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CONIVAPTAN AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Conivaptan and tolvaptan are arginine vasopressin receptor antagonists. Conivaptan is a dual antagonist of both V1a and V2 receptors, and tolvaptan is a selective antagonist with a greater affinity for the V2 receptor than for the V1a receptor.

Specific Substances

    A) CONIVAPTAN
    1) Conivaptan Hydrochloride
    2) CI-1025
    3) YM-087
    4) CAS 210101-16-9 (conivaptan)
    5) CAS 168626-94-6 (conivaptan hydrochloride)
    TOLVAPTAN
    1) OPC-41061
    2) CAS 150683-30-0

    1.2.1) MOLECULAR FORMULA
    1) CONIVAPTAN HYDROCHLORIDE: C32-H26-N4-O2,HCl (Prod Info VAPRISOL(R) injection, 2007)
    2) TOLVAPTAN: C26-H25-Cl-N2-O3 (Prod Info SAMSCA(TM) oral tablets, 2009)

Available Forms Sources

    A) FORMS
    1) CONIVAPTAN: Conivaptan is available as 20 mg/4 mL ampules for intravenous administration (Prod Info VAPRISOL(R) injection, 2007).
    2) TOLVAPTAN: Tolvaptan is available as 15 mg and 30 mg non-scored tablets for oral administration (Prod Info SAMSCA(TM) oral tablets, 2009).
    B) USES
    1) CONIVAPTAN: Conivaptan is FDA-approved for the treatment of hypervolemic and euvolemic hyponatremia in hospitalized patients (Prod Info VAPRISOL(R) injection, 2007).
    2) TOLVAPTAN: Tolvaptan is FDA-approved for the treatment of hypervolemic and euvolemic hyponatremia that could not be corrected with fluid restriction in patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH) (Prod Info SAMSCA(TM) oral tablets, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Indicated for the treatment of hypervolemic and euvolemic hyponatremia.
    B) PHARMACOLOGY: Antagonism of the arginine vasopressin V2 receptors in the renal collecting ducts causes an increase in urine water excretion resulting in increased free water clearance, decreased urine osmolality, and increased serum sodium concentrations.
    C) EPIDEMIOLOGY: Limited data. Overdose is rare and rarely causes significant toxicity.
    D) WITH THERAPEUTIC USE
    1) COMMON: CONIVAPTAN: Infusion site reactions (eg, pain, erythema, phlebitis), orthostatic hypotension, hypokalemia, and headache are the most common adverse effects. TOLVAPTAN: The most common adverse effects following therapeutic administration include thirst, dry mouth, asthenia, constipation, polyuria, and hyperglycemia. Pyrexia was reported in conivaptan and tolvaptan-treated patients during clinical efficacy trials.
    E) WITH POISONING/EXPOSURE
    1) There are no reports of toxicity following acute overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Conivaptan and tolvaptan are both classified as pregnancy category C. There have been no reports of teratogenicity with conivaptan administration during animal studies; however, teratogenic effects (ie, cleft palate, brachymelia, microphthalmia, skeletal malformations) were reported in animals following tolvaptan administration.

Laboratory Monitoring

    A) Monitor vital signs, fluid status, serum electrolytes and urine output after significant overdoses.
    B) Conivaptan and tolvaptan plasma levels are not widely available or useful in guiding therapy after overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) In case of overdose, treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. There is no known antidote.
    C) DECONTAMINATION
    1) Decontamination is generally not indicated as toxicity is limited (480 mg of tolvaptam was well tolerated in volunteers). Consider activated charcoal after very large ingestions or if toxic coingestants are involved and the patients is alert and able to protect their airway.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION
    1) Due to high protein binding (99%), hemodialysis and hemoperfusion are NOT likely to be beneficial.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with inadvertent overdoses can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients with deliberate ingestions demonstrating severe fluid and electrolyte imbalance should be admitted.
    4) CONSULT CRITERIA: Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    G) PITFALLS
    1) When managing a suspected conivaptan or tolvaptan overdose, the possibility of coingestion of other drugs should be considered.
    H) PHARMACOKINETICS
    1) CONIVAPTAN: Protein binding is 99%. Volume of distribution at steady state was 34 liters following a 50 milligram intravenous dose. CYP3A4 is the sole cytochrome P450 isoenzyme responsible for the metabolism. The median half-lives (range) were 5.3 hours (3.3 to 9.3 hours) and 8.1 hours (4.1 to 22.5 hours) in patients administered intravenous conivaptan 20 mg/day and 40 mg/day, respectively.
    2) TOLVAPTAN: At least 40% is absorbed as tolvaptan or its metabolites following oral administration. Protein binding is 99%. The apparent volume of distribution of tolvaptan is approximately 3 L/kg . Metabolism primarily occurs via cytochrome P450 3A enzymes. Elimination entirely occurs via non-renal routes. The terminal phase half-life was approximately 12 hours following oral single doses up to 480 mg and multiple dosing up to 300 mg once daily.

