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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 for hyponatremia, 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 reinitiation of tolvaptan for hyponatremia 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 selective vasopressin V2-receptor antagonist
    Used for treatment of hypervolemic and euvolemic hyponatremia, including in patients with heart failure and SIADH (Samsca) and to slow kidney function decline in patients with rapidly progressing autosomal dominant polycystic kidney disease (Jynarque)
    Associated with serious and potentially fatal liver injury

    COMMON BRAND NAMES

    JYNARQUE, Samsca

    HOW SUPPLIED

    JYNARQUE/Samsca Oral Tab: 15mg, 30mg, 15-45mg, 30-60mg, 30-90mg

    DOSAGE & INDICATIONS

    For the treatment of clinically significant hypervolemic and euvolemic hyponatremia (i.e., serum sodium less than 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).

    For the treatment of autosomal dominant polycystic kidney disease (ADPKD) to slow kidney function decline in patients at risk of developing rapidly progressing ADPKD.
    Oral dosage (Jynarque)
    Adults

    60 mg/day PO administered as 45 mg PO upon waking and 15 mg 8 hours later. If tolerated, titrate after at least a week to a total daily dose of 90 mg PO (60 mg PO upon waking and 30 mg PO 8 hours later) and then to a target daily dose of 120 mg PO (90 mg PO upon waking and 30 mg PO 8 hours later). Based on tolerability, down-titration may be needed. Encourage patients to drink enough water to avoid thirst or dehydration. Monitor AST, ALT, and bilirubin at baseline, at 2 and 4 weeks after initiation, monthly for 18 months, and every 3 months thereafter.

    MAXIMUM DOSAGE

    Adults

    60 mg/day PO for up to 30 days for hyponatremia (Samsca); 120 mg/day PO for autosomal dominant polycystic kidney disease (Jynarque).

    Geriatric

    60 mg/day PO for up to 30 days for hyponatremia (Samsca); 120 mg/day PO for autosomal dominant polycystic kidney disease (Jynarque).

    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

    Samsca: Avoid in patients with underlying hepatic disease.
    Jynarque: At the onset of signs or symptoms consistent with hepatic injury OR if ALT, AST, or bilirubin increase to more than 2 times upper limit of normal (ULN), immediately discontinue therapy and obtain repeat tests within 48 to 72 hours; continue testing, if appropriate. If laboratory abnormalities stabilize or resolve, reinitiate therapy with increased frequency of monitoring as long as ALT and AST remain below 3 times ULN. Do not restart therapy in patients who experience signs or symptoms of hepatic injury or whose ALT and AST ever exceed 3 times ULN during treatment, unless there is another explanation for liver injury and that injury has resolved. In patients with stable, low baseline ALT and AST, an increase above 2 times baseline, even if less than 2 times ULN, may indicate early liver injury. Suspension of treatment may be warranted; obtain repeat tests within 48 to 72 hours prior to reinitiating therapy and monitor more frequently.

    Renal Impairment

    CrCl 10 to 79 mL/minute: No dosage adjustment needed.
    CrCl less than 10 mL/minute 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.

    Oral Administration

    May administer with or without food.
     
    Samsca (for hyponatremia)
    Only initiate and reinitiate treatment in a hospital where serum sodium concentrations and volume status can be closely monitored.
    Avoid fluid restriction during the first 24 hours of therapy. Advise patients to drink fluid in response to thirst.
    Monitor for neurologic changes associated with rapid correction of serum sodium concentrations (more than 12 mEq/L over 24 hours).
    Limit duration to 30 days due to the risk of hepatic injury.
     
    Jynarque (for autosomal dominant polycystic kidney disease)
    Encourage patients to drink enough water to avoid thirst and dehydration.

    STORAGE

    JYNARQUE:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Samsca:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    In patients being treated for low sodium concentrations, 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 of tolvaptan and hypertonic saline is not recommended.

    Dehydration, hypernatremia, hyponatremia, hypovolemia

    Jynarque is contraindicated in patients with uncorrected hyponatremia or hypernatremia (i.e., abnormal blood sodium concentrations). Tolvaptan is contraindicated in patients with hypovolemia (including hypovolemic hyponatremia). The risks of developing hypotension and renal failure from worsening hypovolemia outweigh the possible benefits of therapy with tolvaptan. Dehydration or hypovolemia may occur during the course of tolvaptan therapy, particularly in patients who are fluid-restricted or those who are volume-depleted and receiving diuretics. Fluid restriction should be avoided during the first 24 hours of hyponatremia treatment. Tolvaptan is contraindicated in patients unable to sense or respond to thirst; such patients are at increased risk of incurring an overly rapid correction of serum sodium, hypernatremia, and hypovolemia. Encourage patients to drink enough water to avoid thirst and dehydration. Monitor for weight loss, tachycardia, and hypotension. If clinically significant dehydration or hypovolemia occurs, discontinue or interrupt tolvaptan therapy and provide supportive care with careful management of vital signs and fluid and electrolyte balance.

