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Drug overview for TOLVAPTAN (tolvaptan):
Generic name: TOLVAPTAN (tol-VAP-tan)
Drug class: Antidiuretic Hormone Antagonists
Therapeutic class: Cardiovascular Therapy Agents
Tolvaptan, a benzazepine derivative, is a selective, nonpeptide antagonist of arginine vasopressin (antidiuretic hormone) V2 receptors.
No enhanced Uses information available for this drug.
Generic name: TOLVAPTAN (tol-VAP-tan)
Drug class: Antidiuretic Hormone Antagonists
Therapeutic class: Cardiovascular Therapy Agents
Tolvaptan, a benzazepine derivative, is a selective, nonpeptide antagonist of arginine vasopressin (antidiuretic hormone) V2 receptors.
No enhanced Uses information available for this drug.
DRUG IMAGES
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The following indications for TOLVAPTAN (tolvaptan) have been approved by the FDA:
Indications:
Hyponatremia
SIADH syndrome
Professional Synonyms:
Decreased serum Na
Decreased serum sodium
Low serum sodium
Syndrome of inappropriate vasopressin secretion
Indications:
Hyponatremia
SIADH syndrome
Professional Synonyms:
Decreased serum Na
Decreased serum sodium
Low serum sodium
Syndrome of inappropriate vasopressin secretion
The following dosing information is available for TOLVAPTAN (tolvaptan):
The usual initial adult dosage of tolvaptan for the treatment of clinically important euvolemic or hypervolemic hyponatremia is 15 mg once daily; dosage may be increased at intervals of at least 24 hours to 30 mg once daily and subsequently up to the maximum recommended dosage of 60 mg once daily as needed to achieve the desired serum sodium concentration. The duration of tolvaptan therapy should be limited to 30 days in order to minimize the risk of hepatic injury (see Hepatic Injury under Warnings/Precautions: Other Warnings/Precautions, in Cautions). Serum electrolytes and fluid status should be monitored frequently during initiation and titration of tolvaptan therapy.
Fluid restriction should be avoided during the first 24 hours of therapy. Patients receiving tolvaptan should be advised that they may continue drinking fluids in response to thirst. Following discontinuance of tolvaptan, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium concentration and fluid status.
Concomitant use of tolvaptan and potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A is contraindicated. Concomitant use of tolvaptan and moderate inhibitors of CYP3A should be avoided. Concomitant use of tolvaptan and potent inducers of CYP3A also should be avoided; if tolvaptan is used concomitantly with potent inducers of CYP3A, the expected clinical effects of tolvaptan may not be observed at the recommended dosage, and patient response should be monitored and the dosage adjusted accordingly.
Concomitant use of tolvaptan and inhibitors of the P-glycoprotein transport system may require reduction of tolvaptan dosage. (See Cautions: Contraindications and see Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes and also see Drug Interactions: Drugs Affecting the P-glycoprotein Transport System.)
Fluid restriction should be avoided during the first 24 hours of therapy. Patients receiving tolvaptan should be advised that they may continue drinking fluids in response to thirst. Following discontinuance of tolvaptan, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium concentration and fluid status.
Concomitant use of tolvaptan and potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A is contraindicated. Concomitant use of tolvaptan and moderate inhibitors of CYP3A should be avoided. Concomitant use of tolvaptan and potent inducers of CYP3A also should be avoided; if tolvaptan is used concomitantly with potent inducers of CYP3A, the expected clinical effects of tolvaptan may not be observed at the recommended dosage, and patient response should be monitored and the dosage adjusted accordingly.
Concomitant use of tolvaptan and inhibitors of the P-glycoprotein transport system may require reduction of tolvaptan dosage. (See Cautions: Contraindications and see Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes and also see Drug Interactions: Drugs Affecting the P-glycoprotein Transport System.)
