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  • CLASSES

    Vasopressin Antagonists

    DEA CLASS

    Rx

    DESCRIPTION

    Non-peptide dual V1A and V2 vasopressin receptor antagonist; available IV; indicated for the treatment of euvolemic and hyprevolemic hyponatremia in hospitalized patients; increases serum sodium concentrations and increases free water clearance; prominent ADRs include injection site reactions, hypokalemia, thirst, and hypotension; efficacy and safety is being investigated for CHF.

    COMMON BRAND NAMES

    Vaprisol

    HOW SUPPLIED

    Vaprisol Intravenous Inj Sol: 0.2-5%

    DOSAGE & INDICATIONS

    For the treatment of hospitalized patients with euvolemic hyponatremia (e.g., syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hypothyroidism, adrenal insufficiency, pulmonary disorders) or hypervolemic hyponatremia (e.g., cirrhosis, nephrotic syndrome).
    NOTE: Conivaptan is not indicated for the treatment of heart failure and has not been shown to be effective for the treatment of the signs and symptoms of heart failure.
    NOTE: Conivaptan should be administered only in settings where serum sodium concentrations, volume status, and blood pressure can be closely monitored.
    NOTE: It has not been established that utilizing conivaptan to raise serum sodium concentrations provides a symptomatic benefit to patients.
    Intravenous dosage
    Adults, including the Geriatric

    Initially, 20 mg IV loading dose administered over 30 minutes, followed by a maintenance dose of 20 mg IV continuous infusion over 24 hours. Following the initial day of treatment, conivaptan may be administered for an additional 1 to 3 days as an IV continuous infusion of 20 mg/day. If serum sodium is not rising at the desired rate, titrate up to 40 mg/day IV continuous infusion. The total duration of infusion (after the loading dose) should not exceed 4 days. Monitor serum sodium concentrations and volume status frequently. An overly rapid rise in serum sodium (greater than 12 mEq/L over 24 hours) may result in serious neurologic sequelae. For patients who develop an excessively fast rise in serum sodium concentration, discontinue conivaptan and carefully monitor serum sodium and neurologic status. If the serum sodium continues to rise, conivaptan should not be resumed. If hyponatremia persists or recurs, and the patient has had no evidence of neurologic sequelae or rapid rise in serum sodium, conivaptan may be resumed at a reduced dosage. For patients who develop hypovolemia or hypotension, the drug should be discontinued, followed by frequent monitoring of volume status and vital signs. Once the patient attains euvolemia and is normotensive again, conivaptan may be restarted at a reduced dosage to treat hyponatremia.

    For the treatment of increased intracranial pressure†.
    Intravenous dosage
    Adults

    Dosage not established. A single dose of 20 mg IV over 30 minutes has been reported in a case report and small (n = 10) prospective trial.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    20 mg IV loading dose; 40 mg/day IV continuous infusion; maximum duration of IV infusion is 4 days.

    Elderly

    20 mg IV loading dose; 40 mg/day IV continuous infusion; maximum duration of IV infusion is 4 days.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment: 10 mg IV loading dose over 30 minutes followed by a continuous IV infusion of 10 mg over 24 hours for 2 to 4 days. Dosage may be titrated upward to 20 mg/day if serum sodium is not increasing at the desired rate.

    Renal Impairment

    CrCl 30 mL/minute or more: No dosage adjustment needed.
    CrCl less than 30 mL/minute: Not recommended.

    ADMINISTRATION

     
    NOTE: Conivaptan should be administered only in settings where serum sodium concentrations, volume status, and blood pressure can be monitored closely. Neurologic status should also be monitored closely to avoid overly rapid correction of serum sodium concentration (> 12 mEq/L over 24 hours) during treatment of hyponatremia.
     
    NOTE: Vascular irritation and injection site reaction may occur frequently (> 50%) despite appropriate preparation and administration of IV conivaptan. Monitor closely for injection-related reactions which may include edema, erythema, phlebitis, or pain at the infusion site.

    Injectable Administration

    For intravenous (IV) administration only.
    Do not mix or administer with other IV fluids or medications.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Available as concentrated ampules (20 mg/4 mL) and as premixed 5% dextrose flexible containers (20 mg/100 mL).
    Proper dilution and preparation of the concentrated ampules are required to reduce the risk of injection site reactions. Each ampule is for single use only. Discard any unused content of the ampule.
    Administer via a large vein and change the infusion site every 24 hours to minimize the risk of vascular irritation.
     
    Preparation and administration of intravenous (IV) loading dose from concentrated ampule:
    Withdraw 4 mL (20 mg) of conivaptan from one ampule and add to an infusion bag containing 100 mL of 5% Dextrose for injection. Gently invert the bag several times to ensure complete mixing of the solution.
    Dilute only with 5% Dextrose for injection; conivaptan is physically and/or chemically incompatible with Lactated Ringer's injection and 0.9% Sodium Chloride for injection. After diluting with 5% Dextrose for injection, the solution is stable for up to 24 hours. The diluted solution should be used immediately and administration completed within 24 hours of mixing.
    Infuse the loading dose over 30 minutes.
     
    Preparation and administration of continuous intravenous (IV) infusion maintenance dose from concentrated ampule:
    Following the loading dose, the recommended initial maintenance dose is 20 mg IV continuous infusion over 24 hours. To prepare a continuous IV infusion bag containing 20 mg, withdraw 4 mL (20 mg) of conivaptan from one ampule and add to an infusion bag containing 250 mL of 5% Dextrose for injection. Gently invert the bag several times to ensure complete mixing of the solution.
    After appropriate titration, the maximum maintenance dose is 40 mg IV continuous infusion over 24 hours. To prepare a continuous IV infusion bag containing 40 mg, withdraw 8 mL (40 mg) of conivaptan from two ampules and add to an infusion bag containing 250 mL of 5% Dextrose for injection. Gently invert the bag several times to ensure complete mixing of the solution.
    Dilute only with 5% Dextrose for injection; conivaptan is physically and/or chemically incompatible with  Lactated Ringer's injection and 0.9% Sodium Chloride for injection. After diluting with 5% Dextrose for injection, the solution is stable for up to 24 hours. The diluted solution should be used immediately and administration completed within 24 hours of mixing.
     
    Administration of IV loading dose and maintenance continuous IV infusion dose from premixed flexible container:
    Loading dose: Administer one 20 mg/100 mL premixed flexible container over 30 minutes.
    Maintenance dose: For patients who require a maintenance dose of 20 mg/day, administer one 20 mg/100 mL premixed flexible container over 24 hours. For patients requiring a maintenance dose of 40 mg/day, administer two consecutive 20 mg/100 mL premixed flexible containers over 24 hours.
    Do not use premixed flexible containers in series connections. This practice may result in the formation of air embolism resulting from residual air being drawn from the primary container before completion of fluid drawn from the secondary container.
    Conivaptan is compatible with 0.9% Sodium Chloride injection for up to 22 hours when the two solutions are coadministered via a Y-site connection at a rate of 4.2 mL/hr for conivaptan and 2.1 mL/hr or 6.3 mL/hr for Sodium Chloride. Do not coadminister with Lactated Ringer's injection.

    STORAGE

    Vaprisol:
    - Avoid excessive heat (above 104 degrees F)
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from freezing
    - Protect from light
    - Store at 77 degrees F; brief exposure up to 104 degrees F does not adversely affect product

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Coadministration of conivaptan with potent CYP3A4 inhibitors such as clarithromycin, ketoconazole, itraconazole, ritonavir, and indinavir, is contraindicated, and coadministration of conivaptan with CYP3A4 substrates should be avoided.

    Corn hypersensitivity
    Heart failure, hyponatremia

    The number of patients with underlying heart failure treated with conivaptan for hypervolemic hyponatremia is too small to establish safety in this population. Conivaptan should only be used in patients with underlying heart failure if the benefits of raising the serum sodium outweigh the risks of increased side effects.

    Hypotension, hypovolemia

    Conivaptan is contraindicated in patients with hypovolemic hyponatremia. Intravenous infusion of conivaptan has been associated with hypotension, including orthostatic hypotension. Conivaptan should be discontinued if hypovolemia or hypotension develops; monitor volume status and vital signs frequently. Once the patient attains euvolemia and is normotensive again, conivaptan may be restarted at a reduced dosage if needed for further treatment of euvolemic hyponatremia.

    Alcoholism, malnutrition

    Proper dilution, preparation, and administration of IV conivaptan are required to reduce the risk of injection site reactions. An overly rapid increase in serum sodium concentration during drug administration (> 12 mEq/L/24 hours) can result in serious neurologic sequelae. In controlled clinical trials, 9% of patients receiving conivaptan at doses of 20 to 40 mg/day had an overly rapid correction of serum sodium. However, none of these patients had permanent neurologic sequelae. Although not observed in conivaptan clinical studies, osmotic demyelination syndrome has been reported following the rapid correction of low serum sodium concentrations. Symptoms of osmotic demyelination include dysarthria, mutism, dysphagia, lethargy, changes in affect, spastic quadriparesis, seizures, coma, or death. 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 or those very low baseline serum sodium concentrations (hyponatremia). Serum sodium and neurological status should be monitored during conivaptan administration. Conivaptan should be discontinued if the patient develops an undesirable rapid rise in serum sodium concentrations. If serum sodium concentrations continue to rise, do not resume conivaptan. If hyponatremia persists or recurs (assuming it is after an initial discontinuation of conivaptan due to a rapid rise in serum sodium) and the patients has no evidence of neurological sequelae from the rapid rise in serum sodium, conivaptan may be resumed at a reduced dose.

    Anuria, renal disease, renal failure, renal impairment

    Conivaptan is contraindicated in patients with anuria, as no clinical benefit can be expected in patients unable to make urine. Use of conivaptan in patients with severe renal impairment (i.e., severe renal disease or renal failure, CrCl < 30 mL/minute) is not recommended due to high incidence of infusion site phlebitis and unlikely benefit.

    Hepatic disease

    Use conivaptan with caution in patients with hepatic disease. The effects of hepatic impairment on the pharmacokinetics of intravenous conivaptan have not been systematically evaluated. Increased systemic exposure after administration of oral conivaptan has been observed in patients with stable cirrhosis and moderate hepatic impairment. Dosage adjustments are recommended in patients with hepatic impairment.

    Geriatric

    Although a nearly 2-fold higher drug exposure is reported for geriatric male subjects receiving 60 mg of oral conivaptan, drug exposure is reported to be similar for lower oral doses (15 to 30 mg). Though not compared directly to younger patients, the median conivaptan plasma concentrations following recommended IV dosage and maintenance infusion regimens appear to be similar for elderly hyponatremic patients and the general study population. In clinical trials of intravenous conivaptan, 52% of patients were >= 65 years and 34% were >= 75 years. No overall differences in adverse events were observed in elderly patients when compared with the general study population.

    Pregnancy

    There are no available data with conivaptan in human pregnancy to inform a drug-associated risk for major birth defects and miscarriage. When pregnant rats were given conivaptan at doses producing systemic exposures less than those achieved with a therapeutic human dose based on AUC comparisons, the offspring showed decreased neonatal viability, weaning indices, and body weight and delayed reflex and physical development, including sexual maturation. No maternal adverse effects were seen. However, when pregnant rabbits were given conivaptan at doses about twice the human exposure, no adverse maternal or fetal effects were noted. Pharmacokinetic data demonstrate that conivaptan that is taken up by fetal tissue is slowly cleared, suggesting that fetal accumulation is possible. Delayed delivery was observed when conivaptan was administered orally to rats at a dose providing systemic exposure equivalent to the human therapeutic exposure.