    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 for hyponatremia, 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 reinitiation of tolvaptan for hyponatremia 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.

    Autosomal dominant polycystic kidney disease, hepatic disease, hepatotoxicity

    Samsca is contraindicated for use for the treatment of autosomal dominant polycystic kidney disease (ADPKD); only Jynarque should be prescribed for ADPKD. Tolvaptan can cause serious and potentially fatal liver injury. Jynarque is contraindicated for use in patients with a history of hepatic disease or in patients with signs or symptoms of significant liver impairment (hepatotoxicity), not including uncomplicated polycystic liver disease. Samsca should be avoided in patients with underlying hepatic disease. Acute liver failure requiring liver transplantation has been reported with the postmarketing use of tolvaptan for ADPKD. Discontinuing therapy in response to laboratory abnormalities or signs or symptoms of liver injury can reduce the risk of severe hepatotoxicity. Measure transaminases and bilirubin before ADPKD treatment, at 2 weeks and 4 weeks after initiation, monthly for the first 18 months, and then every 3 months thereafter. In patients receiving tolvaptan for hyponatremia, 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.

    Anuria, urinary tract obstruction

    Tolvaptan is contraindicated in patients with anuria since no clinical benefit is expected in patients unable to make urine. In patients with autosomal dominant polycystic kidney disease (ADPKD), tolvaptan is contraindicated in patients with uncorrected urinary outflow obstruction (urinary tract obstruction).

    Hyperkalemia

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

    Geriatric

    Reported clinical experience has not identified differences in safety or efficacy between geriatric patients and the general study population; however, greater sensitivity of some elderly persons to tolvaptan therapy cannot be ruled out. In general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range.

    Pregnancy

    There are insufficient data on the use of tolvaptan in pregnant women to determine if there is a drug associated risk of adverse developmental outcomes during pregnancy. Tolvaptan has been shown to have adverse effects on the fetus when given to pregnant animals at maternally toxic doses. At 17-times the human exposure, reduced fetal weights and delayed fetal ossification in rats were observed. In rabbits, increased abortions, embryo-fetal death, cleft palate, open eyelids, brachymelia, microphthalmia, and skeletal malformations were observed at 3-times the human exposure. Advise pregnant women of the potential risk to the fetus.

    Breast-feeding

    There are no data on the presence of tolvaptan in human milk, the effects on the breast-feeding infant, or the effects on milk production. Due to the potential for serious adverse reactions, including liver toxicity, electrolyte abnormalities, hypotension, and volume depletion in breast-fed infants, breast-feeding is not advised during treatment with tolvaptan.

    ADVERSE REACTIONS

    Severe

    diabetic ketoacidosis / Delayed / 0-2.0
    thrombosis / Delayed / 0-2.0
    disseminated intravascular coagulation (DIC) / Delayed / 0-2.0
    stroke / Early / 0-2.0
    rhabdomyolysis / Delayed / 0-2.0
    pulmonary embolism / 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
    hepatotoxicity / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 7.0-7.0
    hyperglycemia / Delayed / 6.0-6.0
    elevated hepatic enzymes / Delayed / 0-4.9
    hypernatremia / Delayed / 0.7-4.0
    hyperuricemia / Delayed / 3.9-3.9
    palpitations / Early / 3.5-3.5
    dehydration / Delayed / 2.1-3.3
    hypovolemia / Early / 2.1-2.3
    colitis / Delayed / 0-2.0
    vaginal bleeding / Delayed / 0-2.0
    bleeding / Early / 0-2.0
    prolonged bleeding time / Delayed / 0-2.0
    respiratory depression / Rapid / 0-2.0
    hyperbilirubinemia / Delayed / Incidence not known