The manufacturer states that tolvaptan therapy should be initiated or reinitiated only in a hospital setting, where serum sodium concentrations and therapeutic response can be monitored closely; too rapid a correction of hyponatremia may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death. (See Overly Rapid Correction of Serum Sodium Concentration under Warnings/Precautions: Warnings, in Cautions.) Tolvaptan is administered orally without regard to meals.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| TOLVAPTAN 15 MG TABLET | Maintenance | Adults take 1 tablet (15 mg) by oral route once daily |
| TOLVAPTAN 30 MG TABLET | Maintenance | Adults take 1 tablet (30 mg) by oral route once daily |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| TOLVAPTAN 15 MG TABLET | Maintenance | Adults take 1 tablet (15 mg) by oral route once daily |
| TOLVAPTAN 30 MG TABLET | Maintenance | Adults take 1 tablet (30 mg) by oral route once daily |
The following drug interaction information is available for TOLVAPTAN (tolvaptan):
There are 2 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Tolvaptan/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of tolvaptan.(1) Toxicity may result from an overly rapid correction of serum sodium. CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of tolvaptan.(1) Elevated levels of tolvaptan may lead to increased clinical effects such as hypotension, hypovolemia, and thirst, as well as toxicity in the form of neurologic sequelae such as osmotic demyelination syndrome (ODS). ODS can lead to coma and death. Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and coma.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of tolvaptan and strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of itraconazole states that concurrent use with tolvaptan is contraindicated during and two weeks after itraconazole treatment.(2) DISCUSSION: Tolvaptan is a substrate of CYP3A4. Concurrent administration of ketoconazole (200 mg daily) increased tolvaptan exposure by 5-fold. Administration of ketoconazole at dosages of 400 mg daily would be expected to produce greater increases, as would concurrent administration with other strong CYP3A4 inhibitors.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(3) |
APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZOKINVY, ZYDELIG, ZYKADIA |
| Lemborexant (Greater Than 5 mg)/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(1,2) |
DAYVIGO |
There are 5 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Tolvaptan/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of tolvaptan.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of tolvaptan.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent administration with strong CYP3A4 inducers should be avoided. If concurrent use is required, the dosage of tolvaptan may need to be increased.(1) DISCUSSION: Concurrent administration of rifampin, a strong inducer of CYP3A4, decreased tolvaptan exposure by 85%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1,2) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFABUTIN, RIFADIN, RIFAMPIN, SEZABY, TALICIA, TEGRETOL, TEGRETOL XR, TENCON, TIBSOVO, XTANDI |
| Tolvaptan/Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of tolvaptan.(1) CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from tolvaptan.(1) Elevated levels of tolvaptan may lead to increased clinical effects such as hypotension, hypovolemia, and thirst, as well as toxicity in the form of neurologic sequelae such as osmotic demyelination syndrome (ODS). ODS can lead to coma and death. Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and coma.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of Samsca for the treatment of clinically significant hypervolemic and euvolemic hyponatremia states that concurrent administration with moderate CYP3A4 inhibitors should be avoided.(1) The US manufacturer of Jynarque for the management to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease states concurrent administration with moderate CYP3A4 inhibitors warrants a dose reduction of Jynarque as follows: - Standard morning and evening dose: 90 mg and 30 mg should be dose adjusted to 45 mg and 15 mg, respectively - Standard morning and evening dose: 60 mg and 30 mg should be dose adjusted to 30 mg and 15 mg, respectively - Standard morning and evening dose: 45 mg and 15 mg should be dose adjusted to 15 mg and 15 mg, respectively Interrupt Jynarque temporarily for short term therapy with moderate CYP3A4 inhibitors if the recommended reduced doses are not available.(2) DISCUSSION: Fluconazole 400 mg (moderate inhibitor of CYP3A4) given one day prior and 200 mg given concomitantly produced an 80% and 200% increase in tolvaptan maximum concentration (Cmax) and area-under-curve (AUC), respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, schisandra, treosulfan and verapamil.(1-4) |