    Breast-feeding

    There are no data regarding conivaptan or its metabolites in human milk or the effects of conivaptan on the breast-fed infant or milk production. Conivaptan is present in rat milk. The maximum concentrations of conivaptan in rat milk were reached 1 hour after intravenous administration and were up to 3 times the maternal plasma concentrations after a dose that produced a systemic exposure less than human therapeutic exposure. Because of potential for serious adverse effects, including electrolyte abnormalities, hypotension, and volume depletion, in the breast-fed infant, avoid breast-feeding during treatment with conivaptan.

    Infertility, reproductive risk

    Discuss reproductive risk with female patients. Based on animal data, conivaptan may impair fertility or cause infertility in females of reproductive potential. It is not known whether these effects on fertility are reversible.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / 2.0-5.0
    heart failure / Delayed / Incidence not known
    osmotic demyelination syndrome / Early / Incidence not known

    Moderate

    phlebitis / Rapid / 32.0-51.0
    hypokalemia / Delayed / 10.0-22.0
    orthostatic hypotension / Delayed / 6.0-14.0
    hypernatremia / Delayed / 9.0-9.0
    peripheral edema / Delayed / 3.0-8.0
    hypotension / Rapid / 5.0-8.0
    hypertension / Early / 6.0-8.0
    hyponatremia / Delayed / 6.0-8.0
    constipation / Delayed / 6.0-8.0
    erythema / Early / 6.0-6.0
    anemia / Delayed / 5.0-6.0
    confusion / Early / 0-5.0
    hypomagnesemia / Delayed / 2.0-5.0
    edema / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 63.0-73.0
    fever / Early / 5.0-11.0
    headache / Early / 8.0-10.0
    diarrhea / Early / 0-7.0
    vomiting / Early / 5.0-7.0
    polydipsia / Early / 3.0-6.0
    pruritus / Rapid / 1.0-5.0
    insomnia / Early / 4.0-5.0
    nausea / Early / 3.0-5.0
    infection / Delayed / 2.0-5.0