    Mild

    polyuria / Early / 4.0-69.5
    polydipsia / Early / 12.0-63.7
    xerostomia / Early / 13.0-16.0
    fatigue / Early / 13.6-13.6
    diarrhea / Early / 13.3-13.3
    dizziness / Early / 11.3-11.3
    asthenia / Delayed / 9.0-9.0
    dyspepsia / Early / 7.9-7.9
    anorexia / Delayed / 4.0-7.2
    rash / Early / 4.2-4.2
    fever / Early / 4.0-4.0
    nausea / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of dolutegravir due to the potential for increased dolutegravir exposure. Tolvaptan is a BCRP inhibitor; dolutegravir is a BCRP substrate.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Aliskiren; Valsartan: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of valsartan due to the potential for increased valsartan exposure. If use concurrently in patients with hyponatremia, monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; valsartan is an OATP1B1/3 substrate.
    Amiloride: (Moderate) Monitor serum potassium closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, 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 tolvaptan and potassium-sparing diuretics are used together. In clinical studies, 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 tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Amiodarone: (Major) Avoid coadministration of amiodarone when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with amiodarone. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Amlodipine; Atorvastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of atorvastatin due to increased atorvastatin exposure and potential for myopathy, including rhabdomyolysis. Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    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 potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of valsartan due to the potential for increased valsartan exposure. If use concurrently in patients with hyponatremia, monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; valsartan is an OATP1B1/3 substrate. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Amlodipine; Olmesartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo.
    Amlodipine; Telmisartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo.
    Amlodipine; Valsartan: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of valsartan due to the potential for increased valsartan exposure. If use concurrently in patients with hyponatremia, monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; valsartan is an OATP1B1/3 substrate.
    Amoxicillin; Clarithromycin; Lansoprazole: (Severe) The concomitant use of tolvaptan and clarithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Amoxicillin; Clarithromycin; Omeprazole: (Severe) The concomitant use of tolvaptan and clarithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    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-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).
    Apalutamide: (Major) Avoid coadministration of tolvaptan with apalutamide due to decreased plasma concentrations of tolvaptan. If concomitant use of apalutamide is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of multi-day regimens of oral aprepitant when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with multi-day regimens of oral aprepitant. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of aprepitant. Tolvaptan is a sensitive CYP3A4 substrate; aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    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).
    Aspirin, ASA; Pravastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of pravastatin due to increased pravastatin exposure and potential for myopathy, including rhabdomyolysis. Pravastatin is a substrate of the OATP1B1/3 and OAT3 transporters. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1/B3 and OAT3.
    Atazanavir: (Severe) The concomitant use of tolvaptan and atazanavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; atazanavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Atazanavir; Cobicistat: (Severe) The concomitant use of tolvaptan and atazanavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; atazanavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. (Severe) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Atenolol; Chlorthalidone: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Atorvastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of atorvastatin due to increased atorvastatin exposure and potential for myopathy, including rhabdomyolysis. Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Atorvastatin; Ezetimibe: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of atorvastatin due to increased atorvastatin exposure and potential for myopathy, including rhabdomyolysis. Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of tolvaptan with phenobarbital due to decreased plasma concentrations of tolvaptan. If concomitant use of phenobarbital is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    Azilsartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo.
    Azilsartan; Chlorthalidone: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of tolvaptan with phenobarbital due to decreased plasma concentrations of tolvaptan. If concomitant use of phenobarbital is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    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 tolvaptan and thiazide diuretics are used together. Coadministration 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 tolvaptan and thiazide diuretics are used together. Coadministration 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 tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Bivalirudin: (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).
    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) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of bosentan due to the potential for increased bosentan exposure. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; bosentan is an OATP1B1/3 substrate.
    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 tolvaptan and bumetanide are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Cabozantinib: (Minor) Monitor for an increase in tolvaptan-related adverse reactions if coadministration with cabozantinib is necessary; a dose reduction of tolvaptan may be needed. Tolvaptan is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Candesartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    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 tolvaptan and thiazide diuretics are used together. Coadministration 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) Avoid coadministration of tolvaptan with carbamazepine due to decreased plasma concentrations of tolvaptan. If concomitant use of carbamazepine is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    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: (Severe) The concomitant use of tolvaptan and chloramphenicol is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; chloramphenicol is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Chlorothiazide: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Chlorthalidone: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Chlorthalidone; Clonidine: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration 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).
    Ciprofloxacin: (Major) Avoid coadministration of ciprofloxacin when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with ciprofloxacin. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of ciprofloxacin. Tolvaptan is a sensitive CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Clarithromycin: (Severe) The concomitant use of tolvaptan and clarithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    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: (Severe) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Severe) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of tenofovir disoproxil fumarate due to the potential for increased tenofovir exposure. Tolvaptan is a BCRP inhibitor; tenofovir disoproxil fumarate is a BCRP substrate.