Range Of Toxicity

    A) TOXICITY: Overdose data are limited. Tolvaptan administration of single oral doses up to 480 mg and multiple dosing up to 300 mg once daily for 5 days were well tolerated in healthy subjects. Conivaptan administration of a 20 mg loading dose followed by a continuous intravenous infusion of 80 mg/day for 4 days or 120 mg/day for 2 days were also well tolerated.
    B) THERAPEUTIC DOSE: CONIVAPTAN: The loading dose is 20 mg administered intravenously over 30 minutes, following by a continuous infusion of 20 mg/24 hours. The dose may be increased up to a maximum daily dose of 40 mg and up to 4 days of therapy. TOLVAPTAN: Initial dose: 15 mg orally once daily. After 24 hours, the dose may be increased to 30 mg once daily, up to a maximum dose of 60 mg once daily.

Clinical Effects

Summary Of Exposure

    A) USES: Indicated for the treatment of hypervolemic and euvolemic hyponatremia.
    B) PHARMACOLOGY: Antagonism of the arginine vasopressin V2 receptors in the renal collecting ducts causes an increase in urine water excretion resulting in increased free water clearance, decreased urine osmolality, and increased serum sodium concentrations.
    C) EPIDEMIOLOGY: Limited data. Overdose is rare and rarely causes significant toxicity.
    D) WITH THERAPEUTIC USE
    1) COMMON: CONIVAPTAN: Infusion site reactions (eg, pain, erythema, phlebitis), orthostatic hypotension, hypokalemia, and headache are the most common adverse effects. TOLVAPTAN: The most common adverse effects following therapeutic administration include thirst, dry mouth, asthenia, constipation, polyuria, and hyperglycemia. Pyrexia was reported in conivaptan and tolvaptan-treated patients during clinical efficacy trials.
    E) WITH POISONING/EXPOSURE
    1) There are no reports of toxicity following acute overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) CONIVAPTAN: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), pyrexia was reported in 11% and 5% of the conivaptan groups, respectively, compared with none of the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    2) TOLVAPTAN: In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), pyrexia occurred in 4% of the patients in the tolvaptan group (n=223), and 1% of the patients in the placebo group (n=220) (Prod Info SAMSCA(TM) oral tablets, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ATRIAL FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), atrial fibrillation was reported in 5% and 2% of the conivaptan groups, respectively, compared with none in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), hypertension was reported in 8% and 6% of the conivaptan groups, respectively, compared with none in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    C) LOW BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN
    1) During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), hypotension was reported in 8% and 5% of the conivaptan groups, respectively, compared with 3% in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    2) ORTHOSTATIC HYPOTENSION: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), orthostatic hypotension was reported in 14% and 6% of the conivaptan groups, respectively, compared with none in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    D) PHLEBITIS
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), phlebitis was reported in 51% and 32% of the conivaptan groups, respectively, compared with 1% in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    E) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), peripheral edema was reported in 3% and 8% of the conivaptan groups, respectively, compared with 1% in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) TOLVAPTAN
    1) In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), dizziness occurred in 7% of the patients in the tolvaptan group (n=223), and 5% of the patients in the placebo group (n=220). Of the 223 patients in the tolvaptan group, 1 patient had dizziness associated with dehydration (Schrier et al, 2006).
    2) In a double-blind, randomized, trial, 9.4%, 4.8%, and 4.9% of patients in the tolvaptan 30-mg (n=64), 45-mg (n=62), and 60-mg groups (n=61), respectively, experienced dizziness compared with 3.2% of the patients in the placebo group (n=62) (Gheorghiade et al, 2003).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), headache was reported in 8% and 10% of the conivaptan groups, respectively, compared with 3% in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), insomnia was reported in 5% and 4% of the conivaptan groups, respectively, compared with none in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    D) NEUROLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) OSMOTIC DEMYELINATION SYNDROME: Too rapid correction of hyponatremia (eg, greater than 12 mEq/24 hours) may result in osmotic demyelination syndrome, characterized by dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death (Prod Info SAMSCA(TM) oral tablets, 2009; Prod Info VAPRISOL(R) injection, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) TOLVAPTAN: In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), anorexia occurred in 4% of the patients in the tolvaptan group (n=223), and 1% of the patients in the placebo group (n=220) (Prod Info SAMSCA(TM) oral tablets, 2009).
    B) APTYALISM
    1) WITH THERAPEUTIC USE
    a) TOLVAPTAN
    1) In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), dry mouth occurred in 13% of the patients in the tolvaptan group (n=223), and 4% of the patients in the placebo group (n=220) (Prod Info SAMSCA(TM) oral tablets, 2009; Schrier et al, 2006).