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and dolutegravir, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of dolutegravir. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with dolutegravir.
    Abemaciclib: (Major) A dose reduction of abemaciclib is required if coadministration with conivaptan is necessary due to increased plasma concentrations of abemaciclib. In patients at the recommended starting doses of either 200 mg or 150 mg twice daily, reduce the dose of abemaciclib to 100 mg twice daily. In patients who have already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg twice daily. If conivaptan is discontinued, resume the original dose of abemaciclib after 3 to 5 half-lives of conivaptan. Abemaciclib is a CYP3A4 substrate and conivaptan is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor was predicted to increase exposure to unbound abemaciclib and its active metabolites by 1.7-fold to 2.2-fold.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and conivaptan; significantly increased acalabrutinib exposure may occur. If short-term conivaptan use is unavoidable, interrupt acalabrutinib therapy; subsequent treatment with acalabrutinib may be initiated no sooner than 1 week after the infusion of conivaptan. Acalabrutinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Acetaminophen; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with conivaptan may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of conivaptan could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and conivaptan is a CYP3A4 inhibitor.
    Ado-Trastuzumab emtansine: (Major) Avoid concomitant use of ado-trastuzumab emtansine with conivaptan, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until no sooner than 1 week after the infusion of conivaptan is complete, or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Conivaptan is a strong CYP3A4 inhibitor; conivaptan (40 mg/day IV) increases the mean AUC values of midazolam by approximately 2-fold and 3-fold when coadministered with midazolam 1 mg IV or 2 mg PO, respectively.. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Afatinib: (Major) If the concomitant use of conivaptan and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of conivaptan. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and conivaptan is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Coadministration of oral conivaptan (40 mg twice daily) with the P-gp substrate, digoxin (single dose, 0.5 mg) reduced digoxin clearance by 30%, and resulted in 79% and 43% increases in digoxin Cmax and AUC values, respectively. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Alfentanil: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as alfentanil, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with alfentanil. Treatment with alfentanil may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Alfuzosin: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as alfuzosin, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with alfuzosin. Treatment with alfuzosin may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Aliskiren: (Moderate) Avoid concurrent use of conivaptan and aliskiren. Coadministration of conivaptan and aliskiren may result in increased serum concentrations of aliskiren. Conivaptan inhibits CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with aliskiren. Subsequent treatment with CYP3A substrates, such as aliskiren, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Aliskiren; Amlodipine: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) Avoid concurrent use of conivaptan and aliskiren. Coadministration of conivaptan and aliskiren may result in increased serum concentrations of aliskiren. Conivaptan inhibits CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with aliskiren. Subsequent treatment with CYP3A substrates, such as aliskiren, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) Avoid concurrent use of conivaptan and aliskiren. Coadministration of conivaptan and aliskiren may result in increased serum concentrations of aliskiren. Conivaptan inhibits CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with aliskiren. Subsequent treatment with CYP3A substrates, such as aliskiren, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Avoid concurrent use of conivaptan and aliskiren. Coadministration of conivaptan and aliskiren may result in increased serum concentrations of aliskiren. Conivaptan inhibits CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with aliskiren. Subsequent treatment with CYP3A substrates, such as aliskiren, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Aliskiren; Valsartan: (Moderate) Avoid concurrent use of conivaptan and aliskiren. Coadministration of conivaptan and aliskiren may result in increased serum concentrations of aliskiren. Conivaptan inhibits CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of CYP3A4 and P-gp. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with aliskiren. Subsequent treatment with CYP3A substrates, such as aliskiren, may be initiated no sooner than 1 week after completion of conivaptan therapy. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Almotriptan: (Major) Avoid coadministration of conivaptan and almotriptan; subsequent almotriptan use should be initiated no sooner than 1 week after the infusion of conivaptan is complete. Conivaptan may increase the systemic exposure of almotriptan. Almotriptan is a CYP3A4 substrate and conivaptan is a potent CYP3A4 inhibitor.
    Alprazolam: (Major) Coadministration of alprazolam and conivaptan is not recommended. Subsequent treatment with CYP3A substrates, such as alprazolam, may be initiated no sooner than 1 week after completion of conivaptan therapy. Conivaptan is a potent CYP3A4 inhibitor. Intravenous conivaptan 40 mg/day increases the mean AUC values by approximately 2-fold and 3-fold when coadministered with midazolam 1 mg IV or 2 mg PO, respectively. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Amiodarone: (Moderate) Conivaptan is a substrate of CYP3A4 and coadministration with CYP3A4 inhibitors like amiodarone could lead to an increase in conivaptan serum concentrations.
    Amitriptyline; Chlordiazepoxide: (Major) Concomitant use of conivaptan and chlordiazepoxide, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with chlordiazepoxide. Subsequent treatment with CYP3A substrates, such as chlordiazepoxide, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Amlodipine: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Amlodipine; Atorvastatin: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and atorvastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with atorvastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as atorvastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as atorvastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Amlodipine; Benazepril: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Amlodipine; Olmesartan: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Amlodipine; Telmisartan: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Amlodipine; Valsartan: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Amoxicillin; Clarithromycin; Lansoprazole: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like clarithromycin is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and clarithromycin. In addition, conivaptan inhibits CYP3A4; clarithromycin is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and lansoprazole, a CYP3A4/P-gp substrate. Concurrent use may result in elevated lansoprazole serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as lansoprazole, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with lansoprazole. Treatment with lansoprazole may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Amoxicillin; Clarithromycin; Omeprazole: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like clarithromycin is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and clarithromycin. In addition, conivaptan inhibits CYP3A4; clarithromycin is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and omeprazole, a CYP3A4/P-gp substrate. Concurrent use may result in elevated omeprazole serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as omeprazole, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with omeprazole. Treatment with omeprazole may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Conivaptan has been associated with hypokalemia. Consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as amphotericin B.
    Amphotericin B lipid complex (ABLC): (Moderate) Conivaptan has been associated with hypokalemia. Consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as amphotericin B.
    Amphotericin B liposomal (LAmB): (Moderate) Conivaptan has been associated with hypokalemia. Consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as amphotericin B.
    Amphotericin B: (Moderate) Conivaptan has been associated with hypokalemia. Consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as amphotericin B.
    Amprenavir: (Major) Coadministration of conivaptan, which is extensively metabolized by CYP3A4 isoenzymes, with a potent CYP3A4 inhibitor could lead to increased conivaptan serum concentrations. Due to the contraindications noted by the manufacturer, it is prudent to avoid coadministration of conivaptan with anti-retroviral protease inhibitors that inhibit CYP3A4, including amprenavir.
    Angiotensin II receptor antagonists: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Angiotensin-converting enzyme inhibitors: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Apixaban: (Major) Concomitant administration of conivaptan, a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and apixaban, a CYP3A/P-gp substrate, results in increased exposure to apixaban and an increase in the risk of bleeding. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided and subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. The manufacturer of apixaban recommends reducing the dose of apixaban to 2.5 mg twice daily when coadministered with a dual inhibitor of CYP3A4 and P-gp. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and conivaptan.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of conivaptan with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased conivaptan exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in conivaptan- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Conivaptan is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Conivaptan is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may additionally increase plasma concentrations of conivaptan. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as conivaptan. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated.
    Armodafinil: (Major) Coadministration of armodafinil, a CYP3A/P-gp substrate and mild inducer of CYP3A, with conivaptan, a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, may result in elevated armodafinil concentrations and decreased conivaptan concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided and subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Arsenic Trioxide: (Major) Because electrolyte abnormalities increase the risk of QT interval prolongation and serious arrhythmias, avoid the concomitant use of arsenic trioxide with drugs that may cause electrolyte abnormalities, particularly hypokalemia and hypomagnesemia. Examples of drugs that may cause electrolyte abnormalities include conivaptan. If concomitant drug use is unavoidable, frequently monitor serum electrolytes (and replace as necessary) and electrocardiograms.
    Artemether; Lumefantrine: (Moderate) Conivaptan is a substrate/inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Conivaptan is a substrate/inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Aspirin, ASA; Omeprazole: (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and omeprazole, a CYP3A4/P-gp substrate. Concurrent use may result in elevated omeprazole serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as omeprazole, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with omeprazole. Treatment with omeprazole may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with conivaptan may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of conivaptan could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and conivaptan is a CYP3A4 inhibitor.
    Atazanavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like atazanavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and atazanavir. In addition, conivaptan inhibits CYP3A4; atazanavir is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Atazanavir; Cobicistat: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like atazanavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and atazanavir. In addition, conivaptan inhibits CYP3A4; atazanavir is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. (Major) Avoid coadministration of conivaptan, a CYP3A4 inhibitor/substrate and cobicistat, a CYP3A4 inhibitor/substrate. Concurrent use may result in increased serum concentrations of both drugs. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cobicistat.
    Atorvastatin: (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and atorvastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with atorvastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as atorvastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as atorvastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Atorvastatin; Ezetimibe: (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and atorvastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with atorvastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as atorvastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as atorvastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Axitinib: (Major) Avoid coadministration of conivaptan with axitinib, due to the risk of increased axitinib-related adverse reactions. According to the manufacturer of conivaptan, subsequent treatment with axitinib may be initiated no sooner than 1 week after the infusion of conivaptan is completed, although the manufacturer of axitinib suggests that reducing the dose by 50% is acceptable if avoidance is not possible. Subsequent doses can be increased or decreased based on individual safety and tolerability, resuming the original dose of axitinib approximately 3 to 5 half-lives after conivaptan is discontinued. Axitinib is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor. Intravenous conivaptan increased the mean AUC of midazolam by approximately 2-fold and 3-fold when administered intravenously or by mouth, respectively. Coadministration with another strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers.
    Azelastine; Fluticasone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Azilsartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Azilsartan; Chlorthalidone: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Azithromycin: (Moderate) Use caution when administering conivaptan and azithromycin concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as azithromycin, may increase azithromycin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Beclomethasone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as conivaptan, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, conivaptan may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) Ergotamine is a CYP3A4 substrate. Conivaptan is a potent inhibitor of CYP3A4 and may increase concentrations of ergotamine. The risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities, or other serious effects) is potentially increased by the concomitant use of CYP3A4 inhibitors. Coadministration of ergotamine and conivaptan should be avoided to minimize the risk of ergot toxicity. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates (i.e., ergotamine) may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Benazepril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Beta-adrenergic blockers: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Betamethasone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Bexarotene: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bexarotene, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bexarotene. Treatment with bexarotene may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Boceprevir: (Severe) Coadministration of conivaptan with potent CYP3A4 inhibitors like boceprevir is contraindicated. Exposure to both drugs may be elevated during concurrent use, increasing the risk for serious adverse events. Coadministration of conivaptan with another potent CYP3A4 inhibitor resulted in 4- and 11- fold increases in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and boceprevir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein; boceprevir is a substrate of both CYP3A4 and P-gp.
    Bortezomib: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bortezomib, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bortezomib. Treatment with bortezomib may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Bosentan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bosentan, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bosentan. Treatment with bosentan may be initiated no sooner than 1 week after completion of conivaptan therapy. In addition, there is potential for additive hypotensive effects when coadministered with vasodilators such as bosentan. Intravenous infusion of conivaptan has been associated with orthostatic hypotension.
    Bosutinib: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, and conivaptan, a strong CYP3A4 inhibitor, as bosutinib plasma exposure may increase.
    Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as conivaptan. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level.
    Brigatinib: (Major) Avoid coadministration of brigatinib with conivaptan if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. According to the manufacturer of conivaptan, subsequent treatment with a CYP3A4 substrate like brigatinib may be initiated no sooner than 1 week after the infusion of conivaptan is completed. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of conivaptan, resume the brigatinib dose that was tolerated prior to initiation of conivaptan. Brigatinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Bromocriptine: (Major) Avoid concomitant use of bromocriptine and conivaptan. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; conivaptan is a strong inhibitor of CYP3A4. Subsequent treatment with CYP3A substrates, such as bromocriptine, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Budesonide: (Major) Coadministration of conivaptan, a CYP3A4 and P-glycoprotein (P-gp) inhibitor with budesonide, a CYP3A and P-gp substrate, can increase budesonide exposure leading to increased or prolonged therapeutic effects and adverse events. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Treatment with budesonide may be initiated no sooner than 1 week after completion of conivaptan therapy. Theoretically, inhibition of CYP3A4 may also be clinically significant for inhaled forms of budesonide, including budesonide nasal spray. In addition, conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Budesonide; Formoterol: (Major) Coadministration of conivaptan, a CYP3A4 and P-glycoprotein (P-gp) inhibitor with budesonide, a CYP3A and P-gp substrate, can increase budesonide exposure leading to increased or prolonged therapeutic effects and adverse events. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Treatment with budesonide may be initiated no sooner than 1 week after completion of conivaptan therapy. Theoretically, inhibition of CYP3A4 may also be clinically significant for inhaled forms of budesonide, including budesonide nasal spray. In addition, conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Bupivacaine Liposomal: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bupivacaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bupivacaine. Treatment with bupivacaine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Bupivacaine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bupivacaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bupivacaine. Treatment with bupivacaine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Bupivacaine; Lidocaine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bupivacaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bupivacaine. Treatment with bupivacaine may be initiated no sooner than 1 week after completion of conivaptan therapy. (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as lidocaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with lidocaine. Treatment with lidocaine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Buprenorphine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as buprenorphine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with buprenorphine. Treatment with buprenorphine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Buprenorphine; Naloxone: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as buprenorphine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with buprenorphine. Treatment with buprenorphine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with conivaptan if possible due to increased cabazitaxel exposure; subsequent treatment with cabazitaxel may be initiated no sooner than 1 week after the infusion of conivaptan is completed. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and conivaptan is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
    Cabozantinib: (Major) According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates such as cabozantinib should be avoided due to the risk of increased cabozantinib-related toxicities. Subsequent treatment with CYP3A substrates should be initiated no sooner than 1 week after completion of conivaptan therapy. If coadministration is absolutely necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day. Cabozantinib is primarily metabolized by CYP3A4 and conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%
    Caffeine; Ergotamine: (Severe) Ergotamine is a CYP3A4 substrate. Conivaptan is a potent inhibitor of CYP3A4 and may increase concentrations of ergotamine. The risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities, or other serious effects) is potentially increased by the concomitant use of CYP3A4 inhibitors. Coadministration of ergotamine and conivaptan should be avoided to minimize the risk of ergot toxicity. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates (i.e., ergotamine) may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Canagliflozin: (Moderate) Canagliflozin is a substrate of drug transporter P-glycoprotein (P-gp). Conivaptan is a P-gp inhibitor and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate of drug transporter P-glycoprotein (P-gp). Conivaptan is a P-gp inhibitor and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    Candesartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Captopril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Carbamazepine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as carbamazepine, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with carbamazepine. Treatment with carbamazepine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as conivaptan, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