    Conivaptan: (Severe) Both tolvaptan and conivaptan are vasopressin antagonists. Coadministration represents therapeutic duplication and could cause deleterious effects. Additionally, because conivaptan is a strong CYP3A4 inhibitor and tolvaptan is a sensitive CYP3A4 substrate, concomitant use is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Crizotinib: (Major) Avoid coadministration of crizotinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with crizotinib. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Cyclosporine: (Major) Avoid coadministration of cyclosporine when tolvaptan is administered for hyponatremia; a reduction in the tolvaptan dose according to clinical response may be required if coadministration cannot be avoided. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with cyclosporine. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate; cyclosporine is a moderate CYP3A4 inhibitor and a P-gp inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    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 65%.
    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) Avoid coadministration of danazol when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with danazol. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Darunavir: (Severe) The concomitant use of tolvaptan and darunavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Darunavir; Cobicistat: (Severe) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. (Severe) The concomitant use of tolvaptan and darunavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Severe) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. (Severe) The concomitant use of tolvaptan and darunavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) The concomitant use of tolvaptan and ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Delavirdine: (Severe) The concomitant use of tolvaptan and delavirdine is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; delavirdine is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    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) Avoid coadministration of diltiazem when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with diltiazem. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Docetaxel: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of docetaxel due to the potential for increased docetaxel exposure. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; docetaxel is an OATP1B1/3 substrate.
    Dolutegravir: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of dolutegravir due to the potential for increased dolutegravir exposure. Tolvaptan is a BCRP inhibitor; dolutegravir is a BCRP substrate.
    Dolutegravir; Rilpivirine: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of dolutegravir due to the potential for increased dolutegravir exposure. Tolvaptan is a BCRP inhibitor; dolutegravir is a BCRP substrate.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of tenofovir disoproxil fumarate due to the potential for increased tenofovir exposure. Tolvaptan is a BCRP inhibitor; tenofovir disoproxil fumarate is a BCRP substrate.
    Dronedarone: (Major) Avoid coadministration of dronedarone when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with dronedarone. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    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.
    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) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of tenofovir disoproxil fumarate due to the potential for increased tenofovir exposure. Tolvaptan is a BCRP inhibitor; tenofovir disoproxil fumarate is a BCRP substrate. (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; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of tenofovir disoproxil fumarate due to the potential for increased tenofovir exposure. Tolvaptan is a BCRP inhibitor; tenofovir disoproxil fumarate is a BCRP substrate. (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.
    Elbasvir; Grazoprevir: (Severe) Concurrent administration of grazoprevir with tolvaptan is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; the oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1/3.
    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.
    Eluxadoline: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of eluxadoline due to the potential for increased eluxadoline exposure. If administered concurrently, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); the oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1. Coadministration with another inhibitor of OATP1B1 increased the exposure to eluxadoline by 4.4-fold.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of tenofovir disoproxil fumarate due to the potential for increased tenofovir exposure. Tolvaptan is a BCRP inhibitor; tenofovir disoproxil fumarate is a BCRP substrate.
    Emtricitabine; Tenofovir disoproxil fumarate: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of tenofovir disoproxil fumarate due to the potential for increased tenofovir exposure. Tolvaptan is a BCRP inhibitor; tenofovir disoproxil fumarate is a BCRP substrate.
    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 tolvaptan and thiazide diuretics are used together. Coadministration 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).
    Encorafenib: (Moderate) Coadministration of encorafenib with tolvaptan may result in increased toxicity or decreased efficacy of tolvaptan. Tolvaptan is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Enzalutamide: (Major) Avoid coadministration of tolvaptan with enzalutamide due to decreased plasma concentrations of tolvaptan. If concomitant use of enzalutamide is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    Eprosartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Erythromycin: (Major) Avoid coadministration of erythromycin when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with erythromycin. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of erythromycin. Tolvaptan is a sensitive CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of erythromycin when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with erythromycin. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of erythromycin. Tolvaptan is a sensitive CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    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 ethacrynic acid and tolvaptan are used together. Coadministration 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; Ferrous bisglycinate: (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.
    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.
    Ezetimibe; Simvastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of simvastatin due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin acid is a substrate of the transport protein OATP1B1. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Fluconazole: (Major) Avoid coadministration of fluconazole when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with fluconazole. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of fluconazole. Tolvaptan is a sensitive CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration of fluconazole increased the tolvaptan AUC by 200%. (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.
    Fluvastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of fluvastatin due to increased fluvastatin exposure and potential for myopathy, including rhabdomyolysis. Fluvastatin is a substrate of the OATP1B1 transporter. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Fluvoxamine: (Major) Avoid coadministration of fluvoxamine when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with fluvoxamine. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Fosamprenavir: (Severe) The concomitant use of tolvaptan and fosamprenavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a P-glycoprotein (P-gp) substrate and sensitive CYP3A4 substrate; fosamprenavir is a strong inhibitor of CYP3A4. Some data suggest that amprenavir, the active metabolite of fosamprenavir, can induce CYP3A4 and P-gp, therefore, the interaction with tolvaptan may be unpredictable. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    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 tolvaptan and thiazide diuretics are used together. Coadministration 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) Avoid coadministration of tolvaptan with fosphenytoin due to decreased plasma concentrations of tolvaptan. If concomitant use of fosphenytoin is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and phenytoin, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    Furosemide: (Major) Monitor serum sodium closely if tolvaptan and furosemide are used together. Coadministration increases the risk of too rapid correction of serum sodium. Although tolvaptan did not meaningfully alter the pharmacokinetics of furosemide in drug interaction studies, FDA-approved labeling suggests avoiding coadministration of furosemide, an OAT3 substrate, in patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), because the oxobutyric acid metabolite of tolvaptan is an OAT3 inhibitor.
    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: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of glecaprevir due to the potential for increased glecaprevir exposure. Additionally, a reduction in tolvaptan dosage for hyponatremia treatment may be necessary if coadministered due to the potential for increased tolvaptan plasma concentrations. Tolvaptan is a BCRP inhibitor and P-gp substrate, and the oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; glecaprevir is a P-gp inhibitor and BCRP and OATP1B1/3 substrates. (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of pibrentasvir due to the potential for increased pibrentasvir exposure. Additionally, a reduction in tolvaptan dosage for hyponatremia treatment may be necessary if coadministered due to the potential for increased tolvaptan plasma concentrations. Tolvaptan is a P-gp substrate and BCRP inhibitor; pibrentasvir is a P-gp inhibitor and BCRP substrate.
    Glyburide: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of glyburide due to the potential for increased glyburide exposure. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; glyburide is an OATP1B1/3 substrate.
    Glyburide; Metformin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of glyburide due to the potential for increased glyburide exposure. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; glyburide is an OATP1B1/3 substrate.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit juice while taking tolvaptan. Coadministration of grapefruit juice and tolvaptan has increased tolvaptan exposure by up to 1.8-fold.
    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 tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration 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 potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration 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 potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration 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 tolvaptan and potassium-sparing diuretics are used together. In clinical studies, 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 tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Monitor serum potassium closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, 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 tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Valsartan: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of valsartan due to the potential for increased valsartan exposure. If use concurrently in patients with hyponatremia, monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; valsartan is an OATP1B1/3 substrate. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    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.
    Idelalisib: (Severe) The concomitant use of tolvaptan and idelalisib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; idelalisib is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Imatinib: (Major) Avoid coadministration of imatinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with imatinib. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Indinavir: (Severe) The concomitant use of tolvaptan and indinavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; indinavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Irbesartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo.
    Isavuconazonium: (Major) Avoid coadministration of isavuconazonium when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with isavuconazonium. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of isavuconazonium. Tolvaptan is a sensitive CYP3A4 substrate; isavuconazole, the active moiety of isavuconazonium, is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Isoniazid, INH: (Major) Avoid coadministration of isoniazid when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with isoniazid. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; isoniazid is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of isoniazid when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with isoniazid. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; isoniazid is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%. (Major) Avoid coadministration of tolvaptan with rifampin due to decreased plasma concentrations of tolvaptan. If concomitant use of rifampin is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and rifampin is a strong CYP3A4 inducer. In a drug interaction study, coadministration decreased tolvaptan exposure by 85%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of isoniazid when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with isoniazid. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; isoniazid is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%. (Major) Avoid coadministration of tolvaptan with rifampin due to decreased plasma concentrations of tolvaptan. If concomitant use of rifampin is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and rifampin is a strong CYP3A4 inducer. In a drug interaction study, coadministration decreased tolvaptan exposure by 85%.
    Itraconazole: (Severe) Tolvaptan is contraindicated for use during and for 2 weeks after itraconazole therapy due to increased exposure to tolvaptan. Tolvaptan is a P-glycoprotein (P-gp) substrate and sensitive CYP3A4 substrate; itraconazole is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    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.
    Ivosidenib: (Moderate) Monitor for loss of efficacy of tolvaptan during coadministration of ivosidenib; a tolvaptan dose adjustment may be necessary. Tolvaptan is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased tolvaptan concentrations.
    Ketoconazole: (Severe) The concomitant use of tolvaptan and ketoconazole is contraindicated due to increased tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ketoconazole is a strong inhibitor of CYP3A4. In a drug interaction study, coadministration of ketoconazole 200 mg 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.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of tenofovir disoproxil fumarate due to the potential for increased tenofovir exposure. Tolvaptan is a BCRP inhibitor; tenofovir disoproxil fumarate is a BCRP substrate.
    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) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of ledipasvir due to the potential for increased ledipasvir exposure. Additionally, a reduction in tolvaptan dosage for hyponatremia treatment may be necessary if coadministered due to the potential for increased tolvaptan plasma concentrations. Tolvaptan is a P-gp substrate and BCRP inhibitor; ledipasvir is a P-gp inhibitor and BCRP substrate.
    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.
    Letermovir: (Major) Concurrent use is contraindicated if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. Otherwise, avoid coadministration of letermovir when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with letermovir. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    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.