AKYNZEO, APONVIE, APREPITANT, ATAZANAVIR SULFATE, CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, CINVANTI, CLOFAZIMINE, COPIKTRA, CRESEMBA, DANZITEN, DARUNAVIR, DIFLUCAN, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, E.E.S. 200, E.E.S. 400, EMEND, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, FLUCONAZOLE, FLUCONAZOLE-NACL, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, FOSAMPRENAVIR CALCIUM, GLEEVEC, GRAFAPEX, IMATINIB MESYLATE, IMKELDI, INREBIC, MATZIM LA, NILOTINIB HCL, OGSIVEO, ORLADEYO, PREVYMIS, PREZISTA, REYATAZ, SUNLENCA, TASIGNA, TAVNEOS, TIADYLT ER, TIAZAC, TRANDOLAPRIL-VERAPAMIL ER, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR, XALKORI, XENLETA |
| Lomitapide (Less Than or Equal To 30 mg)/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve). CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1) PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1) PATIENT MANAGEMENT: The maximum lomitapide dose should be 30 mg daily for patients taking concomitant weak CYP3A4 inhibitors. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide 10 mg daily or more, decrease the dose of lomitapide by 50%. In patients taking lomitapide 5 mg daily, continue current dose. DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) Weak CYP3A4 inhibitors linked to this interaction include alprazolam, amiodarone, amlodipine, asciminib, atorvastatin, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, larotrectinib, lacidipine, lapatinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, vonoprazan, and zileuton.(1-3) |
JUXTAPID |
| Vasopressin Antagonists/Hypertonic Saline SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent administration of vasopressin antagonists and hypertonic saline may result in overly rapid correction of serum sodium levels.(1,2) CLINICAL EFFECTS: Overly rapid correction of serum sodium levels may result in osmotic demyelination. Symptoms of osmotic demyelination include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and/or death.(1,2) PREDISPOSING FACTORS: Patients who are malnourished, have a history of alcoholism, and/or advanced liver disease may be more susceptible to adverse effects of overly rapid hyponatremia correction.(1,2) PATIENT MANAGEMENT: Avoid the concurrent use of vasopressin antagonists and hypertonic saline. In patients who are malnourished, have a history of alcoholism, and/or advanced liver disease, use slower rates of sodium correction.(1,2) DISCUSSION: Overly rapid correction of serum sodium levels may result in osmotic demyelination. Symptoms of osmotic demyelination include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and/or death. Patients who are malnourished, have a history of alcoholism, and/or advanced liver disease may be more susceptible to adverse effects of overly rapid hyponatremia correction. Avoid the concurrent use of vasopressin antagonists and hypertonic saline. In patients who are malnourished, have a history of alcoholism, and/or advanced liver disease, use slower rates of sodium correction.(1,2) |
SODIUM CHLORIDE |
| Eliglustat/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP2D6, eliglustat metabolism can be further inhibited.(1) CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP3A4 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1) PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP2D6, is a poor metabolizer of CYP2D6, and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The concurrent use of eliglustat with weak inhibitors of CYP3A4 in poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with weak inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 4.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and 5.4-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amlodipine, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, and vonoprazan.(3,4) |
CERDELGA |
There are 7 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Loperamide/CYP3A4; CYP2C8; P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase loperamide systemic absorption and facilitate entry into central nervous system (CNS).(1) CLINICAL EFFECTS: Concurrent use of inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase levels of loperamide, resulting in respiratory depression.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Use loperamide with caution in patients receiving inhibitors of CYP3A4, CYP2C8, and/or P-gp. Consider lower doses of loperamide in these patients and monitor for adverse effects. The manufacturer of lonafarnib recommends starting loperamide at a dose of 1 mg and slowly increasing the dose as needed.(2) DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, itraconazole (100 mg twice daily for 5 days - first dose 200 mg), gemfibrozil (600 mg twice daily), and the combination of itraconazole and gemfibrozil (same dosages) increased the area-under-curve (AUC) of single doses of loperamide (4 mg) by 2.9-fold, 1.6-fold, and 4.2-fold, respectively.(3) In a study of healthy subjects, lonafarnib (100 mg twice daily for 5 days) increased the AUC and maximum concentration (Cmax) of single dose loperamide (2 mg) by 299% and 214%, respectively.(3) In a study in 18 healthy males, quinidine increased the AUC of a single dose of loperamide by 2.2-fold and markedly decreased pupil size.(4) In a study in 8 healthy subjects, subjects experienced respiratory depression when a single dose of loperamide (16 mg) was administered with a single dose of quinidine (600 mg) but not when loperamide was administered alone.(6) Loperamide plasma levels increased 2-fold to 3-fold.(5) |