    Ceritinib: (Major) Avoid coadministration of ceritinib with conivaptan due to increased exposure to both drugs. Subsequent treatment with ceritinib should be started no sooner than 1 week after completion of the conivaptan infusion. Ceritinib is a CYP3A4 substrate and inhibitor. Conivaptan is a sensitive CYP3A4 substrate, as well as a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ceritinib AUC by 2.9-fold and the Cmax by 22%. Coadministration with the same strong inhibitor increased the AUC and Cmax of conivaptan by 11-fold and 4-fold, respectively.
    Cerivastatin: (Moderate) Conivaptan should be used with caution with CYP3A4 substrates like cerivastatin. Concomitant administration may increase the risk of rhabdomyolysis.
    Cevimeline: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as cevimeline, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cevimeline. Treatment with cevimeline may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Chlordiazepoxide: (Major) Concomitant use of conivaptan and chlordiazepoxide, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with chlordiazepoxide. Subsequent treatment with CYP3A substrates, such as chlordiazepoxide, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Chlordiazepoxide; Clidinium: (Major) Concomitant use of conivaptan and chlordiazepoxide, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with chlordiazepoxide. Subsequent treatment with CYP3A substrates, such as chlordiazepoxide, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Cilostazol: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as cilostazol, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cilostazol. Treatment with cilostazol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Cinacalcet: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as cinacalcet, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cinacalcet. Treatment with cinacalcet may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ciprofloxacin: (Moderate) Coadministration of conivaptan with CYP3A4 inhibitors, such as ciprofloxacin, could lead to an increase in conivaptan serum concentrations. Conivaptan is a substrate of CYP3A4. According to the manufacturer, coadministration of conivaptan with strong CYP3A4 inhibitors is contraindicated. Until further data are available, it is prudent to coadminister conivaptan with caution or to avoid coadministering conivaptan with other drugs known to be significant inhibitors of CYP3A4 isoenzymes, such as ciprofloxacin.
    Cisapride: (Severe) Post-marketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Because of the potential severity of these drug interactions (increased plasma cisapride concentrations and QT prolongation), cisapride should not be used with conivaptan, which may inhibit the metabolism of cisapride through CYP3A4.
    Cisplatin: (Moderate) Conivaptan has been associated with hypokalemia. Consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as cisplatin.
    Clarithromycin: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like clarithromycin is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and clarithromycin. In addition, conivaptan inhibits CYP3A4; clarithromycin is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Clindamycin: (Major) Avoid concomitant use of clindamycin and conivaptan. Concurrent use may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; conivaptan is a strong inhibitor of CYP3A4. Subsequent treatment with CYP3A substrates, such as clindamycin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Clobazam: (Major) Coadministration of clobazam, a CYP3A4/P-gp substrate and mild 3A4 inducer, and conivaptan, a CYP3A4/P-gp inhibitor and CYP3A4 substrate, may result in elevated clobazam concentrations and potentially decreased conivaptan concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Treatment with clobazam may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Clonazepam: (Major) Concomitant use of conivaptan and clonazepam, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with clonazepam. Subsequent treatment with CYP3A substrates, such as clonazepam, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Clorazepate: (Major) Concomitant use of conivaptan and clorazepate, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with clorazepate. Subsequent treatment with CYP3A substrates, such as clorazepate, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Clozapine: (Moderate) Caution is advisable during concurrent use of conivaptan and clozapine. Conivaptan is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Major) Avoid coadministration of conivaptan, a CYP3A4 inhibitor/substrate and cobicistat, a CYP3A4 inhibitor/substrate. Concurrent use may result in increased serum concentrations of both drugs. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cobicistat.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of conivaptan, a CYP3A4 inhibitor/substrate and cobicistat, a CYP3A4 inhibitor/substrate. Concurrent use may result in increased serum concentrations of both drugs. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cobicistat.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of conivaptan, a CYP3A4 inhibitor/substrate and cobicistat, a CYP3A4 inhibitor/substrate. Concurrent use may result in increased serum concentrations of both drugs. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cobicistat. (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with conivaptan due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; conivaptan is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and conivaptan in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Treatment with colchicine may be initiated no sooner than 1 week after completion of conivaptan therapy. Conivaptan can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a strong CYP3A4 inhibitor/P-gp inhibitor like conivaptan in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and conivaptan if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; conivaptan is a strong CYP3A inhibitor.
    Corticotropin, ACTH: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Cortisone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Crizotinib: (Major) Avoid coadministration of crizotinib with conivaptan due to increased crizotinib exposure. Treatment with crizotinib should be initiated no sooner than 1 week after completion of conivaptan therapy. Crizotinib is a CYP3A substrate. Conivaptan is a strong CYP3A4 inhibitor. Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Cyclobenzaprine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as cyclobenzaprine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cyclobenzaprine. Treatment with cyclobenzaprine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Cyclosporine: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and cyclosporine, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and cyclosporine. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as cyclosporine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with conivaptan, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like conivaptan in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with conivaptan, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Major) Avoid the concomitant use of dabrafenib and conivaptan; altered levels of either drug may occur. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients closely for dabrafenib adverse reactions (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and for loss of conivaptan efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; conivaptan is a strong CYP3A4 inhibitor and a sensitive CYP3A4 substrate.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as conivaptan. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Danazol: (Moderate) Conivaptan is a substrate of CYP3A4. Coadministration of conivaptan with CYP3A4 inhibitors like danazol could lead to an increase in conivaptan serum concentrations.
    Dapagliflozin; Saxagliptin: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and saxagliptin, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of saxagliptin. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as saxagliptin, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with saxagliptin.
    Dapsone: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as dapsone, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with dapsone. Treatment with dapsone may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Darifenacin: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as darifenacin, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with darifenacin. Treatment with darifenacin may be initiated no sooner than 1 week after completion of conivaptan therapy. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Darunavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like darunavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and darunavir. In addition, conivaptan inhibits CYP3A4; darunavir is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Darunavir; Cobicistat: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like darunavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and darunavir. In addition, conivaptan inhibits CYP3A4; darunavir is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. (Major) Avoid coadministration of conivaptan, a CYP3A4 inhibitor/substrate and cobicistat, a CYP3A4 inhibitor/substrate. Concurrent use may result in increased serum concentrations of both drugs. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with cobicistat.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like ritonavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and ritonavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Per the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Dasatinib: (Moderate) Dasatinib inhibits CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme, such as conivaptan, are administered concurrently with dasatinib as increased adverse reactions may occur.
    Daunorubicin: (Moderate) The plasma concentrations of daunorubicin may be elevated when administered concurrently with conivaptan. Clinical monitoring for adverse effects, such as myelosuppression or cardiomyopathy, is recommended during coadministration. Conivaptan is a p-glycoprotein (P-gp) inhibitor, while daunorubicin is a P-gp substrate.
    Deflazacort: (Major) Avoid coadministration of deflazacort and conivaptan. If coadministration cannot be avoided, decrease deflazacort dose to one third of the recommended dosage when coadministered with conivaptan. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; conivaptan is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Delavirdine: (Major) Coadministration of conivaptan, which is extensively metabolized by CYP3A4 isoenzymes, with a potent CYP3A4 inhibitor could lead to increased conivaptan serum concentrations. Due to the contraindications noted by the manufacturer, it is prudent to avoid coadministration of conivaptan with other CYP3A4 inhibitors, including delavirdine.
    Desloratadine: (Minor) Use caution when administering conivaptan and desloratadine concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as desloratadine, can increase desloratadine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Desloratadine; Pseudoephedrine: (Minor) Use caution when administering conivaptan and desloratadine concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as desloratadine, can increase desloratadine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Dexamethasone: (Major) Coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and dexamethasone, a CYP3A4/P-gp substrate and CYP3A4 inducer, may result in elevated dexamethasone concentrations and decreased conivaptan concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Treatment with dexamethasone may be initiated no sooner than 1 week after completion of conivaptan therapy. In addition, conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and quinidine, a CYP3A4/P-gp substrate. Concurrent use may result in elevated quinidine serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as quinidine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with quinidine. Treatment with quinidine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Diazepam: (Major) Concomitant use of conivaptan and diazepam, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with diazepam. Subsequent treatment with CYP3A substrates, such as diazepam, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Dienogest; Estradiol valerate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Digoxin: (Moderate) Coadministration of digoxin with oral conivaptan results in a reduction in clearance of digoxin. If digoxin is administered with conivaptan, the clinician should be alert to the possibility of increases in digoxin plasma concentrations. In addition, electrolyte disturbances like hypokalemia and hypomagnesemia may occur with administration of conivaptan. Drug-induced hypokalemia increases the potential for proarrhythmic effects during treatment with digoxin.
    Dihydroergotamine: (Severe) Dihydroergotamine is a CYP3A4 substrate. Conivaptan is a potent inhibitor of CYP3A4 and may increase concentrations of dihydroergotamine. The risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities, and/or other serious effects) is potentially increased by the concomitant use of CYP3A4 inhibitors. Coadministration of dihydroergotamine and conivaptan should be avoided to minimize the risk of ergot toxicity. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates (i.e., dihydroergotamine) may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Diltiazem: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and diltiazem, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and diltiazem. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as diltiazem, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Disopyramide: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as disopyramide, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with disopyramide. Treatment with disopyramide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Docetaxel: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and docetaxel, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of docetaxel. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as docetaxel, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with docetaxel.
    Dofetilide: (Major) Hypokalemia may occur with administration of potassium-depleting drugs such as conivaptan, increasing the potential for dofetilide-induced torsade de pointes. Conivaptan has been associated with hypokalemia (9.8%). Potassium levels should be within the normal range prior and during administration of dofetilide. Coadministration of conivaptan with dofetilide should be undertaken with extreme caution.
    Dolutegravir: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and dolutegravir, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of dolutegravir. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with dolutegravir.
    Donepezil: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as donepezil, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with donepezil. Treatment with donepezil may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Donepezil; Memantine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as donepezil, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with donepezil. Treatment with donepezil may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Doxazosin: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents. Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with conivaptan. Conivaptan is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
    Doxorubicin: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and doxorubicin, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of doxorubicin. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as doxorubicin, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with doxorubicin.
    Dronabinol, THC: (Major) Avoid the coadministration of dronabinol with conivaptan, due to the increased risk of serious dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, seizures, and hemodynamic instability, as well as feeling high, dizziness, confusion, somnolence). Subsequent treatment with dronabinol should be initiated no sooner than 1 week after the infusion of conivaptan is completed. Dronabinol is a CYP2C9 and 3A4 substrate; conivaptan is a strong inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol. Coadministration of intravenous conivaptan (40 mg per day) increased the mean AUC values of another CYP3A4 substrate, midazolam, by approximately 2-fold and 3-fold.
    Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A. Conivaptan is an inhibitor and a substrate of CYP3A4. No data exist regarding the appropriate dose adjustment needed to allow safe administration of dronedarone with CYP3A4 inhibitors; therefore, use caution when coadministering dronedarone with CYP3A4 inhibitors such as conivaptan. Also, the effects of dronedarone on the pharmacokinetics of convaptan have not been described, although an increase in conivaptan serum concentrations is possible.
    Drospirenone; Estradiol: (Minor) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include conivaptan. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Drospirenone; Ethinyl Estradiol: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy. (Minor) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include conivaptan.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy. (Minor) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. Strong CYP3A4 inhibitors include conivaptan.
    Dutasteride: (Moderate) According to the manufacturer, concomitant use of conivaptan (a strong CYP3A4 inhibitor) and CYP3A substrates (such as dutasteride) should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with dutasteride. Treatment with dutasteride may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of conivaptan. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as conivaptan, should be avoided. (Moderate) According to the manufacturer, concomitant use of conivaptan (a strong CYP3A4 inhibitor) and CYP3A substrates (such as dutasteride) should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with dutasteride. Treatment with dutasteride may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Efavirenz: (Moderate) Conivaptan is a potent CYP3A4 inhibitor with potential to reduce the metabolism of efavirenz. In addition, efavirenz has potential to induce CYP3A4 isoenzymes, which could increase the metabolism of conivaptan, a sensitive CYP3A4 substrate. Although this potential interaction has not been studied, coadminister these drugs with caution.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Conivaptan is a potent CYP3A4 inhibitor with potential to reduce the metabolism of efavirenz. In addition, efavirenz has potential to induce CYP3A4 isoenzymes, which could increase the metabolism of conivaptan, a sensitive CYP3A4 substrate. Although this potential interaction has not been studied, coadminister these drugs with caution. (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir; grazoprevir with conivaptan should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Conivaptan is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir and grazoprevir are metabolized by CYP3A. In addition, plasma concentrations of conivaptan (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
    Eletriptan: (Severe) Conivaptan is a potent CYP3A4inhibitor and a P-glycoprotein (P-gp) inhibitor; eletriptan is a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of eletriptan. According to the manufacturer of eletriptan, eletriptan is contraindicated for use within 72 hours of usage of any drug that is a potent CYP3A4 inhibitor whereby the inhibition effect is described in the prescribing information for the potential interacting drug. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as eletriptan, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with eletriptan.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of conivaptan and eliglustat is contraindicated. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both conivaptan and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Subsequent to the end of the conivaptan infusion, at least 1 week must pass before eliglustat may be initiated in IMs or PMs, or the dosage increased in EMs. Conivaptin is a strong CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as conivaptan, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Minor) Close clinical monitoring is advised when administering conivaptan with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Conivaptan is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events. (Minor) Close clinical monitoring is advised when administering conivaptan with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Conivaptan is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Enalapril, Enalaprilat: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Enalapril; Felodipine: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and felodipine, a CYP3A4 substrate. Coadministration of felodipine with potent CYP3A4 inhibitors may lead to a several-fold increase in felodipine plasma concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as felodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Eplerenone: (Severe) Coadministration of conivaptan and eplerenone is contraindicated. Conivaptan potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. Treatment with eplerenone may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Epoprostenol: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Eprosartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Ergoloid Mesylates: (Severe) Ergoloid mesylates are CYP3A4 substrates. Conivaptan is a potent inhibitor of CYP3A4 and may increase concentrations of ergoloid mesylates. The risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities, or other serious effects) is potentially increased by the concomitant use of CYP3A4 inhibitors. Coadministration of ergoloid mesylates and conivaptan should be avoided to minimize the risk of ergot toxicity. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates (i.e., ergoloid mesylates) may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ergonovine: (Severe) Ergonovine is a CYP3A4 substrate. Conivaptan is a potent inhibitor of CYP3A4 and may increase concentrations of ergonovine. The risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities, or other serious effects) is potentially increased by the concomitant use of CYP3A4 inhibitors. Coadministration of ergonovine and conivaptan should be avoided to minimize the risk of ergot toxicity. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates (i.e., ergonovine) may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ergotamine: (Severe) Ergotamine is a CYP3A4 substrate. Conivaptan is a potent inhibitor of CYP3A4 and may increase concentrations of ergotamine. The risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities, or other serious effects) is potentially increased by the concomitant use of CYP3A4 inhibitors. Coadministration of ergotamine and conivaptan should be avoided to minimize the risk of ergot toxicity. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates (i.e., ergotamine) may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with conivaptan due to the risk of increased erlotinib-related adverse reactions. According to the manufacturer of conivaptan, treatment with erlotinib may be initiated no sooner than 1 week after completion of conivaptan therapy. The manufacturer of erlotinib suggests that if concomitant use is unavoidable and severe reactions occur, the dose of erlotinib should be reduced by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Conivaptan is a strong CYP3A4 inhibitor. Conivaptan has increased the mean AUC of another CYP3A4 substrate, midazolam, by 2- to 3-fold. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with conivaptan may also increase erlotinib exposure.
