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Treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients
Hypersensitivity to conivaptan, corn or corn products, or any component of the formulation; use in hypovolemic hyponatremia; concurrent use with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, indinavir, and clarithromycin); anuria
Euvolemic or hypervolemic hyponatremia: IV: 20 mg infused over 30 minutes as a loading dose, followed by a continuous infusion of 20 mg over 24 hours (0.83 mg/hour) for 2-4 days; may increase to a maximum dose of 40 mg over 24 hours (1.7 mg/hour) if serum sodium not rising sufficiently; total duration of therapy not to exceed 4 days. Note: If patient requires 40 mg/24 hours, may administer two consecutive 20 mg/100 mL premixed solutions over 24 hours (ie, 20 mg over 12 hours followed by 20 mg over 12 hours).
Refer to adult dosing.
CrCl ≥30mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: Use not recommended; clinical response reduced; contraindicated in anuria (no benefit expected).
Mild impairment: No dosage adjustment necessary.
Moderate impairment: 10 mg infused over 30 minutes as a loading dose, followed by a continuous infusion of 10 mg over 24 hours (0.42 mg/hour) for 2-4 days; may increase to a maximum dose of 20 mg over 24 hours (0.83 mg/hour) if serum sodium not rising sufficiently; total duration of therapy not to exceed 4 days.
Severe impairment: Use not recommended (not studied).
For intravenous use only; infuse into large veins and change infusion site every 24 hours to minimize vascular irritation. Do not administer with any other product in the same intravenous line or container.
Store at 25 ‚ °C (77 ‚ °F); brief excursions permitted up to 40 ‚ °C (104 ‚ °F). Protect from light and freezing. Do not remove protective overwrap until ready for use.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous, as hydrochloride:
Vaprisol: 20 mg (100 mL)
Stable in D5W
Y-site administration: Incompatible with LR.
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Conivaptan. Fluconazole and isavuconazonium considerations are addressed in separate monographs. Exceptions: Fluconazole; Isavuconazonium Sulfate. Avoid combination
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy
Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy
Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination
Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy
Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination
Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification
Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy
Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Conivaptan. Avoid combination
CYP3A4 Substrates: Conivaptan may increase the serum concentration of CYP3A4 Substrates. Avoid combination
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Digoxin: Conivaptan may increase the serum concentration of Digoxin. Monitor therapy
Dofetilide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dofetilide. Monitor therapy
Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination
Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination
Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy
Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy
Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination
Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy
Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination
Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination
Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification
Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination
Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy
Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination
Propafenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination
St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy
Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination
Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination
Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination
Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy
Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy
Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy
Rate of serum sodium increase, blood pressure, volume status, urine output
>10%:
Cardiovascular: Orthostatic hypotension (6% to 14%)
Endocrine & metabolic: Hypokalemia (10% to 22%)
Local: Injection site reaction (63% to 73%; including erythema at injection site, injection site pain, injection site phlebitis, swelling at injection site)
Miscellaneous: Fever (5% to 11%)
1% to 10%:
Cardiovascular: Hypertension (6% to 8%), hypotension (5% to 8%), peripheral edema (3% to 8%), phlebitis (5%), atrial fibrillation (2% to 5%), ECG abnormality ( ≤5%)
Central nervous system: Headache (8% to 10%), insomnia (4% to 5%), confusion ( ≤5%), pain (2%)
Dermatologic: Pruritus (1% to 5%), erythema (3%)
Endocrine & metabolic: Hyponatremia (6% to 8%), increased thirst (3% to 6%), hypomagnesemia (2% to 5%), hyperglycemia ( ≤3%), hypoglycemia ( ≤3%), dehydration (2%)
Gastrointestinal: Constipation (6% to 8%), vomiting (5% to 7%), diarrhea ( ≤7%), nausea (3% to 5%), xerostomia (4%), oral candidiasis (2%)
Genitourinary: Urinary tract infection (4% to 5%), hematuria (2%)
Hematologic & oncologic: Anemia (5% to 6%)
Renal: Polyuria (5% to 6%)
Respiratory: Pneumonia (2% to 5%), pharyngolaryngeal pain (1% to 5%)
<1% (Limited to important or life-threatening): Atrial arrhythmia, sepsis
AUC for oral administration in patients with renal impairment (CrCl 30 to 60 mL/minute or CrCl 10 to 29 mL/minute) was 70% to 85% higher, respectively, compared with those with healthy renal function. IV conivaptan resulted in higher exposure than oral conivaptan in study subjects without renal impairment.