LOPERAMIDE |
| Rivaroxaban/Selected P-gp and Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Amiodarone, azithromycin, brodalumab, chloramphenicol, cimetidine, cyclosporine, felodipine, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, hydroquinidine, ivacaftor, nilotinib, piperine, pirtobrutinib, quinidine, ranolazine, simeprevir, ticagrelor and tolvaptan may inhibit the metabolism of rivaroxaban by CYP3A4 and by P-glycoprotein.(1,2) CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a weak inhibitor of CYP3A4 may result in elevated levels of and clinical effects of rivaroxaban, including an increased risk of bleeding, in patients with decreased renal function.(1,2) PREDISPOSING FACTORS: Patients with decreased renal function (CrCL of 15 ml/min to 80 ml/min) may be predisposed to this interaction.(1) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The US manufacturer states no precautions are necessary with the concurrent use of these agents and rivaroxaban in patients with normal renal function.(1) It would be prudent to closely monitor concurrent use in patients with reduced renal function (CrCL of 15 ml/min to 80 ml/min). If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Clarithromycin (500 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rivaroxaban by 50% and 40%, respectively.(1,2) Erythromycin (500 mg three times daily) increased the AUC and Cmax of a single dose of rivaroxaban by 30% and 30%, respectively.(1-3) In patients with mild renal impairment (CrCl of 50 ml/min to 79 ml/min) who were receiving erythromycin, rivaroxaban levels were increased 76% when compared to administration of rivaroxaban in patients with normal renal function receiving rivaroxaban alone. In patients with moderate renal impairment (CrCl of 30 ml/min to 49 ml/min) who were receiving erythromycin, rivaroxaban levels were increased 99% when compared to administration of rivaroxaban in patients with normal renal function receiving rivaroxaban alone.(1) Fluconazole increased the AUC and Cmax of a single dose of rivaroxaban by 40%% and 30%, respectively.(1) These changes are not expected to be clinically significant in patients with normal renal function.(1,2) In a case report, an 88-year-old woman with renal impairment on rivaroxaban presented with an elevated INR of 2.5 and a rivaroxaban peak plasma concentration above the upper limit of detection at >800 mcg/L (therapeutic range 58-211 mcg/L). Nothing in her medical history suggested a reason for supratherapeutic rivaroxaban levels except for a 7-week amiodarone regimen that was discontinued 3 weeks prior. This suggests the potential for amiodarone to persist in the body weeks after its use and precipitate drug-drug interactions.(4) A retrospective cohort study examined 24,943 patients aged 66 years and older with concurrent therapy of an anticoagulant, either rivaroxaban (40.0%), apixaban (31.9%), or dabigatran (28.1%), with either azithromycin or clarithromycin. The primary outcome of hospital admission with major hemorrhage within 30 days on concurrent therapy was higher in patients on clarithromycin (0.77%) compared to azithromycin (0.43%) with an adjusted hazard ratio of 1.71 (95% CI, 1.20-2.45). In a self-controlled case series, 744 major hemorrhage events were identified among 647 unique individuals taking anticoagulants who were exposed to clarithromycin. The rate of events that occurred during clarithromycin use had a significant rate ratio of 1.44 (95% CI, 1.08-1.92).(5) A propensity matched cohort evaluated the concurrent use of combined P-gp and moderate CYP3A4 inhibitors with apixaban or rivaroxaban. Combined inhibitors included amiodarone, diltiazem, erythromycin, dronedarone, and verapamil. Bleeding occurred in 26.4% of patients in the inhibitor group compared to 18.4% in the control group (hazard ratio 1.8; 95% CI 1.19-2.73; p=0.006). Although not statistically significant, patients in the inhibitor group also had a higher rate of major bleeding (15% vs 10.3%) and minor bleeding (8.9% vs 5.2%), respectively.(6) A summary of pharmacokinetic interactions with rivaroxaban and amiodarone concluded that concurrent use should be avoided if CrCl < 80 ml/min.