    Lopinavir; Ritonavir: (Severe) The concomitant use of tolvaptan and lopinavir; ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. (Severe) The concomitant use of tolvaptan and ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Losartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo.
    Lovastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of lovastatin due to increased lovastatin exposure and potential for myopathy, including rhabdomyolysis. Lovastatin is a substrate of the OATP1B1 transporter. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Lovastatin; Niacin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of lovastatin due to increased lovastatin exposure and potential for myopathy, including rhabdomyolysis. Lovastatin is a substrate of the OATP1B1 transporter. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of tolvaptan with lumacaftor; ivacaftor due to decreased plasma concentrations of tolvaptan. If concomitant use of lumacaftor; ivacaftor is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    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.
    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; Repaglinide: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of repaglinide due to the potential for increased repaglinide exposure. The oxobutyric acid metabolite of tolvaptan is an OATP1B1 inhibitor; repaglinide is an OATP1B1 substrate.
    Methotrexate: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of methotrexate due to the potential for increased methotrexate exposure. The oxobutyric acid metabolite of tolvaptan is an OAT3 inhibitor and tolvaptan is a BCRP inhibitor; methotrexate is a substrate of both OAT3 and BCRP.
    Methyclothiazide: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Metolazone: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Mifepristone: (Severe) The concomitant use of tolvaptan and chronic mifepristone therapy is contraindicated. Concurrent use is expected to increase tolvaptan exposure. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Tolvaptan is a sensitive CYP3A4 substrate; mifepristone is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Mitotane: (Major) Avoid coadministration of tolvaptan with mitotane due to decreased plasma concentrations of tolvaptan. If concomitant use of mitotane is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure 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.
    Nateglinide: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of nateglinide due to the potential for increased nateglinide exposure. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; nateglinide is an OATP1B1/3 substrate.
    Nebivolol; Valsartan: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of valsartan due to the potential for increased valsartan exposure. If use concurrently in patients with hyponatremia, monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; valsartan is an OATP1B1/3 substrate.
    Nefazodone: (Severe) The concomitant use of tolvaptan and nefazodone is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; nefazodone is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Nelfinavir: (Severe) The concomitant use of tolvaptan and nelfinavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; nelfinavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    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.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of netupitant when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with netupitant. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of netupitant. Tolvaptan is a sensitive CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    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.
    Niacin; Simvastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of simvastatin due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin acid is a substrate of the transport protein OATP1B1. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Nicardipine: (Moderate) Coadministration of tolvaptan and nicardipine may result in increased exposure to tolvaptan. Monitor for increased tolvaptan-related adverse effects. Tolvaptan is a sensitive CYP3A4 substrate; nicardipine is a CYP3A4 inhibitor.
    Nilotinib: (Major) Avoid coadministration of nilotinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with nilotinib. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Olmesartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) The concomitant use of tolvaptan and ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    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).
    Osimertinib: (Moderate) Coadministration of tolvaptan and osimertinib 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; osimertinib is a P-gp inhibitor.
    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.
    Paclitaxel: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of paclitaxel due to the potential for increased paclitaxel exposure. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; paclitaxel is an OATP1B1/3 substrate.
    Pazopanib: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of pazopanib due to the potential for increased pazopanib exposure. Tolvaptan is a BCRP inhibitor; pazopanib is a BCRP substrate.
    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).
    Phenobarbital: (Major) Avoid coadministration of tolvaptan with phenobarbital due to decreased plasma concentrations of tolvaptan. If concomitant use of phenobarbital is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    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) Avoid coadministration of tolvaptan with phenytoin due to decreased plasma concentrations of tolvaptan. If concomitant use of phenytoin is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    Pitavastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of pitavastatin due to increased pitavastatin exposure and potential for myopathy, including rhabdomyolysis. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; pitavastatin is an OATP1B1/3 substrate.
    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: (Severe) The concomitant use of tolvaptan and posaconazole is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; posaconazole is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Potassium 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).
    Potassium-sparing diuretics: (Moderate) Monitor serum potassium closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, 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.
    Pravastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of pravastatin due to increased pravastatin exposure and potential for myopathy, including rhabdomyolysis. Pravastatin is a substrate of the OATP1B1/3 and OAT3 transporters. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1/B3 and OAT3.
    Primidone: (Major) Avoid coadministration of tolvaptan with primidone due to decreased plasma concentrations of tolvaptan. If concomitant use of primidone is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    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) Avoid coadministration of quinine when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with quinine. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of quinine. Tolvaptan is a sensitive CYP3A4 substrate; quinine is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    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.
    Repaglinide: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of repaglinide due to the potential for increased repaglinide exposure. The oxobutyric acid metabolite of tolvaptan is an OATP1B1 inhibitor; repaglinide is an OATP1B1 substrate.
    Ribociclib: (Severe) The concomitant use of tolvaptan and ribociclib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ribociclib is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Ribociclib; Letrozole: (Severe) The concomitant use of tolvaptan and ribociclib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ribociclib is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Rifabutin: (Major) Avoid coadministration of tolvaptan with rifabutin due to decreased plasma concentrations of tolvaptan. If concomitant use of rifabutin is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and rifabutin is a CYP3A4 inducer. In a drug interaction study, coadministration with rifampin decreased tolvaptan exposure by 85%.