Increased systemic exposure (up to a mean 2.8-fold increase) after oral administration has been seen in patients with stable cirrhosis and moderate hepatic impairment. IV conivaptan resulted in higher exposure than oral conivaptan in study subjects without hepatic impairment.
Concerns related to adverse effects:
- Hypotension: Discontinue if hypotension occur; may correct and reinitiate if necessary.
- Hypovolemia: Discontinue if hypovolemia occurs; may correct and reinitiate if necessary.
- Injection-site reactions: May cause injection-site reactions.
Disease-related concerns:
- Heart failure: Safety and efficacy have not been established in patients with hypervolemic hyponatremia associated with heart failure. Consider alternative treatment options due to limited data in this population. Use in 79 hypervolemic, hyponatremic heart failure patients led to increased adverse events, atrial arrhythmias, and sepsis when compared to 10 similar heart failure patients treated with placebo. In other heart failure studies, conivaptan did not show significant improvements in outcomes over placebo.
- Hepatic impairment: No dosage adjustment necessary in mild hepatic impairment; no clinically relevant increase in systemic exposure was observed. Use caution in patients with moderate hepatic impairment; systemic exposure is approximately doubled; dosage adjustment required. Systemic exposure has not been studied in the setting of severe hepatic impairment; avoid use.
Concurrent drug therapy issues:
- Digoxin: Coadministration of conivaptan and digoxin may increase the serum concentration of digoxin; monitor digoxin concentrations.
- High potential for interactions: Use contraindicated in patients taking strong CYP3A4 inhibitors; use caution in patients taking moderate or strong CYP3A4 inducers and major CYP3A4 substrates (see Drug Interactions). Consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.
Other warnings/precautions:
- Appropriate use: Monitor closely for rate of serum sodium increase and neurological status; rapid serum sodium correction (>12 mEq/L/24 hours) can lead to seizures, permanent neurological damage, coma, or death. Discontinue use if rate of serum sodium increase is undesirable; may reinitiate infusion (at reduced dose) if hyponatremia persists in the absence of neurological symptoms typically associated with rapid sodium rise. Of note, raising serum sodium concentrations with conivaptan has not demonstrated symptomatic benefit.
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Adverse events were observed in animal reproduction studies.
Conivaptan is an arginine vasopressin (AVP) receptor antagonist with affinity for AVP receptor subtypes V1A and V2. The antidiuretic action of AVP is mediated through activation of the V2 receptor, which functions to regulate water and electrolyte balance at the level of the collecting ducts in the kidney. Serum levels of AVP are commonly elevated in euvolemic or hypervolemic hyponatremia, which results in the dilution of serum sodium and the relative hyponatremic state. Antagonism of the V2 receptor by conivaptan promotes the excretion of free water (without loss of serum electrolytes) resulting in net fluid loss, increased urine output, decreased urine osmolality, and subsequent restoration of normal serum sodium concentrations.
Hepatic via CYP3A4 to four minimally-active metabolite
Feces (83%); urine (12%, primarily as metabolites)
~5-8 hours
99%
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache, thirst, constipation, diarrhea, dry mouth, nausea, vomiting, insomnia, or injection site irritation or pain. Have patient report immediately to prescriber signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), dysphagia, difficulty speaking, blood in urine, painful urination, polyuria, sweating a lot, behavioral changes, fast breathing, tremors, or redness or white patches in mouth or throat (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.