    Erythromycin: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and erythromycin, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and erythromycin. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as erythromycin, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Erythromycin; Sulfisoxazole: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and erythromycin, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and erythromycin. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as erythromycin, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Estazolam: (Major) Concomitant use of conivaptan and estazolam, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with estazolam. Subsequent treatment with CYP3A substrates, such as estazolam, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol; Levonorgestrel: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol; Norethindrone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol; Norgestimate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4, such as conivaptan, may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Eszopiclone: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as eszopiclone, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with eszopiclone. Treatment with eszopiclone may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Desogestrel: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Etonogestrel: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Levonorgestrel: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Norelgestromin: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Norethindrone: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Norgestimate: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethinyl Estradiol; Norgestrel: (Major) Avoid coadministration of conivaptan, a P-glycoprotein (P-gp) inhibitor and strong 3A4 inhibitor, and ethinyl estradiol, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in increased concentrations of both conivaptan and ethinyl estradiol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethinyl estradiol. Treatment with ethinyl estradiol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ethosuximide: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as ethosuximide, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethosuximide. Treatment with ethosuximide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Etoposide, VP-16: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and etoposide, VP-16, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of etoposide, VP-16. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as etoposide, VP-16, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with etoposide, VP-16.
    Everolimus: (Major) Avoid coadministration of conivaptan with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus; subsequent treatment with everolimus should be initiated no sooner than 1 week after the conivaptan infusion is completed. Coadministration of conivaptan with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); conivaptan is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased everolimus exposure by 15-fold.
    Ezetimibe; Simvastatin: (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and simvastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as simvastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as simvastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Felodipine: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and felodipine, a CYP3A4 substrate. Coadministration of felodipine with potent CYP3A4 inhibitors may lead to a several-fold increase in felodipine plasma concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as felodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Fentanyl: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and fentanyl, a CYP3A4/P-gp substrate. Concurrent use may result in elevated fentanyl serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as fentanyl, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with fentanyl. Treatment with fentanyl may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Fesoterodine: (Moderate) Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. In theory, the potent CYP3A4 inhibitory effects of conivaptan may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. Fesoterodine doses greater than 4 mg/day are not recommended during concurrent use of potent 3A4 inhibitors.
    Fexofenadine: (Minor) Use caution when administering conivaptan and fexofenadine concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as fexofenadine, can increase fexofenadine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Fexofenadine; Pseudoephedrine: (Minor) Use caution when administering conivaptan and fexofenadine concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as fexofenadine, can increase fexofenadine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Flibanserin: (Severe) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as conivaptan, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Fluconazole: (Major) Coadministration of conivaptan (CYP3A4 substrate) with itraconazole or ketoconazole is contraindicated according to the manufacturer. Coadministration of oral conivaptan 10 mg with ketoconazole 200 mg has resulted in a 4-fold and 11-fold increase in the Cmax and AUC of conivaptan, respectively. The effect of coadministration of ketoconazole with intravenous conivaptan has not been studied. Intravenous conivaptan results in higher drug exposure than oral conivaptan. The clinical significance of increased conivaptan plasma concentrations is unknown. Due to the contraindication with itraconazole and ketoconazole, it is prudent for clinicians to avoid coadministering conivaptan with other systemic azole antifungals which inhibit CYP3A4 isoenzymes such as fluconazole, IV miconazole, and voriconazole.
    Fludrocortisone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Flunisolide: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Flurazepam: (Major) Concomitant use of conivaptan and flurazepam, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with flurazepam. Subsequent treatment with CYP3A substrates, such as flurazepam, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Fluticasone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Fluticasone; Salmeterol: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids. (Moderate) The coadministration of vilanterol with strong CYP3A4 inhibitors such as conivaptan can result in elevated vilanterol plasma concentrations and increased risk for adverse reactions.
    Fluticasone; Vilanterol: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids. (Moderate) The coadministration of vilanterol with strong CYP3A4 inhibitors such as conivaptan can result in elevated vilanterol plasma concentrations and increased risk for adverse reactions.
    Fluvoxamine: (Moderate) Coadministration of conivaptan with CYP3A4 inhibitors, like fluvoxamine, could lead to an increase in conivaptan serum concentrations.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with conivaptan. Conivaptan is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with conivaptan, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol; Mometasone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Fosamprenavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like fosamprenavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and fosamprenavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein; fosamprenavir is a substrate of both CYP3A4 and P-gp. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Fosinopril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Galantamine: (Major) According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as galantamine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with galantamine. Treatment with galantamine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Gefitinib: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as gefitinib, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with gefitinib. Treatment with gefitinib may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and conivaptan as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); conivaptan is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and conivaptan as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); conivaptan is an inhibitor of P-gp.
    Glyburide: (Moderate) Glyburide is a substrate of drug transporter P-glycoprotein (P-gp). Conivaptan is a P-gp inhibitor and may theoretically increase concentrations of glyburide. Patients should be monitored for changes in glycemic control.
    Glyburide; Metformin: (Moderate) Glyburide is a substrate of drug transporter P-glycoprotein (P-gp). Conivaptan is a P-gp inhibitor and may theoretically increase concentrations of glyburide. Patients should be monitored for changes in glycemic control.
    Grapefruit juice: (Moderate) Although not studied, grapefruit juice (food) may interact with conivaptan. Grapefruit juice contains compounds (psoralen derivatives and possibly the flavonoid naringenin) that inhibit the cytochrome P-450 CYP3A4 isozyme in the gut wall. Since conivaptan is metabolized by CYP3A4 isoenzymes, concurrent administration with grapefruit juice could theoretically increase conivaptan serum concentrations. The clinical significance of this potential interaction has not been evaluated.
    Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Guanfacine: (Severe) Conivaptan may significantly increase guanfacine plasma concentrations; avoid concomitant use. Subsequent therapy with guanfacine may be initiated no sooner than 1 week after the infusion of conivaptan is complete. Guanfacine is primarily metabolized by CYP3A4 and conivaptan is a strong CYP3A4 inhibitor. Additive hypotension may also occur between conivaptan and other agents that can lower blood pressure.
    Halofantrine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as halofantrine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with halofantrine. Treatment with halofantrine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Haloperidol: (Moderate) Conivaptan is a substrate and inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and substrates or inhibitors of CYP3A4. Elevated haloperidol concentrations occurring through inhibition of CYP3A4 may increase the risk of adverse effects, including QT prolongation. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
    Homatropine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Ibuprofen: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and conivaptan are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as conivaptan, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocortisone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Ibrutinib: (Major) Avoid the concomitant use of ibrutinib and conivaptan; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Treatment with ibrutinib should be initiated no sooner than 1 week after the infusion of conivaptan is completed. Ibrutinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with conivaptan may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of conivaptan could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and conivaptan is a CYP3A4 inhibitor.
    Idelalisib: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like idelalisib is contraindicated. The plasma concentrations of conivaptan may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and idelalisib.
    Ifosfamide: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and conivaptan, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Iloprost: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Imatinib: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and imatinib, STI-571, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and imatinib, STI-571. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Indacaterol: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and indacaterol, a CYP3A4/P-gp substrate when possible. Concurrent use may result in increased serum concentrations of indacaterol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times) of the coadministered substrate. Theoretically, similar pharmacokinetic effects could be seen with indacaterol. Dual inhibitors of CYP3A4/P-gp have increased indacaterol concentrations by 1.9-fold.
    Indacaterol; Glycopyrrolate: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and indacaterol, a CYP3A4/P-gp substrate when possible. Concurrent use may result in increased serum concentrations of indacaterol. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times) of the coadministered substrate. Theoretically, similar pharmacokinetic effects could be seen with indacaterol. Dual inhibitors of CYP3A4/P-gp have increased indacaterol concentrations by 1.9-fold.
    Indinavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like indinavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and indinavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein; indinavir is a substrate of both CYP3A4 and P-gp. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Irbesartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Irinotecan Liposomal: (Major) If possible, avoid concomitant use of irinotecan liposomal with conivaptan, a strong CYP3A4 inhibitor, due to increased risk of irinotecan-related toxicity. Discontinue conivaptan at least 1 week prior to initiation of liposomal irinotecan therapy. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Major) Avoid coadministration of conivaptan, a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and irinotecan, a CYPA4/P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Severe) Concomitant use of isavuconazonium with conivaptan is contraindicated due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; conivaptan is a strong inhibitor of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inhibitors is contraindicated. Isavuconazole serum concentrations were increased 5-fold when coadministered with ketoconazole, another strong CYP3A4 inhibitor. Elevated conivaptan concentrations would also be expected with coadministration, as conivaptan is a CYP3A4 substrate and isavuconazole is a moderate CYP3A4 inhibitor.
    Isoniazid, INH: (Moderate) Coadministration of conivaptan with CYP3A4 inhibitors, like isoniazide, could lead to an increase in conivaptan serum concentrations.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Coadministration of conivaptan with CYP3A4 inhibitors, like isoniazide, could lead to an increase in conivaptan serum concentrations. (Moderate) Coadministration of rifampin, a strong CYP3A4 inducer and P-glycoprotein (P-gp) substrate, and conivaptan, a CYP3A4 substrate and P-gp inhibitor, may result in elevated rifampin concentrations and decreased conivaptan concentrations. Monitor for increased adverse effects of rifampin and reduced efficacy of conivaptan.
    Isoniazid, INH; Rifampin: (Moderate) Coadministration of conivaptan with CYP3A4 inhibitors, like isoniazide, could lead to an increase in conivaptan serum concentrations. (Moderate) Coadministration of rifampin, a strong CYP3A4 inducer and P-glycoprotein (P-gp) substrate, and conivaptan, a CYP3A4 substrate and P-gp inhibitor, may result in elevated rifampin concentrations and decreased conivaptan concentrations. Monitor for increased adverse effects of rifampin and reduced efficacy of conivaptan.
    Isradipine: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and isradipine, a CYP3A4 substrate. Coadministration may result in elevated isradipine plasma concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as isradipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Itraconazole: (Severe) Coadministration of conivaptan with itraconazole is contraindicated. Use of conivaptan is not recommended for 2 weeks after itraconazole therapy; use of itraconazole is not recommended for at least 1 week after completion of conivaptan therapy. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and itraconazole. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein; itraconazole is a substrate of both CYP3A4 and P-gp.
    Ivabradine: (Severe) Coadministration of ivabradine and conivaptan is contraindicated. Ivabradine is primarily metabolized by CYP3A4; conivaptan is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) Avoid concurrent use of conivaptan and ivacaftor. The manufacturer of conivaptan recommends subsequent treatment with drugs metabolized primarily via CYP3A-mediated metabolism, such as ivacaftor, may be initiated or resumed no sooner than 1 week after the infusion of conivaptan is complete. When used with a strong CYP3A inhibitor, such as conivaptan, the manufacturer of ivacaftor recommends administering ivacaftor at the usual recommended dose, but reducing the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and conivaptan is a strong CYP3A inhibitor. Ivacaftor is also a weak inhibitor of CYP3A, and conivaptan is metabolized by CYP3A. Coadministration may increase both conivaptan and ivacaftor exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as conivaptan should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose.
    Ketoconazole: (Severe) Coadministration of conivaptan (CYP3A4 substrate) with ketoconazole, a potent CYP3A4 inhibitor, is contraindicated according to the manufacturer. Coadministration of oral conivaptan 10 mg with ketoconazole 200 mg resulted in a 4-fold and 11-fold increase in the Cmax and AUC of conivaptan, respectively. The effect of coadministration of ketoconazole with intravenous conivaptan has not been studied. In addition, conivaptan inhibits both CYP3A4; ketoconazole is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Lansoprazole: (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and lansoprazole, a CYP3A4/P-gp substrate. Concurrent use may result in elevated lansoprazole serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as lansoprazole, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with lansoprazole. Treatment with lansoprazole may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Lansoprazole; Naproxen: (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and lansoprazole, a CYP3A4/P-gp substrate. Concurrent use may result in elevated lansoprazole serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as lansoprazole, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with lansoprazole. Treatment with lansoprazole may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Lapatinib: (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with conivaptan, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ledipasvir; Sofosbuvir: (Moderate) Caution is warranted when conivaptan is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of conivaptan; monitor for potential reduction in efficacy. Conivaptan is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of conivaptan; monitor for potential reduction in efficacy. Conivaptan is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Levobupivacaine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as levobupivacaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with levobupivacaine. Treatment with levobupivacaine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Levomethadyl: (Major) Conivaptan inhibits hepatic CYP3A4 and may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
    Levomilnacipran: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Conivaptan is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Lidocaine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as lidocaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with lidocaine. Treatment with lidocaine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Lisinopril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Lomitapide: (Severe) Concomitant use of conivaptan and lomitapide is contraindicated. If treatment with conivaptan is unavoidable, lomitapide should be stopped during the course of treatment. Conivaptan is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor.