    Rifampin: (Major) Avoid coadministration of tolvaptan with rifampin due to decreased plasma concentrations of tolvaptan. If concomitant use of rifampin is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and rifampin is a strong CYP3A4 inducer. In a drug interaction study, coadministration decreased tolvaptan exposure by 85%.
    Rifapentine: (Major) Avoid coadministration of tolvaptan with rifapentine due to decreased plasma concentrations of tolvaptan. If concomitant use of rifapentine is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and rifapentine is a CYP3A4 inducer. In a drug interaction study, coadministration with rifampin decreased tolvaptan exposure by 85%.
    Ritonavir: (Severe) The concomitant use of tolvaptan and ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Rosuvastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of rosuvastatin due to increased rosuvastatin exposure and potential for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the BCRP and OATP1B1 transporters. Tolvaptan is a BCRP inhibitor and the oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Sacubitril; Valsartan: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of valsartan due to the potential for increased valsartan exposure. If use concurrently in patients with hyponatremia, monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; valsartan is an OATP1B1/3 substrate.
    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) The concomitant use of tolvaptan and saquinavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; saquinavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Simvastatin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of simvastatin due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin acid is a substrate of the transport protein OATP1B1. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    Simvastatin; Sitagliptin: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of simvastatin due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin acid is a substrate of the transport protein OATP1B1. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1.
    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) A dose reduction of tolvaptan may be needed if coadministration of velpatasvir is necessary, due to a possible increase in tolvaptan-related adverse reactions. Tolvaptan is a substrate of P-glycoprotein (P-gp); velpatasvir is a P-gp inhibitor.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of voxilaprevir due to the potential for increased voxilaprevir exposure. Additionally, a reduction in tolvaptan dosage for hyponatremia treatment may be necessary if coadministered due to the potential for increased tolvaptan plasma concentrations. Tolvaptan is a P-gp substrate, and the oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; voxilaprevir is a P-gp inhibitor and OATP1B1/3 substrate. (Moderate) A dose reduction of tolvaptan may be needed if coadministration of velpatasvir is necessary, due to a possible increase in tolvaptan-related adverse reactions. Tolvaptan is a substrate of P-glycoprotein (P-gp); velpatasvir is a P-gp inhibitor.
    Spironolactone: (Moderate) Monitor serum potassium closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, 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) Avoid coadministration of tolvaptan with St. John's Wort due to decreased plasma concentrations of tolvaptan. If concomitant use of St. John's Wort is unavoidable in patients receiving tolvaptan for hyponatremia, monitor for decreased efficacy of tolvaptan, and increase the dose as clinically indicated. Additional recommendations are not available for concomitant use when tolvaptan is administered for autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is a sensitive CYP3A4 substrate, and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tolvaptan exposure by 85%.
    Streptogramins: (Severe) The concomitant use of tolvaptan and dalfopristin; quinupristin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; dalfopristin; quinupristin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. 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 telithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; telithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Telmisartan: (Moderate) Monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo.
    Temsirolimus: (Moderate) Monitor for an increase in tolvaptan-related adverse reactions if coadministration with temsirolimus is necessary. Tolvaptan is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of tolvaptan.
    Tenofovir Alafenamide: (Moderate) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of tenofovir alafenamide due to the potential for increased tenofovir exposure. Tolvaptan is a BCRP inhibitor, and the oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; tenofovir alafenamide is a BCRP and OATP1B1/3 substrate.
    Tenofovir, PMPA: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of tenofovir disoproxil fumarate due to the potential for increased tenofovir exposure. Tolvaptan is a BCRP inhibitor; tenofovir disoproxil fumarate is a BCRP substrate.
    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.
    Tezacaftor; 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.
    Thiazide diuretics: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Tipranavir: (Severe) The concomitant use of tolvaptan and tipranavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; tipranavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    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) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of oral topotecan due to the potential for increased topotecan exposure. The effect of tolvaptan on intravenous topotecan is unknown. If coadministration of tolvaptan and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. Tolvaptan is a BCRP inhibitor; topotecan is a BCRP substrate. When oral topotecan was administered concomitantly with escalating doses of a dual BCRP and P-gp inhibitor, exposure to both total topotecan and topotecan lactone increased by approximately 2.5-fold compared with control.
    Torsemide: (Moderate) Monitor serum sodium closely if torsemide and tolvaptan are used together. Coadministration 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) Avoid coadministration of verapamil when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with verapamil. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%. (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 tolvaptan and potassium-sparing diuretics are used together. In clinical studies, 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.
    Valsartan: (Major) In patients receiving tolvaptan for autosomal dominant polycystic kidney disease (ADPKD), avoid coadministration of valsartan due to the potential for increased valsartan exposure. If use concurrently in patients with hyponatremia, monitor serum potassium concentrations after initiation of tolvaptan therapy in patients receiving angiotensin II receptor antagonists. Tolvaptan therapy results in an acute reduction in extracellular fluid volume which may result in increased serum potassium. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers than when angiotensin II receptor blockers were administered with placebo. The oxobutyric acid metabolite of tolvaptan is an OATP1B1/3 inhibitor; valsartan is an OATP1B1/3 substrate.
    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.
    Verapamil: (Major) Avoid coadministration of verapamil when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with verapamil. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Voriconazole: (Severe) The concomitant use of tolvaptan and voriconazole is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; voriconazole is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    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

