may be necessary if coadministered with pibrentasvir due to increased tolvaptan exposure; pibrentasvir exposure may also increase. Pibrentasvir and tolvaptan are both substrates and inhibitors of P-glycoprotein (P-gp)
    Glimepiride; Pioglitazone: (Major) Tolvaptan is metabolized by CYP3A4. Pioglitazone is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Grapefruit juice: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Grapefruit juice is an inhibitor CYP3A4 and P-gp. Coadministration of grapefruit juice and tolvaptan results in a 1.8-fold increase in tolvaptan exposure. Tolvaptan and grapefruit juice should be coadministered together cautiously. If tolvaptan and grapefruit juice are coadministered, a reduction in the dose of tolvaptan may be required.
    Griseofulvin: (Major) Tolvaptan is metabolized by CYP3A4. Griseofulvin is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Heparin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Hetastarch: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Monitor serum potassium closely if these drugs are used together. In clinical studies, tolvaptan was administered concomitantly with potassium-sparing diuretics. Hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics than when potassium-sparing diuretics were administered with placebo. (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Monitor serum potassium closely if these drugs are used together. In clinical studies, tolvaptan was administered concomitantly with potassium-sparing diuretics. Hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics than when potassium-sparing diuretics were administered with placebo. (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Ibritumomab Tiuxetan: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Ibrutinib: (Moderate) Use ibrutinib and tolvaptan together with caution; plasma concentrations of tolvaptan may increase resulting in increased toxicity. Coadministration may necessitate a decrease in tolvaptan dose. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; tolvaptan is a P-gp substrate and inhibitor.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with tolvaptan, a CYP3A substrate, as tolvaptan toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imatinib: (Major) Tolvaptan is metabolized by CYP3A4. Imatinib, STI-571 is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Indinavir: (Severe) Tolvaptan is metabolized by CYP3A4. Indinavir is a strong inhibitor of CYP3A4. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use of tolvaptan and indinavir is contraindicated.
    Irbesartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Isavuconazonium: (Major) The concomitant use of tolvaptan and moderate CYP3A4 inhibitors, such as isavuconazonium, should be avoided, and coadministration of tolvaptan and P-glycoprotein (P-gp) inhibitors, such as isavuconazonium, may necessitate a dose reduction of tolvaptan. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Coadministration of moderate CYP3A4 inhibitors with tolvaptan may cause a marked elevation in tolvaptan concentrations.
    Isoniazid, INH: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as isoniazid, INH, is contraindicated. Tolvaptan is metabolized by CYP3A4. Isoniazid, INH is a strong inhibitor of CYP3A4. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as isoniazid, INH, is contraindicated. Tolvaptan is metabolized by CYP3A4. Isoniazid, INH is a strong inhibitor of CYP3A4. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Isoniazid, INH; Rifampin: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as isoniazid, INH, is contraindicated. Tolvaptan is metabolized by CYP3A4. Isoniazid, INH is a strong inhibitor of CYP3A4. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Itraconazole: (Severe) Coadministration of tolvaptan and itraconazole is contraindicated; use of tolvaptan is not recommended for 2 weeks after itraconazole. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Itraconazole is a strong inhibitor of CYP3A4 and P-gp. Other strong CYP3A4 inhibitors, increased tolvaptan exposure 5-fold.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and tolvaptan concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as tolvaptan, can increase tolvaptan exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ketoconazole: (Severe) Concomitant use of tolvaptan and ketoconazole is contraindicated. Tolvaptan is metabolized by CYP3A4. Ketoconazole 200 mg, a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Lapatinib: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Lapatinib is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Ledipasvir; Sofosbuvir: (Major) Caution and close monitoring of adverse reactions is advised when administering tolvaptan with ledipasvir; sofosbuvir. Both ledipasvir and tolvaptan are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tolvaptan; monitor for potential reduction in efficacy. Tolvaptan is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tolvaptan; monitor for potential reduction in efficacy. Tolvaptan is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Levetiracetam: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Lisinopril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Lomitapide: (Moderate) Concomitant use of lomitapide and tolvaptan may result in increased serum concentrations of tolvaptan. According to the manufacturer of lomitapide, dose reduction of tolvaptan should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and tolvaptan is a P-gp substrate.
    Loop diuretics: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and loop diuretics increases the risk of too rapid correction of serum sodium.