    Loop diuretics: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Loperamide: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and loperamide, a CYP3A4/P-gp substrate. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Concurrent use may result in elevated loperamide serum concentrations further increasing the risk of cardiac toxicities and CNS effects. According to the manufacturer of conivaptan, concomitant use with CYP3A substrates, such as loperamide, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with loperamide. Treatment with loperamide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Loperamide; Simethicone: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and loperamide, a CYP3A4/P-gp substrate. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Concurrent use may result in elevated loperamide serum concentrations further increasing the risk of cardiac toxicities and CNS effects. According to the manufacturer of conivaptan, concomitant use with CYP3A substrates, such as loperamide, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with loperamide. Treatment with loperamide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Lopinavir; Ritonavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like lopinavir; ritonavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and lopinavir; ritonavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein; ritonavir is a substrate of both CYP3A4 and P-gp. Per the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like ritonavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and ritonavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Per the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Loratadine: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and loratadine, a CYP3A4/P-gp substrate. Concurrent use may result in elevated loratadine serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as loratadine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with loratadine. Treatment with loratadine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Loratadine; Pseudoephedrine: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and loratadine, a CYP3A4/P-gp substrate. Concurrent use may result in elevated loratadine serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as loratadine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with loratadine. Treatment with loratadine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Losartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Lovastatin: (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and lovastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with lovastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as lovastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as lovastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Lovastatin; Niacin: (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and lovastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with lovastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as lovastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as lovastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of conivaptan and ivacaftor. The manufacturer of conivaptan recommends subsequent treatment with drugs metabolized primarily via CYP3A-mediated metabolism, such as ivacaftor, may be initiated or resumed no sooner than 1 week after the infusion of conivaptan is complete. When used with a strong CYP3A inhibitor, such as conivaptan, the manufacturer of ivacaftor recommends administering ivacaftor at the usual recommended dose, but reducing the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and conivaptan is a strong CYP3A inhibitor. Ivacaftor is also a weak inhibitor of CYP3A, and conivaptan is metabolized by CYP3A. Coadministration may increase both conivaptan and ivacaftor exposure leading to increased or prolonged therapeutic effects and adverse events. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of conivaptan; avoid concurrent use if possible. If concomitant use of conivaptan is necessary, monitor efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when conivaptan is used in a patient already taking lumacaftor; ivacaftor. If a patient is already receiving conivaptan therapy, waiting at least 1 week after the last conivaptan dose before starting lumacaftor; ivacaftor would simplify treatment initiation. However, if the decision is made to begin lumacaftor; ivacaftor in a patient already receiving conivaptan, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking conivaptan. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Conivaptan is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of conivaptan and decrease its therapeutic efficacy. Although conivaptan is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor, itraconazole, increased ivacaftor exposure by 4.3-fold.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of conivaptan; avoid concurrent use if possible. If concomitant use of conivaptan is necessary, monitor efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when conivaptan is used in a patient already taking lumacaftor; ivacaftor. If a patient is already receiving conivaptan therapy, waiting at least 1 week after the last conivaptan dose before starting lumacaftor; ivacaftor would simplify treatment initiation. However, if the decision is made to begin lumacaftor; ivacaftor in a patient already receiving conivaptan, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking conivaptan. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Conivaptan is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of conivaptan and decrease its therapeutic efficacy. Although conivaptan is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor, itraconazole, increased ivacaftor exposure by 4.3-fold.
    Lurasidone: (Severe) Concurrent use of lurasidone with strong CYP3A4 inhibitors, such as conivaptan, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4.
    Maraviroc: (Major) Coadministration of conivaptan, a potent CYP3A4/P-glycoprotein (P-gp) inhibitor, and maraviroc, a CYP3A4/P-gp substrate, may result in elevated maraviroc concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided and treatment with a CYP3A substrate may be initiated no sooner than 1 week after completion of conivaptan therapy. According to the manufacturer of maraviroc, a reduced adult maraviroc dose of 150 mg PO twice daily is recommended when it is administered in the presence of a potent CYP3A inhibitor, with or without a concomitant CYP3A inducer; Coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCl less than 30 mL/min. Dose recommendations in pediatrics when maraviroc is administered with a potent CYP3A4 inhibitor are: 150 mg PO twice daily for children weighing 40 kg or more, 100 mg PO twice daily for children weighing 30 to 39 kg, 75 mg PO twice daily (or 80 mg PO twice daily for solution) for children weighing 20 to 29 kg, and 50 mg PO twice daily for children weighing 10 to 19 kg.
    Mefloquine: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and mefloquine, a CYP3A4/P-gp substrate. Concurrent use may result in elevated mefloquine serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as mefloquine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with mefloquine. Treatment with mefloquine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Metformin; Repaglinide: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as repaglinide, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with repaglinide. Treatment with repaglinide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Metformin; Saxagliptin: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and saxagliptin, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of saxagliptin. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as saxagliptin, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with saxagliptin.
    Methadone: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and methadone, a CYP3A4/P-gp substrate. Concurrent use may result in elevated methadone serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as methadone, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with methadone. Treatment with methadone may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Methylergonovine: (Severe) Methylergonovine is a CYP3A4 substrate. Conivaptan is a potent inhibitor of CYP3A4 and may increase concentrations of methylergonovine. The risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, potentially leading to gangrene, cyanosis, stroke, numbness of the extremities, and/or other serious effects) is potentially increased by the concomitant use of CYP3A4 inhibitors. Coadministration of methylergoinovine and conivaptan should be avoided to minimize the risk of ergot toxicity. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates (i.e., methylergonovine) may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Methylprednisolone: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and methylprednisolone, a CYP3A4/P-gp substrate. Concurrent use may result in elevated methylprednisolone serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as methylprednisolone, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with methylprednisolone. Treatment with methylprednisolone may be initiated no sooner than 1 week after completion of conivaptan therapy. In addition, conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Midazolam: (Major) Concomitant use of conivaptan and midazolam, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean AUC values of midazolam by approximately 2-fold and 3-fold when coadministered with midazolam 1 mg IV or 2 mg PO, respectively. Subsequent treatment with CYP3A substrates, such as midazolam, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and conivaptan as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Consider an alternative agent to replace conivaptan. According to the manufacturer of conivaptan (strong CYP3A4 inhibitor), subsequent treatment with CYP3A substrates, such as midostaurin, may be initiated no sooner than 1 week after completion of conivaptan therapy. The manufacturer of midostaurin recommends that if coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Mifepristone, RU-486: (Severe) Conivaptan is a sensitive substrate of CYP3A. Coadministration with strong CYP3A inhibitors, such as mifepristone, increases conivaptan exposure and is contraindicated. Extreme caution must be used if use together is considered medically necessary. The lowest possible dose and/or a decreased frequency of dosing must be used with therapeutic drug monitoring when possible. Use together may increase the risk for serious side effects from conivaptan, such as seizures, hypotension, confusion or other effects.
    Mitomycin: (Moderate) Use caution when administering conivaptan and mitomycin concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as mitomycin, can increase mitomycin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Mitotane: (Major) Use caution if mitotane and conivaptan are used concomitantly, and monitor for decreased efficacy of conivaptan and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and conivaptan is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of conivaptan.
    Modafinil: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as modafinil, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with modafinil. Treatment with modafinil may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Moexipril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Mometasone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Morphine: (Moderate) Use caution when administering conivaptan and morphine concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as morphine, can increase morphine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Morphine; Naltrexone: (Moderate) Use caution when administering conivaptan and morphine concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as morphine, can increase morphine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Nebivolol; Valsartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Nefazodone: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like nefazodone is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and nefazodone. In addition, conivaptan inhibits CYP3A4; nefazodone is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Nelfinavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like nelfinavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and nelfinavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein; nelfinavir is a substrate of both CYP3A4 and P-gp. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Neratinib: (Major) Avoid concomitant use of conivaptan with neratinib due to an increased risk of neratinib-related toxicity. Subsequent treatment with neratinib may be initiated no sooner than 1 week after the infusion of conivaptan is completed. Neratinib is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 481%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Conivaptan is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Conivaptan is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
    Niacin; Simvastatin: (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and simvastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as simvastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as simvastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Nicardipine: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor, and nicardipine, a CYP3A4/P-gp substrate. Coadministration may result in elevated concentrations of nicardipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as nicardipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Nifedipine: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and nifedipine, a CYP3A4 substrate. Coadministration may result in elevated nifedipine plasma concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as nifedipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Nilotinib: (Major) Concomitant use of nilotinib, a CYP3A4/P-glycoprotein (P-gp) substrate and CYP3A4 inhibitor, and conivaptan, a CYP3A4 substrate/inhibitor and P-gp inhibitor, may result in increased concentrations of both agents. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Treatment with nilotinib may be initiated no sooner than 1 week after completion of conivaptan therapy. According to the manufacturer of nilotinib, concomitant use of nilotinib and a strong CYP3A4 inhibitor should be avoided. If a strong CYP3A4 inhibitor cannot be avoided, interruption of nilotinib treatment is advised. If nilotinib must be continued, consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Nimodipine: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and nimodipine, a CYP3A4 substrate. Coadministration may result in elevated nimodipine plasma concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as nimodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Nintedanib: (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and nintedanib, a CYP3A4/P-gp substrate. Concurrent use may result in elevated nintedanib serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as nintedanib, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with lansoprazole. Treatment with nintedanib may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Nisoldipine: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and nisoldipine, a CYP3A4 substrate. Coadministration may result in elevated nisoldipine plasma concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as nisoldipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Octreotide: (Moderate) Conivaptan is a substrate of CYP3A4. Coadministration of conivaptan with CYP3A4 inhibitors could lead to an increase in conivaptan serum concentrations. According to the manufacturer, coadministration of conivaptan with strong CYP3A4 inhibitors (e.g., ketoconazole) is contraindicated. Until the further data are available, it is prudent to coadminister conivaptan with caution or to avoid coadministering conivaptan with drugs known to be significant inhibitors of CYP3A4 isoenzymes, such as octreotide.
    Olaparib: (Major) Avoid coadministration of olaparib with conivaptan and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and conivaptan is a strong CYP3A4 inhibitor.
    Olmesartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like ritonavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and ritonavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Per the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Omeprazole: (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and omeprazole, a CYP3A4/P-gp substrate. Concurrent use may result in elevated omeprazole serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as omeprazole, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with omeprazole. Treatment with omeprazole may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Omeprazole; Sodium Bicarbonate: (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and omeprazole, a CYP3A4/P-gp substrate. Concurrent use may result in elevated omeprazole serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as omeprazole, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with omeprazole. Treatment with omeprazole may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ondansetron: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and ondansetron, a CYP3A4/P-gp substrate. Concurrent use may result in elevated ondansetron serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as ondansetron, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ondansetron. Treatment with ondansetron may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Oxycodone: (Moderate) Concomitant use of oxycodone with conivaptan may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of conivaptan could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4 and conivaptan is a CYP3A4 inhibitor.
    Paclitaxel: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and paclitaxel, a CYP3A4/P-gp substrate. Concurrent use may result in elevated paclitaxel serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as paclitaxel, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with paclitaxel. Treatment with paclitaxel may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Palbociclib: (Major) Avoid coadministration of conivaptan with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of conivaptan may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If conivaptan is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of conivaptan) to the dose used before initiation of conivaptan. Palbociclib is primarily metabolized by CYP3A4 and conivaptan is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A and conivaptan is a sensitive CYP3A4 substrate.
    Panobinostat: (Major) Avoid coadministration of conivaptan, a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and panobinostat, a CYPA4/P-gp substrate. Exposure to panobinostat may increase when the drugs are used together. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. According to the manufacturer of panobinostat, if panobinostat is administered with a strong CYP3A4 inhibitor the initial dose of panobinostat should be reduced from 20 mg PO to 10 mg PO. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
    Pantoprazole: (Minor) Concurrent administration of pantoprazole with conivaptan may result in increased pantoprazole plasma concentrations; monitor for adverse effects if these drugs are administered together. Pantoprazole is a P-glycoprotein (P-gp) substrate and conivaptan is a P-gp inhibitor.
    Paricalcitol: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as paricalcitol, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with paricalcitol. Treatment with paricalcitol may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Pazopanib: (Major) Avoid administering pazopanib with strong CYP3A4 inhibitors, such as conivaptan. If co-administration with a strong CYP3A4 inhibitor is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. The concomitant use of pazopanib, a weak CYP3A4 inhibitor and a CYP3A4 substrate, and conivaptan, a strong CYP3A4 inhibitor and CYP3A4 substrate, may result in altered pazopanib and/or conivaptan concentrations.
    Perampanel: (Moderate) Concurrent use of perampanel with conivaptan may increase perampanel plasma concentrations. Conivaptan is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Perindopril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Perindopril; Amlodipine: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and amlodipine, a CYP3A4 substrate. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as amlodipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Phenicol Derivatives: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like chloramphenicol is contraindicated. The plasma concentrations of conivaptan may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and chloramphenicol.
    Phenoxybenzamine: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Phentolamine: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 17 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as conivaptan. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions.
    Pimozide: (Major) Concurrent use of pimozide and conivaptan should be avoided. Pimozide is metabolized primarily through CYP3A4, and conivaptan is a CYP3A4 inhibitor. Elevated pimozide concentrations occurring through inhibition of CYP3A4 can lead to QT prolongation, ventricular arrhythmias, and sudden death. Treatment with pimozide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ponatinib: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and conivaptan, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Posaconazole: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like posaconazole is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and posaconazole. In addition, conivaptan inhibits P-glycoprotein; posaconazole is a substrate of P-gp.
    Potassium-sparing diuretics: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Prednisolone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Prednisone: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and prednisone, a CYP3A4/P-gp substrate. Concurrent use may result in elevated prednisone serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as prednisone, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with prednisone. Treatment with prednisone may be initiated no sooner than 1 week after completion of conivaptan therapy. In addition, conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Quazepam: (Major) Concomitant use of conivaptan and quazepam, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with quazepam. Subsequent treatment with CYP3A substrates, such as quazepam, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Quetiapine: (Major) Coadministration of conivaptan, a potent CYP3A4 inhibitor, with quetiapine may result in increased exposure to quetiapine, a CYP3A4 substrate. The manufacturer of conivaptan recommends avoiding concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4. Subsequent treatment with CYP3A substrates, such as quetiapine, may be initiated no sooner than 1 week after completion of conivaptan therapy. The quetiapine manufacturer recommends reducing the quetiapine dose to one sixth of the current dose and monitor for quetiapine-related adverse events when combined with a potent CYP3A4 inhibitor. If the CYP3A4 inhibitor is discontinued, increase the quetiapine dose by 6-fold.
    Quinapril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Quinidine: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and quinidine, a CYP3A4/P-gp substrate. Concurrent use may result in elevated quinidine serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as quinidine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with quinidine. Treatment with quinidine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Quinine: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and quinine, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Concurrent use may result in elevated concentrations of both drugs. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as quinine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with quinine. Treatment with quinine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ramelteon: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as ramelteon, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2-3 times). Theoretically, similar pharmacokinetic effects could be seen with ramelteon. Treatment with ramelteon may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ramipril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Ranolazine: (Severe) Concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and ranolazine, a CYP3A4/P-gp substrate and weak CYP3A4 inhibitor is contraindicated. Coadministration may result in elevated concentrations of both conivaptan and ranolazine. According to the manufacturer of ranolazine, concurent use with drugs known to be strong CYP3A inhibitors, such as conivaptan, is contraindicated. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Regorafenib: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and conivaptan, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Repaglinide: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as repaglinide, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with repaglinide. Treatment with repaglinide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Reserpine: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Ribociclib: (Major) Avoid coadministration of ribociclib, a moderate CYP3A4 inhibitor and substrate, with conivaptan, a strong CYP34 inhibitor and substrate, as the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions including QT prolongation; consider an alternative treatment with less potential for CYP3A inhibition. According to the manufacturer of conivaptan, subsequent treatment with a CYP3A substrate like ribociclib may be initiated no sooner than 1 week after the infusion of conivaptan is completed, although the manufacturer of ribociclib recommends reducing the dose of ribociclib to 400 mg once daily if concurrent use of a strong CYP3A4 inhibitor is unavoidable. If conivaptan is discontinued, resume the previous ribociclib dose after at least 5 half-lives of conivaptan.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib, a moderate CYP3A4 inhibitor and substrate, with conivaptan, a strong CYP34 inhibitor and substrate, as the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions including QT prolongation; consider an alternative treatment with less potential for CYP3A inhibition. According to the manufacturer of conivaptan, subsequent treatment with a CYP3A substrate like ribociclib may be initiated no sooner than 1 week after the infusion of conivaptan is completed, although the manufacturer of ribociclib recommends reducing the dose of ribociclib to 400 mg once daily if concurrent use of a strong CYP3A4 inhibitor is unavoidable. If conivaptan is discontinued, resume the previous ribociclib dose after at least 5 half-lives of conivaptan.