    There are insufficient data on the use of tolvaptan in pregnant women to determine if there is a drug associated risk of adverse developmental outcomes during pregnancy. Tolvaptan has been shown to have adverse effects on the fetus when given to pregnant animals at maternally toxic doses. At 17-times the human exposure, reduced fetal weights and delayed fetal ossification in rats were observed. In rabbits, increased abortions, embryo-fetal death, cleft palate, open eyelids, brachymelia, microphthalmia, and skeletal malformations were observed at 3-times the human exposure. Advise pregnant women of the potential risk to the fetus.

    There are no data on the presence of tolvaptan in human milk, the effects on the breast-feeding infant, or the effects on milk production. Due to the potential for serious adverse reactions, including liver toxicity, electrolyte abnormalities, hypotension, and volume depletion in breast-fed infants, breast-feeding is not advised during treatment with tolvaptan.

    MECHANISM OF ACTION

    Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan antagonizes the effect of vasopressin. Decreased binding of vasopressin to the V2-receptor in the kidney lowers adenylate cyclase activity, which results in a decrease in intracellular adenosine 3', 5'-cyclic monophosphate (cAMP) concentrations. Decreased cAMP concentrations prevent aquaporin 2-containing vesicles from fusing with the plasma membrane, which causes an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. In autosomal dominant polycystic kidney disease (ADPKD) cyst epithelial cells, tolvaptan inhibits AVP-stimulated cyst growth in vitro and chloride-dependent fluid secretion into cysts. In animal models, decreased cAMP concentrations are associated with decreases in the total kidney volume growth rate and the rate of formation and enlargement of kidney cysts.

    PHARMACOKINETICS

    Tolvaptan is administered orally. Tolvaptan is highly protein bound (99%) to albumin and alpha1-acid glycoprotein; binding is not affected by disease state. Vd is approximately 3 L/kg. The drug is metabolized almost exclusively by CYP3A. Of the 14 metabolites identified in plasma, urine, and feces, all but 1 were also metabolized by CYP3A; none are pharmacologically active. Approximately 40% of a dose is eliminated in the urine (less than 1% as unchanged tolvaptan) and 59% in the feces (19% as unchanged tolvaptan). Estimated half-life of tolvaptan increases from 3 hours (for a single 15 mg oral dose) to approximately 12 hours (for a single dose of 120 mg or more) due to prolonged absorption of tolvaptan at higher doses. Apparent clearance is approximately 4 mL/kg/minute and does not appear to change with increasing dose. Clearance is reduced to about 2 mL/kg/minute in patients with hyponatremia.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, P-gp
    Tolvaptan is metabolized almost exclusively by CYP3A. In vitro data indicate tolvaptan is a substrate and inhibitor of P-glycoprotein (P-gp).

    Oral Route

    The absolute bioavailability of tolvaptan is 56% (range: 42% to 80%) after a 30-mg dose; bioavailability decreases with increasing doses. Peak concentrations are observed 2 to 4 hours after administration. AUC increases proportionally with dose; however, after administration of doses of 60 mg or more, Cmax increases less than proportionally with dose. Food does not impact bioavailability. Coadministration with a high-fat meal doubles peak concentrations but has no effect on AUC.
     
    A peak increase in serum sodium and urine excretion of approximately 6 mEq and 9 mL/minute, respectively, is observed 4 to 8 hours after administration. Approximately 60% of the peak serum sodium effect is sustained at 24 hours post-dose, but the urinary excretion rate is no longer elevated at this time. Doses above 60 mg do not further increase aquaresis or serum sodium. When given as the recommended split-dose regimen for polycystic kidney disease, tolvaptan inhibits vasopressin from binding to the V2-receptor in the kidney for the entire day, as demonstrated by increased urine output and decreased urine osmolality. Change in mean daily urine volume was about 4 L for a mean total daily volume of about 7 L in patients with an eGFR more than 60 mL/minute/1.73m2. In patients with an eGFR less than 30 mL/minute/1.73m2, mean change was about 2 L for a total daily urine volume of 5 L.
     
    The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S(-) to the R(+) enantiomer of about 3. Tolvaptan's accumulation factor is less than 1.2 when administered as multiple once-daily 300 mg doses or as split dose regimens to patients with polycystic kidney disease. The accumulation factor is 1.3 with the once-daily hyponatremia regimen. There is marked intersubject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging from 30% to 60%.