    Loperamide: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with tolvaptan, a mild P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with tolvaptan, a mild P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as lopinavir; ritonavir, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Ritonavir is a strong inhibitor of CYP3A4 and P-gp, while lopinavir is a P-gp inhibitor. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as ritonavir, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Ritonavir is a strong inhibitor of CYP3A4 and P-gp. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Losartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may alter the exposure of tolvaptan; avoid concurrent use if possible. If concomitant use is necessary, monitor patient response and adjust the tolvaptan dosage accordingly. Tolvaptan is a CYP3A and P-glycoprotein (P-gp) substrate. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp. Although induction of tolvaptan metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Coadministration of tolvaptan with rifampin, another strong CYP3A inducer, reduced tolvaptan plasma concentrations by 85%. Additionally, ivacaftor is a CYP3A substrate and tolvaptan is a weak CYP3A inhibitor. Although ivacaftor exposure could theoretically be increased when given with a CYP3A inhibitor, ivacaftor; lumacaftor dosage adjustments are not recommended with concomitant use of a mild CYP3A inhibitor such as tolvaptan due to the induction effects of lumacaftor.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and tolvaptan concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as tolvaptan, can increase tolvaptan exposure leading to increased or prolonged therapeutic effects and adverse events.
    Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and tolvaptan as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); is an inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Mefloquine: (Major) Tolvaptan is a substrate for P-gp. Mefloquine is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan. If tolvaptan and mefloquine are coadministered, a reduction in the dose of tolvaptan may be required.
    Mestranol; Norethindrone: (Major) The concomitant use of mestranol; norethindrone and tolvaptan should be avoided. Tolvaptan is metabolized by CYP3A4. Ethinyl estradiol is a moderate inhibitor of CYP3A4. Mestranol is rapidly metabolized by demethylation to ethinyl estradiol, the biologically active form, upon absorption. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. The concomitant use of tolvaptan and strong CYP3A4 inhibitors is contraindicated, and concomitant use with moderate CYP3A4 inhibitors should be avoided.
    Metformin; Pioglitazone: (Major) Tolvaptan is metabolized by CYP3A4. Pioglitazone is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Methyclothiazide: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Metolazone: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Metyrapone: (Major) Tolvaptan is metabolized by CYP3A4. Metyrapone is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Mifepristone, RU-486: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Mifepristone, RU-486 is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Mitotane: (Major) Avoid the concomitant use of mitotane with tolvaptan; if coadministration cannot be avoided, monitor for decreased efficacy of tolvaptan and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and tolvaptan is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tolvaptan. Co-administration of tolvaptan with another strong CYP3A inducers (rifampin) reduce tolvaptan plasma concentrations by 85%.
    Modafinil: (Major) Tolvaptan is metabolized by CYP3A4. Modafinil is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Moexipril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Moxifloxacin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Nafcillin: (Major) Tolvaptan is metabolized by CYP3A4. Nafcillin is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Nebivolol; Valsartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Nefazodone: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as nefazodone, is contraindicated. Tolvaptan is metabolized by CYP3A4. Nefazodone is a strong inhibitor of CYP3A4. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Nelfinavir: (Severe) Coadministration of nelfinavir and tolvaptan is contraindicated due to the potential for increased exposure to tolvaptan. Nelfinavir is a strong CYP3A4 inhibitor. The exposure to tolvaptan, a CYP3A4 substrate, was increased by 5-fold in the presence of another strong CYP3A4 inhibitor.
    Neratinib: (Moderate) Monitor for an increase in tolvaptan-related adverse reactions if coadministration with neratinib is necessary; a dose reduction of tolvaptan may be necessary, based on clinical response. Tolvaptan is a P-glycoprotein (P-gp) substrate. Neratinib may inhibit the transport of P-gp substrates.
    Nevirapine: (Major) Tolvaptan is metabolized by CYP3A4. Nevirapine is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Nicardipine: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Nicardipine is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Nintedanib: (Moderate) Tolvaptan is a mild inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of tolvaptan and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Octreotide: (Major) Tolvaptan is metabolized by CYP3A4. Octreotide is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided. In addition, patients receiving diuretics or other agents to control fluid and electrolyte balance may require dosage adjustments while receiving octreotide.
    Olmesartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as ritonavir, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Ritonavir is a strong inhibitor of CYP3A4 and P-gp. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Ondansetron: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Oxcarbazepine: (Major) Tolvaptan is metabolized by CYP3A4. Oxcarbazepine is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Paliperidone: (Major) Tolvaptan is a substrate for P-gp. Paliperidone is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan; a reduction in the dose of tolvaptan may be required.
    Pantoprazole: (Major) Tolvaptan is metabolized by CYP3A4. Pantoprazole is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Perindopril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Perindopril; Amlodipine: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Phentermine; Topiramate: (Major) Tolvaptan is metabolized by CYP3A4. Topiramate is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Phenytoin: (Major) Tolvaptan is metabolized by CYP3A4. Phenytoin is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Pioglitazone: (Major) Tolvaptan is metabolized by CYP3A4. Pioglitazone is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Ponatinib: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and tolvaptan, a P-gp substrate, may increase the exposure of tolvaptan. If these agents are used together, the tolvaptan dosage may need to be reduced based on clinical response.
    Posaconazole: (Major) Posaconazole and tolvaptan should be coadministered with caution due to an increased potential for adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of tolvaptan. Further, both tolvaptan and posaconazole are inhibitors and substrates of the drug efflux protein, P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may cause alterations in the plasma concentrations of both posaconazole and tolvaptan, ultimately resulting in an increased risk of adverse events.
    Potassium Salts: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Potassium-sparing diuretics: (Moderate) Monitor serum potassium closely if these drugs are used together. In clinical studies, tolvaptan was administered concomitantly with potassium-sparing diuretics. Hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics than when potassium-sparing diuretics were administered with placebo.
    Propafenone: (Major) Tolvaptan is a substrate for P-gp. Propafenone is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan; a reduction in the dose of tolvaptan may be required.
    Quinapril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Quinidine: (Major) Tolvaptan is a substrate for P-gp. Quinidine is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan; a reduction in the dose of tolvaptan may be required.
    Quinine: (Major) Tolvaptan is metabolized by CYP3A4. Quinine is a moderate inhibitor and inducer of CYP3A4. Coadministration may cause a marked increase or decrease in tolvaptan concentrations and should be avoided. If coadministration is unavoidable, a change in the dose of tolvaptan may be necessary and patients should be monitored closely for side effects and changes in efficacy.
    Ramipril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Ranolazine: (Moderate) Administering tolvaptan with ranolazine may result in elevated tolvaptan plasma concentrations. Tolvaptan is a substrate of CYP3A4 and P-gp; ranolazine is an inhibitor of P-gp and is a weak inhibitor of CYP3A4. If these drugs are used together, closely monitor for signs of adverse events.
    Ribociclib: (Major) Avoid coadministration of ribociclib with tolvaptan, as the systemic exposure of tolvaptan may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and tolvaptan is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with tolvaptan, as the systemic exposure of tolvaptan may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and tolvaptan is a CYP3A4 substrate.
    Rifamycins: (Major) Tolvaptan is metabolized by CYP3A4. Rifabutin, rifampin, and rifapentine are inducers of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and tolvaptan, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ritonavir: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as ritonavir, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Ritonavir is a strong inhibitor of CYP3A4 and P-gp. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and tolvaptan may result in increases in rivaroxaban exposure and may increase bleeding risk. Tolvaptan is an inhibitor of P-gp (potency unknown), and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Sacubitril; Valsartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and tolvaptan as coadministration may result in increased systemic exposure of tolvaptan. Tolvaptan is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of tolvaptan.
    Saquinavir: (Severe) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Saquinavir is a strong inhibitor of CYP3A4 and P-gp. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use of tolvaptan and saquinavir is contraindicated.
    Simeprevir: (Major) Use caution with concurrent use of simeprevir and tolvaptan as increased plasma concentrations of both drugs may occur. Tolvaptan is a substrate of CYP3A4 and P-glycloprotein (P-gp) as well as an inhibitor of P-gp, while simeprevir is a mild intestinal CYP3A4 inhibitor and a substrate of P-gp in vitro. In general, the use of tolvaptan with CYP3A4 inhibitors should be avoided.
    Sodium Chloride: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with tolvaptan. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp).
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of tolvaptan, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently. (Moderate) Use caution when administering velpatasvir with tolvaptan. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp).