    Rifabutin: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as rifabutin, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with rifabutin. Treatment with rifabutin may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Rifampin: (Moderate) Coadministration of rifampin, a strong CYP3A4 inducer and P-glycoprotein (P-gp) substrate, and conivaptan, a CYP3A4 substrate and P-gp inhibitor, may result in elevated rifampin concentrations and decreased conivaptan concentrations. Monitor for increased adverse effects of rifampin and reduced efficacy of conivaptan.
    Rifaximin: (Moderate) Use caution when administering conivaptan and rifaximin concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as rifaximin, can increase rifaximin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Rilpivirine: (Minor) Close clinical monitoring is advised when administering conivaptan with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Conivaptan is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Riociguat: (Major) Avoid coadministration of conivaptan, a potent inhibitor of CYP3A4 and a P-glycoprotein (P-gp) inhibitor, with riociguat, a CYP3A4/P-gp substrate. Concomitant use of riociguat with conivaptan may result in hypotension. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as riociguat, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with riociguat. Treatment with riociguat may be initiated no sooner than 1 week after completion of conivaptan therapy. According to the manufacturer of riociguat, monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
    Ritonavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like ritonavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and ritonavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Per the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Rivaroxaban: (Major) Avoid concomitant administration of rivaroxaban and conivaptan, a combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitor; significant increases in rivaroxaban exposure may increase bleeding risk. Subsequent treatment with rivaroxaban may be initiated no sooner than 1 week after completion of conivaptan therapy. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Concurrent use of rivaroxaban and ketoconazole, another combined P-gp and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 160% and Cmax by 70%. Increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed. Similar effects may be expected with concurrent conivaptan use.
    Romidepsin: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and romidepsin, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of romidepsin. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as romidepsin, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with romidepsin. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops.
    Ruxolitinib: (Major) Modify the ruxolitinib dosage when coadministered with conivaptan. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with conivaptan. Ruxolitinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of conivaptan use.
    Sacubitril; Valsartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Saquinavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like saquinavir boosted with ritonavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and saquinavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein; saquinavir is a substrate of both CYP3A4 and P-gp. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Saxagliptin: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and saxagliptin, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of saxagliptin. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as saxagliptin, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with saxagliptin.
    Sertraline: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and sertraline, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of sertraline. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with sertraline.
    Sibutramine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as sibutramine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with sibutramine. Treatment with sibutramine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Sildenafil: (Major) Concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as sildenafil, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with sildenafil. Treatment with sildenafil may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Silodosin: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and silodosin, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of silodosin. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with silodosin.
    Simeprevir: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and simeprevir, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and simeprevir. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Simvastatin: (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and simvastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as simvastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as simvastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Simvastatin; Sitagliptin: (Major) Concomitant use of conivaptan, a potent CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and simvastatin, a CYP3A4/P-gp substrate, should be avoided. Conivaptan 30 mg/day IV results in a 3-fold increase in the AUC of simvastatin. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving HMG-CoA reductase inhibitors known to be metabolized by CYP3A4. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as simvastatin, should be avoided. Subsequent treatment with CYP3A substrates, such as simvastatin, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Sirolimus: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and sirolimus, a CYP3A4/P-gp substrate. Concurrent use may result in elevated sirolimus serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as sirolimus, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with sirolimus. Treatment with sirolimus may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Sofosbuvir: (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
    Sofosbuvir; Velpatasvir: (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Use caution when administering velpatasvir with conivaptan. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); conivaptan is an inhibitor of P-gp. Conivaptan is also a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Use caution when administering velpatasvir with conivaptan. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); conivaptan is an inhibitor of P-gp. Conivaptan is also a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sotalol: (Major) Conivaptan has been associated with hypokalemia (9.8%). Drug-induced hypokalemia increases the potential for proarrhythmic effects (e.g., torsade de pointes) due to sotalol. Coadministration of conivaptan with sotalol should be undertaken with extreme caution. Sotalol is contraindicated in patients with uncorrected hypokalemia (< 4 mEq/ml).
    Streptogramins: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like dalfopristin; quinupristin is contraindicated. The plasma concentrations of conivaptan may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and dalfopristin; quinupristin.
    Sufentanil: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as sufentani, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with sufentanil. Treatment with sufentanil may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Sunitinib: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as sunitinib, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with sunitinib. Treatment with sunitinib may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Suvorexant: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as conivaptan. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Tacrolimus: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as tacrolimus, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with tacrolimus. Treatment with tacrolimus may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Tadalafil: (Major) Avoid coadministration of conivaptan and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within72 hours of conivaptan for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as conivaptan, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Tamoxifen: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as tamoxifen, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with tamoxifen. Treatment with tamoxifen may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of conivaptan. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as conivaptan, should be avoided.
    Tasimelteon: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as conivaptan, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering conivaptan with telaprevir due to an increased potential for conivaptan-related adverse events. If conivaptan 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 pathways of conivaptan and telaprevir. Both conivaptan and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. When used in combination, the plasma concentrations of both medications may be elevated.
    Telithromycin: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like telithromycin is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and telithromycin. In addition, conivaptan inhibits CYP3A4; telithromycin is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Telmisartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and conivaptan is necessary, as the systemic exposure of conivaptan may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of conivaptan as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of conivaptan if necessary. Conivaptan is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and conivaptan is a P-gp inhibitor. Coadministration of oral conivaptan with a sensitive P-gp substrate reduced clearance of the substrate by 30%, and resulted in 79% and 43% increases in the Cmax and AUC of the substrate, respectively. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Major) Avoid coadministration of temsirolimus with conivaptan due to the risk of an increase in temsirolimus-related adverse reactions. If concomitant use cannot be avoided, consider a temsirolimus dose reduction to 12.5 mg per week. If conivaptan is discontinued, allow a washout period of approximately 1 week before the temsirolimus dose is increased to the dose used before initiation of conivaptan. Temsirolimus is a CYP3A4 substrate and conivaptan is a strong inhibitor of CYP3A4. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively. Conivaptan increased the mean AUC of midazolam, another CYP3A substrate, by 2-fold (IV) and 3-fold (oral), while also increasing the AUC of simvastatin by 3-fold and amlodipine by 2-fold. Additionally, temsirolimus is an in vitro substrate of P-glycoprotein (P-gp) and conivaptan is a P-gp inhibitor. Coadministration of conivaptan with digoxin, a P-gp substrate, increased the digoxin Cmax and AUC by 79% and 43%, respectively, while reducing clearance by 30%.
    Teniposide: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and teniposide, a CYP3A4/P-gp substrate. Concurrent use may result in elevated teniposide serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as teniposide, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with teniposide. Treatment with teniposide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Tenofovir Alafenamide: (Moderate) Coadministration of conivaptan and tenofovir alafenamide may result in elevated tenofovir concentrations. Conivaptan is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Terazosin: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering conivaptan. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; conivaptan is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Testosterone: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and testosterone, a CYP3A4/P-gp substrate. Concurrent use may result in elevated testosterone serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as testosterone, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with testosterone. Treatment with testosterone may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Thiazide diuretics: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Tiagabine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as tiagabine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with tiagabine. Treatment with tiagabine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Ticagrelor: (Major) Concomitant administration of conivaptan, a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and ticagrelor, a CYP3A/P-gp substrate, may result in increased exposure to ticagrelor and an increase in the risk of bleeding. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided and subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. In addition, ticagrelor is a weak inhibitor of CYP3A4 and concurrent use may increase the serum concentration of ticagrelor.
    Tinidazole: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as tinidazole, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with tinidazole. Treatment with tinidazole may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Tipranavir: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like tipranavir boosted with ritonavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and tipranavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein; tipranavir is a substrate of both CYP3A4 and P-gp. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4. Conivaptan is a moderate inhibitor of CYP3A4 and in the same therapeutic class as tolvaptan. Coadministration of conivaptan with tolvaptan may cause a marked increased in tolvaptan concentrations and should be avoided. Additionally, the coadministration of tolvaptan and conivaptan would represent therapeutic duplication and could cause deleterious effects.
    Topotecan: (Major) Avoid the concomitant use of conivaptan, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of conivaptan and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Trabectedin: (Major) Avoid the concomitant use of trabectedin with conivaptan due to significantly increased trabectedin exposure. If short-term conivaptan (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and conivaptan is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Trandolapril: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Trandolapril; Verapamil: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and verapamil, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and verapamil. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as verapamil, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion. (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Trazodone: (Major) Concomitant use of conivaptan and trazodone, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates, such as trazodone, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Treprostinil: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Triamcinolone: (Moderate) Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Triazolam: (Major) Concomitant use of conivaptan and triazolam, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean midazolam AUC values by approximately 2-fold and 3-fold when coadministered with 1 mg IV and 2 mg PO, respectively, of midazolam, another CYP3A4 substrate. Theoretically, similar pharmacokinetic effects could be seen with triazolam. Subsequent treatment with CYP3A substrates, such as triazolam, may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Trimetrexate: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as trimetrexate, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with trimetrexate. Treatment with trimetrexate may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Umeclidinium; Vilanterol: (Moderate) The coadministration of vilanterol with strong CYP3A4 inhibitors such as conivaptan can result in elevated vilanterol plasma concentrations and increased risk for adverse reactions.
    Valbenazine: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as conivaptan. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
    Valsartan: (Moderate) There is potential for additive hypotensive effects when conivaptan is coadministered with antihypertensive agents.
    Vardenafil: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as vardenafil, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with vardenafil. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. Treatment with vardenafil may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Vemurafenib: (Major) Concomitant use of vemurafenib and conivaptan may result in decreased conivaptan concentrations and increased vemurafenib concentrations. Vemurafenib is a CYP3A4 substrate/inducer and conivaptan is a CYP3A4 substrate an a strong CYP3A4 inhibitor. Avoid using these agents together if possible.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and conivaptan; venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and conivaptan is a strong CYP3A4 and P-gp inhibitor. The concomitant use of these agents together is contraindicated during the initial and dose titration phase of venetoclax. If concomitant use of these drugs is required when the patient is on a steady venetoclax dose (after the titration phase), reduce the venetoclax dosage by at least 75% (maximum dose of 100 mg/day). If conivaptan is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study, the venetoclax Cmax and AUC values were increased by 2.3-fold and 6.4-fold, respectively, when a strong CYP3A4 inhibitor was co-administered in NHL patients.
    Verapamil: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and verapamil, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and verapamil. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as verapamil, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Vilazodone: (Major) Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as conivaptan. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued.
    Vinca alkaloids: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and vinblastine, a CYP3A4/P-gp substrate. Concurrent use may result in increased serum concentrations of vinblastine. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with vinblastine.
    Vorapaxar: (Major) Avoid coadministration of vorapaxar and conivaptan. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with conivaptan, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors, such as voriconazole, is contraindicated. Use of these drugs together may result in significantly elevated conivaptan plasma concentrations, resulting in an increased risk for adverse events. Coadministration of oral conivaptan 10 mg with another potent CYP3A4 inhibitor (ketoconazole 200 mg) resulted in a 4-fold and 11-fold increase in the Cmax and AUC of conivaptan, respectively.
    Vorinostat: (Moderate) Use vorinostat and conivaptan together with caution; the risk of QT prolongation and arrhythmias may be increased if electrolyte abnormalities occur. Conivaptan may cause electrolyte imbalances including low potassium; hypomagnesemia, hypokalemia, or hypocalcemia and may increase the risk of QT prolongation with vorinostat. Frequently monitor serum electrolytes if concomitant use of these drugs is necessary.
    Warfarin: (Minor) Conivaptan is a potent CYP3A4 inhibitor, and may alter the pharacokinetics of warfarin. Monitor the INR response when conivaptan intravenous infusion is administered during warfarin therapy.
    Zafirlukast: (Moderate) Coadministration of conivaptan with CYP3A4 inhibitors like zafirlukast could lead to an increase in conivaptan serum concentrations.
    Ziprasidone: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as ziprasidone, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ziprasidone. Treatment with ziprasidone may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Zolpidem: (Major) Concurrent use of conivaptan, a potent CYP3A4 inhibitor, with CYP3A4 substrates, such as zolpidem, should be avoided. Co-administration of conivaptan with some CYP3A substrates has resulted in mean increases of 2 to 3 times the baseline AUC values of these substrates. According to the manufacturer of conivaptan, treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. If co-administration cannot be avoided, consider using a lower dose of zolpidem to minimize the potential for adverse CNS effects. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no available data with conivaptan in human pregnancy to inform a drug-associated risk for major birth defects and miscarriage. When pregnant rats were given conivaptan at doses producing systemic exposures less than those achieved with a therapeutic human dose based on AUC comparisons, the offspring showed decreased neonatal viability, weaning indices, and body weight and delayed reflex and physical development, including sexual maturation. No maternal adverse effects were seen. However, when pregnant rabbits were given conivaptan at doses about twice the human exposure, no adverse maternal or fetal effects were noted. Pharmacokinetic data demonstrate that conivaptan that is taken up by fetal tissue is slowly cleared, suggesting that fetal accumulation is possible. Delayed delivery was observed when conivaptan was administered orally to rats at a dose providing systemic exposure equivalent to the human therapeutic exposure.