(7) A prospective cohort study of 174 patients evaluated the concurrent use of rivaroxaban and amiodarone. The combination of rivaroxaban and amiodarone was associated with a higher incidence of bleeding events (p=0.041; HR=2.83, 95% CI 1.05-7.66) and clinically relevant non-major bleeding (p=0.021; HR=3.65, 95% CI 1.21-10.94). Concurrent use of amiodarone and rivaroxaban in non-valvular atrial fibrillation patients was an independent risk factor for increased risk of bleeding (p=0.044; OR 2.871, 95% CI 1.028-8.023).(8) P-gp and weak CYP3A4 inhibitors linked to this monograph are: amiodarone, azithromycin, belumosudil, brodalumab, chloramphenicol, cimetidine, cyclosporine, daridorexant, diosmin, flibanserin, fostamatinib, glecaprevir/pibrentasvir, hydroquinidine, istradefylline, ivacaftor, mavorixafor, nilotinib, piperine, pirtobrutinib, quinidine, ranolazine, simeprevir and tolvaptan.(9,10) |
RIVAROXABAN, XARELTO |
| Tacrolimus/Moderate and Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate and weak inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus.(1) CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) Consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a study of 26 renal transplant recipients, conjugated estrogens 3.75 mg daily increased the tacrolimus dose-corrected concentration of tacrolimus by 85.6%. Discontinuation of the conjugated estrogens led to a decrease in tacrolimus concentration of 46.6%.(3) A case report describes a 65-year-old kidney transplant recipient who was stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL. Ten days after starting on estradiol gel 0.5 mg per day, her tacrolimus level rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at baseline to 2 mg/dL. Tacrolimus dose was reduced by 60%, and trough levels and Scr normalized after two weeks.(4) A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir 200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%, while the maximum concentration (Cmax) of tacrolimus was decreased by 40%.(5) An analysis of FAERS data from 2004-2017, found a significant assoc ation between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ration 1.92, 95% CI). A retrospective study of 7 heart transplant patients on concurrent tacrolimus and clotrimazole troche showed a significant correlation between tacrolimus trough concentration and AUC after clotrimazole discontinuation. Tacrolimus clearance and bioavailability after clotrimazole discontinuation was 2.2-fold greater (0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7) A retrospective study of 26 heart transplant patients found that discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5 expresser group had a 3.3-fold increase in apparent oral clearance and AUC of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8) A study of 6 adult kidney transplant recipients found that clotrimazole (5-day course) increased the tacrolimus AUC 250% and the blood trough concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance decreased 60% with coadministration of clotrimazole.(9) A case report describes a 23-year-old kidney transplant recipient who was stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily, prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche 10 mg four times daily. Discontinuation of clotrimazole resulted in a decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting in an increased tacrolimus level of 19.2 ng/ml.(10) A retrospective study in 95 heart transplant recipients on concurrent clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7% was required after clotrimazole discontinuation. Tacrolimus trough concentration was found to have decreased 42.5% after clotrimazole discontinuation.(11) A retrospective study in 65 pancreas transplant patients on concurrent tacrolimus, clotrimazole, cyclosporine, and prednisone found that clotrimazole discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions.(12) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, berotralstat, clofazimine, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant, nirogacestat, and tofisopam.(6) Weak CYP3A4 inhibitors linked to this monograph include: alprazolam, avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant, delavirdine, diosmin, estrogens, flibanserin, fosaprepitant, fostamatinib, ginkgo biloba, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, linagliptin, lomitapide, lumateperone, lurasidone, peppermint oil, piperine, propiverine, ranitidine, remdesivir, resveratrol, rimegepant, simeprevir, sitaxsentan, skullcap, suvorexant, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan-amoxicillin.(6) |
ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL |
| Lemborexant (Less Than or Equal To 5 mg)/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1) CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(1,2) |
DAYVIGO |
| Ubrogepant/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1) CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: alprazolam, amiodarone, amlodipine, asciminib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, dihydroberberine, diosmin, elagolix, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, roxithromycin, simeprevir, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(2,3) |