    Spironolactone: (Moderate) Monitor serum potassium closely if these drugs are used together. In clinical studies, tolvaptan was administered concomitantly with potassium-sparing diuretics. Hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics than when potassium-sparing diuretics were administered with placebo.
    St. John's Wort, Hypericum perforatum: (Major) Tolvaptan is metabolized by CYP3A4. St. John's wort is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Streptogramins: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as dalfopristin; quinupristin, is contraindicated. Tolvaptan is metabolized by CYP3A4. Dalfopristin; quinupristin is a strong inhibitor of CYP3A4. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Tamoxifen: (Major) Coadministration of tolvaptan and tamoxifen may result in increased exposure to tolvaptan; reduce the tolvaptan dose if necessary. Tolvaptan is a substrate for P-gp. Tamoxifen is a P-gp inhibitor.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering tolvaptan with telaprevir due to an increased potential for tolvaptan-related adverse events. If tolvaptan dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of tolvaptan. Tolvaptan is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; telaprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated tolvaptan plasma concentrations.
    Telithromycin: (Severe) The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as telithromycin, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Telithromycin is a strong inhibitor of CYP3A4 and P-gp. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
    Telmisartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Telotristat Ethyl: (Moderate) Avoid coadministration of telotristat ethyl and tolvaptan if possible, as the systemic exposure of tolvaptan may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of tolvaptan as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of tolvaptan if necessary. Tolvaptan is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Coadministration of tolvaptan with a strong CYP3A4 inducer reduces exposure to tolvaptan by 85%. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and tolvaptan is a weak P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with tolvaptan is necessary, and monitor for an increase in temsirolimus- and tolvaptan-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) substrate/inhibitor in vitro. Tolvaptan is also a P-gp substrate/inhibitor; the potency of P-gp inhibition is unknown. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp inhibitors or substrates, but exposure to both tolvaptan and temsirolimus (and active metabolite, sirolimus) is likely to increase.
    Tenofovir Alafenamide: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with tolvaptan, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as tolvaptan, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tolvaptan. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Testosterone: (Major) Tolvaptan is a substrate for P-gp. Testosterone is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan; a reduction in the dose of tolvaptan may be required.
    Thiazide diuretics: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and thiazide diuretics increases the risk of too rapid correction of serum sodium.
    Ticagrelor: (Minor) Coadministration of ticagrelor and tolvaptan may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and tolvaptan is a P-gp inhibitor (potency unknown). Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Tipranavir: (Severe) Tolvaptan is metabolized by CYP3A4. Tipranavir is a strong inhibitor of CYP3A4. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use of tolvaptan and tipranavir is contraindicated.
    Tobramycin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Topiramate: (Major) Tolvaptan is metabolized by CYP3A4. Topiramate is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Topotecan: (Major) Avoid the concomitant use of tolvaptan, a weak P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of tolvaptan and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Torsemide: (Moderate) Monitor serum sodium closely if these drugs are used together. Coadministration of tolvaptan and loop diuretics increases the risk of too rapid correction of serum sodium.
    Trandolapril: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Trandolapril; Verapamil: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Verapamil is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increase in tolvaptan concentrations and should be avoided. (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Hyperkalemia was reported at a rate 1 to 2% higher when tolvaptan was administered with angiotensin converting enzyme inhibitors than when angiotensin converting enzyme inhibitors were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin-converting enzyme inhibitors (ACE inhibitors).
    Triamterene: (Moderate) Monitor serum potassium closely if these drugs are used together. In clinical studies, tolvaptan was administered concomitantly with potassium-sparing diuretics. Hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics than when potassium-sparing diuretics were administered with placebo.
    Ulipristal: (Minor) In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as tolvaptan may increase tolvaptan concentrations. With single doses of ulipristal for emergency contraception it is not clear this interaction will have clinical consequence. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Valsartan: (Moderate) Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, tolvaptan was administered concomitantly with angiotensin II receptor antagonists. Hyperkalemia was reported at a rate 12% higher when tolvaptan was administered with angiotensin receptor blockers than when angiotensin receptor blockers were administered with placebo. Serum potassium concentrations should be monitored closely after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists.