    There are no data regarding conivaptan or its metabolites in human milk or the effects of conivaptan on the breast-fed infant or milk production. Conivaptan is present in rat milk. The maximum concentrations of conivaptan in rat milk were reached 1 hour after intravenous administration and were up to 3 times the maternal plasma concentrations after a dose that produced a systemic exposure less than human therapeutic exposure. Because of potential for serious adverse effects, including electrolyte abnormalities, hypotension, and volume depletion, in the breast-fed infant, avoid breast-feeding during treatment with conivaptan.

    MECHANISM OF ACTION

    Arginine vasopressin (AVP) is a peptide hormone consisting of 9 amino acids produced in the hypothalamus-neurohypophysis system. The actions of AVP are mediated by 3 types of vasopressin receptor subtypes: V1A, V1B, and V2 receptors. Conivaptan is a dual vasopressin antagonist with nanomolar affinity for human vasopressin receptors (V1A and V2) in vitro. Vasopressin receptors are found on the vascular smooth muscle cells, the myocardium and the distal tubule of the kidney. The primary pharmacodynamic effect of conivaptan in hyponatremia is mediated by antagonizing the V2 receptors found in the renal collecting ducts. The V2 receptors are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts. These receptors help to maintain plasma osmolality within the normal range. The predominant pharmacodynamic effect of V2 antagonism results in 'aquaresis', or excretion of free water. The pharmacodynamic effects of conivaptan include increased free water excretion (i.e., effective water clearance or EWC) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. Conivaptan also constricts blood vessels via vascular V1A receptors. Conivaptan is selective for the V1A/V2 receptors in a 10:1 ratio. As an antagonist of the V1A and V2 vasopressin receptors, conivaptan helps rid the body of excess fluid by acting as an 'aquaretic' (urine output is increased while urine osmolality is decreased).
    •Hyponatremia: Conivaptan is currently FDA-approved for euvolemic and hypervolemic hyponatremia. Euvolemic states associated with hyponatremia may occur in patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) , hypothyroidism, adrenal insufficiency, and certain pulmonary disorders. Hypervolemic states associated with hyponatremia include patients with heart failure, cirrhosis, and nephrotic syndrome. Arginine vasopressin (AVP), otherwise known as antidiuretic hormone, plays a critical role in regulating water and electrolyte balance. The levels of AVP are usually elevated in both euvolemic and hypervolemic hyponatremia. Excessive vasopressin results in impairment of free water excretion and contributes to the development of hyponatremia. At recommended doses, IV conivaptan increases serum sodium concentrations and increases free water clearance in euvolemic hyponatremic patients. Following a 20 mg IV loading dose and 40 mg/day IV continuous infusion, 52% of patients achieved an increase of >= 4 mEq/L in serum sodium concentration. The mean change from baseline in serum sodium concentration at the end of 2 or 4 days of 40 mg/day IV infusion was 5.8 mEq/L or 6.4 mEq/L, respectively. The mean serum sodium concentration achieved was 129.4 mEq/L after 2 days and 130 mEq/L after 4 days of conivaptan therapy. Following 40 mg/day IV infusion, 39% (after 2 days) and 67% (after 4 days) of patients achieved either a normal serum sodium concentration of >= 135 mEq/L or an increase in serum sodium > 6 mEq/L. After 4 days, conivaptan IV infusion produced a baseline-corrected cumulative increase in EFW of over 2900 mL compared to approximately 1800 mL with placebo. Studies in animal models of hyponatremia have shown that conivaptan prevents the occurrence of hyponatremia-related physical signs in rats with SIADH.
    •Congestive Heart Failure: Although patients with hyponatremia associated with heart failure have significantly and chronically elevated plasma concentrations of vasopressin, the use of conivaptan for heart failure is currently not indicated. Several clinical trials are underway to further evaluate the safety, efficacy, and hemodynamics of conivaptan for the treatment of heart failure patients. Excessive arginine vasopressin activity has been proposed to contribute to the development of hyponatremia and edema in heart failure. Elevated vasopressin activity may significantly increase pulmonary capillary wedge pressure and systemic vascular resistance while decreasing stroke volume and cardiac output in heart failure patients. Physiologic actions associated with stimulation the V1A receptor include arteriolar vasoconstriction, increased systemic vascular resistance, increased afterload, and myocardial hypertrophy. Physiologic actions associated with V2 receptor stimulation include sodium and water retention, increased preload, increased pulmonary capillary wedge pressure, and increased left ventricular filling pressure. Therefore, it has been proposed that antagonism of V1A and V2 receptors may attenuate the adverse hemodynamic effects from heart failure. Based on preliminary hemodynamic data, conivaptan appears to significantly reduce pulmonary capillary wedge pressure without affecting systemic vascular resistance, heart rate, or cardiac output. Conivaptan has been studied using doses of 10, 20, and 40 mg IV given over 30 minutes in patients with advanced heart failure (NYHA Class III or IV); doses of 20 and 40 mg have resulted in significantly reduced capillary wedge pressure, right atrial pressure, and increased urinary output in the 3—6 hour period following drug administration.

    PHARMACOKINETICS

    Conivaptan is administered intravenously.
     
    Intersubject variability of conivaptan pharmacokinetics is high (94% CV for clearance). It is extensively bound to human plasma proteins, being 99% bound over the concentration range of approximately 10 to 1000 ng/mL. CYP3A4 has been identified as the sole cytochrome P450 isozyme responsible for metabolism. Four metabolites have been identified. The pharmacological activity of the metabolites at V1A and V2 receptors range from approximately 3% to 50% and 50% to 100% that of conivaptan, respectively. The combined exposure of the metabolites following intravenous administration of conivaptan is approximately 7% that of the parent drug. Therefore, the contribution of the metabolites to clinical effects is expected to be minimal.
     
    Affected cytochrome P450 isoenzymes and transporters: CYP3A4 and P-gp
    Conivaptan is a potent inhibitor, and a substrate of, of CYP3A4. Conivaptan is also a P-gp inhibitor.

    Intravenous Route

    The pharmacokinetic parameters of conivaptan following intravenous infusion (40 to 80 mg/day) are non-linear; inhibition of its own metabolism seems to be the major factor for the non-linearity. The absolute bioavailability of conivaptan has not been established due its nonlinear pharmacokinetic properties. One study has estimated the bioavailability to be approximately 44% when comparing the systemic exposure of 60 mg oral conivaptan to 50 mg IV conivaptan. In healthy male subjects, the mean terminal elimination half-life after conivaptan IV infusion is 5 hours, and the mean clearance is 15.2 L/hour. A mass balance study conducted over several days has indicated that approximately 83% of an intravenous or oral dose is excreted in feces, while approximately 12% is excreted in the urine. Over the first 24 hours after dosing, approximately 1% of an intravenous dose is excreted unchanged in the urine.