UBRELVY |
| Sirolimus Protein-Bound/Slt Moderate and Weak CYP3A4 Inhibit SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate and weak CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(1) DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(2) Moderate and weak CYP3A4 inhibitors linked to this monograph include: alprazolam, amlodipine, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, daclatasvir, daridorexant, delavirdine, diosmin, entrectinib, erythromycin, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, remdesivir, resveratrol, rimegepant, roxithromycin, scutellarin, simeprevir, sitaxsentan, suvorexant, ticagrelor, tofisopam, tolvaptan, trofinetide and vonoprazan.(3,4) |
FYARRO |
| Mavacamten/Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Weak CYP3A4 inhibitors may decrease the metabolism of mavacamten.(1) CLINICAL EFFECTS: Concurrent use of weak CYP3A4 inhibitors may increase the plasma levels and the incidence and severity of adverse reactions of mavacamten.(1) PREDISPOSING FACTORS: CYP2C19 poor metabolizers may experience an increased incidence or severity of adverse effects.(1) PATIENT MANAGEMENT: The UK manufacturer of mavacamten states no dose adjustment is necessary when starting mavacamten in patients on weak CYP3A4 inhibitors or in intermediate, normal, rapid, or ultra-rapid CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor. In poor CYP2C19 metabolizers already on mavacamten and starting a weak CYP3A4 inhibitor, reduce mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks. If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily.(1) DISCUSSION: In a PBPK model, concomitant use of mavacamten (15 mg daily) with cimetidine 400 mg twice daily, a weak CYP3A4 inhibitor, was predicted to increase mavacamten area-under-curve (AUC) by 6% and maximum concentration (Cmax) by 4% in poor CYP2C19 metabolizers and by 3% and 2%, respectively, in both intermediate and normal CYP2C19 metabolizers.(2) Weak CYP3A4 inhibitors include: alprazolam, amiodarone, amlodipine, asciminib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, ciprofloxacin, clotrimazole, cranberry, cyclosporine, delavirdine, dihydroberberine, diosmin, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, istradefylline, ivacaftor, lacidipine, lapatinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, pazopanib, peppermint oil, propiverine, propofol, ranitidine, remdesivir, resveratrol, roxithromycin, sitaxsentan, skullcap, suvorexant, teriflunomide, ticagrelor, tolvaptan, trofinetide, and viloxazine.(4,5) |
CAMZYOS |
The following contraindication information is available for TOLVAPTAN (tolvaptan):
Drug contraindication overview.
Patients who require urgent intervention to acutely raise serum sodium concentrations. Tolvaptan has not been studied in these patients. Patients who are unable to sense or appropriately respond to thirst.
Individuals who are unable to autoregulate fluid balance are at substantially increased risk for overly rapid correction of serum sodium concentrations, hypernatremia, and hypovolemia. (See Overly Rapid Correction of Serum Sodium Concentration under Warnings/Precautions: Warnings, in Cautions and see Dehydration and Hypovolemia under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) Hypovolemic hyponatremia. Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits of tolvaptan therapy.
(See Dehydration and Hypovolemia under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) Concomitant use of potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). (See Inhibitors of CYP3A under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) Anuria. Anuric patients are not expected to obtain clinical benefit from tolvaptan therapy.
Patients who require urgent intervention to acutely raise serum sodium concentrations. Tolvaptan has not been studied in these patients. Patients who are unable to sense or appropriately respond to thirst.
Individuals who are unable to autoregulate fluid balance are at substantially increased risk for overly rapid correction of serum sodium concentrations, hypernatremia, and hypovolemia. (See Overly Rapid Correction of Serum Sodium Concentration under Warnings/Precautions: Warnings, in Cautions and see Dehydration and Hypovolemia under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) Hypovolemic hyponatremia. Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits of tolvaptan therapy.
(See Dehydration and Hypovolemia under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) Concomitant use of potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). (See Inhibitors of CYP3A under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) Anuria. Anuric patients are not expected to obtain clinical benefit from tolvaptan therapy.