    Vancomycin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with tolvaptan is necessary, due to a possible increase in tolvaptan-related adverse reactions; the dose of tolvaptan may need to be reduced. Tolvaptan is a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and tolvaptan may result in altered concentrations of tolvaptan and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Tolvaptan is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and tolvaptan. Venetoclax is a substrate of P-glycoprotein (P-gp) and may be a P-gp inhibitor at therapeutic dose levels in the gut; tolvaptan is a substrate and an inhibitor of P-gp. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering tolvaptan at least 6 hours before venetoclax. If tolvaptan is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Verapamil: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Verapamil is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increase in tolvaptan concentrations and should be avoided.
    Voriconazole: (Major) Tolvaptan is metabolized by CYP3A4. Voriconazole is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Zafirlukast: (Major) Tolvaptan is metabolized by CYP3A4. Zafirlukast is a moderate inhibitor of CYP3A4. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and tolvaptan is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Tolvaptan is classified as FDA pregnancy risk category C. It is not known whether tolvaptan can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Tolvaptan has been shown to have adverse effects on the fetus when given to pregnant animals (e.g., cleft palate, brachymelia, microphthyalmia, skeletal malformations, decreased fetal weight, delayed fetal ossification, and embryo-fetal death). The effect of tolvaptan use on labor and obstetric delivery in humans has not been studied. Tolvaptan should be used during pregnancy only if the potential benefit justifies any possible risk to the fetus.

    It is unknown if tolvaptan is excreted into human breast milk. It is excreted into the milk of lactating rats. According to the manufacturer, because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or tolvaptan, taking into consideration the importance of the drug to the mother. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Tolvaptan is an orally active, nonpeptide, selective vasopressin V2 antagonist indicated for the treatment of euvolemic and hypervolemic hyponatremia. Euvolemic states associated with hyponatremia may occur in patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) , hypothyroidism, adrenal insufficiency, and certain pulmonary disorders. Hypervolemic states associated with hyponatremia include patients with heart failure, cirrhosis, and nephrotic syndrome. Arginine vasopressin (AVP), otherwise known as antidiuretic hormone, plays a critical role in regulating water and electrolyte balance. The levels of AVP are usually elevated in both euvolemic and hypervolemic hyponatremia. Excessive vasopressin results in impairment of free water excretion and contributes to the development of hyponatremia. The actions of AVP are mediated by 3 types of vasopressin receptor subtypes: V1A, V1B, and V2 receptors. Vasopressin receptors are found on the vascular smooth muscle cells, the myocardium and the distal tubule of the kidney. Tolvaptan selectively binds to the V2 receptors of the distal nephron with an affinity that is 1.8 times that of AVP. The V2 receptors are functionally coupled to aquaporin channels in the apical membrane of the renal collecting ducts. These receptors help to maintain plasma osmolality within the normal range. Pharmacodynamic effects of vasopressin antagonism by tolvaptan include an increase in free water excretion ('aquaresis'), an increase in serum sodium concentrations, a decrease in urine osmolality, and an increase in urine output.

    PHARMACOKINETICS

    Tolvaptan is administered orally.  A peak increase in serum sodium and urine excretion of approximately 6 mEq and 9 ml/min, respectively, is observed between 4 and 8 hours after administration. At 24 hours post-dose, approximately 60% of the peak serum sodium effect is sustained although the urinary excretion rate is no longer elevated. Doses above 60 mg do not further increase aquaresis or serum sodium. In vitro data indicate tolvaptan is a substrate and inhibitor of P-glycoprotein (P-gp) and is metabolized exclusively by CYP3A4. Tolvaptan is extensively protein bound (99%). In healthy subjects, the clearance of tolvaptan is 4 ml/min/kg; in patients with hyponatremia, clearance is reduced to 2 ml/min/kg. The terminal phase half-life is approximately 12 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  P-gp, CYP3A4
    Tolvaptan is a substrate and inhibitor of P-glycoprotein (P-gp) and is metabolized exclusively by CYP3A4.

    Oral Route

    Generally, the area under the curve (AUC) of tolvaptan increases proportionally with dose; however, after administration of doses >= 60 mg, Cmax increases less than proportionally with dose. Approximately 40% of the dose is absorbed as tolvaptan or its metabolites; food does not affect the bioavailability. Peak serum concentrations and onset of action (aquaresis and increasing serum sodium) are seen within 2—4 hours after oral administration.