There are 5 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Anuria |
| Dehydration |
| Hypernatremia |
| Hypovolemia |
| Osmotic central pontine myelinolysis |
There are 2 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Disease of liver |
| Hyperkalemia |
There are 2 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Alcohol use disorder |
| Protein-calorie malnutrition |
The following adverse reaction information is available for TOLVAPTAN (tolvaptan):
Adverse reaction overview.
Adverse effects reported in 4% or more of patients receiving tolvaptan and more frequently with tolvaptan than with placebo include thirst, dry mouth, pollakiuria or polyuria, asthenia, constipation, hyperglycemia, pyrexia, and anorexia.
Adverse effects reported in 4% or more of patients receiving tolvaptan and more frequently with tolvaptan than with placebo include thirst, dry mouth, pollakiuria or polyuria, asthenia, constipation, hyperglycemia, pyrexia, and anorexia.
There are 23 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Dehydration Hyponatremia Hypovolemia Increased alanine transaminase Increased aspartate transaminase |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Acute respiratory failure Anaphylaxis Angioedema Cerebrovascular accident Deep venous thrombosis Disseminated intravascular coagulation Gastrointestinal hemorrhage Hepatic failure Hepatocellular damage Hyperbilirubinemia Hyperkalemia Ischemic colitis Osmotic central pontine myelinolysis Pulmonary thromboembolism Rhabdomyolysis Thromboembolic disorder Ventricular fibrillation |
There are 12 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Constipation General weakness Increased urinary frequency Polydipsia Polyuria Xerostomia |
Anorexia Fever Hyperglycemia |
| Rare/Very Rare |
|---|
|
Abnormal vaginal bleeding Hypernatremia Skin rash |
The following precautions are available for TOLVAPTAN (tolvaptan):
Safety and efficacy have not been established in children younger than 18 years of age.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Category C. (See Users Guide.) The effect of tolvaptan on labor and delivery is not known.
Tolvaptan is distributed into milk in rats; it is not known whether tolvaptan is distributed into human milk. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
No substantial differences in safety and efficacy relative to younger adults have been observed, but increased sensitivity cannot be ruled out. Increasing age does not appear to affect plasma tolvaptan concentrations. The manufacturer states that dosage adjustment of tolvaptan based on age is not necessary.
The following prioritized warning is available for TOLVAPTAN (tolvaptan):
WARNING: Treatment with this drug should be started or restarted in a hospital for proper monitoring. If your level of sodium in the blood is raised too quickly, it may cause a serious (even fatal) condition called osmotic demyelination syndrome. The risk is higher if you have liver disease, poor nutrition, or if you use/abuse alcohol.
Tell your doctor right away if you have symptoms such as trouble speaking/swallowing, mental/mood changes (such as confusion), weakness/involuntary movement in the arms/legs, or seizures. Do not use this medication to treat a certain kidney problem (autosomal dominant polycystic kidney disease-ADPKD). Due to the risk of serious liver damage, you must be in a special program for you to take this medication to treat ADPKD. Ask your doctor for details.
WARNING: Treatment with this drug should be started or restarted in a hospital for proper monitoring. If your level of sodium in the blood is raised too quickly, it may cause a serious (even fatal) condition called osmotic demyelination syndrome. The risk is higher if you have liver disease, poor nutrition, or if you use/abuse alcohol.
Tell your doctor right away if you have symptoms such as trouble speaking/swallowing, mental/mood changes (such as confusion), weakness/involuntary movement in the arms/legs, or seizures. Do not use this medication to treat a certain kidney problem (autosomal dominant polycystic kidney disease-ADPKD). Due to the risk of serious liver damage, you must be in a special program for you to take this medication to treat ADPKD. Ask your doctor for details.
The following icd codes are available for TOLVAPTAN (tolvaptan)'s list of indications:
| Hyponatremia | |
| E87.1 | Hypo-osmolality and hyponatremia |
| SIADH syndrome | |
| E22.2 | Syndrome of inappropriate secretion of antidiuretic hormone |
Formulary Reference Tool