    2) In a subgroup of patients with hyponatremia (less than 135 mEq/L) and worsening heart failure included in a double-blind, placebo-controlled trial for a mean duration of 9 months (n=475), dry mouth occurred in 13% of the patients in the tolvaptan group and 4% of the patients in the placebo group (Prod Info SAMSCA(TM) oral tablets, 2009).
    3) In a double-blind, randomized, trial, 14.1%, 17.7%, and 23% of patients in the tolvaptan 30-mg (n=64), 45-mg (n=62), and 60-mg groups (n=61), respectively, experienced dry mouth compared with 3.2% of the patients in the placebo group (n=62) (Gheorghiade et al, 2003).
    C) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN
    1) During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), vomiting was reported in 5% and 7% of the conivaptan groups, respectively, compared with none in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    b) TOLVAPTAN
    1) In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), nausea occurred in 8% of the patients in the tolvaptan group (n=223), and 6% of the patients in the placebo group (n=220) (Schrier et al, 2006).
    2) In a subgroup of patients with hyponatremia (less than 135 mEq/L) and worsening heart failure included in a double-blind, placebo-controlled trial for a mean duration of 9 months (n=475), nausea occurred in 21% of the patients in the tolvaptan group and 16% of the patients in the placebo group (Prod Info SAMSCA(TM) oral tablets, 2009).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), constipation was reported in 8% and 6% of the conivaptan groups, respectively, compared with 3% in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    b) TOLVAPTAN: In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), constipation occurred in 7% of the patients in the tolvaptan group (n=223), and 2% of the patients in the placebo group (n=220) (Prod Info SAMSCA(TM) oral tablets, 2009; Schrier et al, 2006).
    E) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) TOLVAPTAN: During a clinical efficacy trial, 6 of 63 patients (10%) with cirrhosis developed gastrointestinal bleeding following treatment with tolvaptan as compared to 1 of 57 placebo-treated patients (2%) (Prod Info SAMSCA(TM) oral tablets, 2009).
    F) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN: During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), diarrhea was reported in 0% and 7% of the conivaptan groups, respectively, compared with none in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) INCREASED FREQUENCY OF URINATION
    1) WITH THERAPEUTIC USE
    a) TOLVAPTAN
    1) In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), increased urinary frequency (pollakiuria and polyuria) occurred in 11% of the patients in the tolvaptan group (n=223), and 3% of the patients in the placebo group (n=220) (Prod Info SAMSCA(TM) oral tablets, 2009; Schrier et al, 2006). Of the 223 patients in the tolvaptan group that were analyzed for adverse events, 1 patient withdrew from the study because of increased urinary frequency (Schrier et al, 2006).
    2) In a subgroup of patients with hyponatremia (less than 135 mEq/L) and worsening heart failure included in a double-blind, placebo-controlled trial for a mean duration of 9 months (n=475), polyuria occurred in 4% of the patients in the tolvaptan group and 1% of the patients in the placebo group (Prod Info SAMSCA(TM) oral tablets, 2009).
    3) In a double-blind, randomized, trial, 21.9%, 24.2%, and 9.8% of patients in the tolvaptan 30-mg (n=64), 45-mg (n=62), and 60-mg groups (n=61), respectively, experienced increased urinary frequency compared with 4.8% of the patients in the placebo group (n=62) (Gheorghiade et al, 2003).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN: During clinical trials, the most common adverse events associated with conivaptan hydrochloride administration in patients and healthy volunteers were infusion site reactions (including erythema and pain), reported in 73% and 63% of subjects receiving 20 mg/day and 40 mg/day, respectively, compared with 4% of patients receiving placebo. Most infusion reactions were mild, but serious reactions led to drug discontinuation in 3% of patients receiving conivaptan compared with 0% of patients receiving placebo (Prod Info VAPRISOL(R) injection, 2007).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) TOLVAPTAN: In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), asthenia occurred in 9% of the patients in the tolvaptan group (n=223), and 4% of the patients in the placebo group (n=220) (Prod Info SAMSCA(TM) oral tablets, 2009; Schrier et al, 2006). Of the 223 patients in the tolvaptan group that were analyzed for adverse events, 1 withdrew from the study from muscle weakness (Schrier et al, 2006).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) TOLVAPTAN: In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), hyperglycemia occurred in 6% of the patients in the tolvaptan group (n=223), and 1% of the patients in the placebo group (n=220) (Prod Info SAMSCA(TM) oral tablets, 2009; Schrier et al, 2006).
    B) INCREASED THIRST
    1) WITH THERAPEUTIC USE
    a) CONIVAPTAN
    1) During an open-label study of euvolemic or hypervolemic patients and healthy volunteers who received conivaptan hydrochloride (20 mg loading dose followed by either 20 mg/day [n=37] or 40 mg/day [n=315] for 2 to 4 days), increased thirst was reported in 3% and 6% of the conivaptan groups, respectively, compared with 1% in the placebo group (n=69) (Prod Info VAPRISOL(R) injection, 2007).
    2) During one study, the most common adverse event observed in patients receiving conivaptan was thirst (Burnier et al, 1999).
    b) TOLVAPTAN
    1) In two multicenter, randomized, double-blind, placebo-controlled trials (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2, SALT-1 and SALT-2), increased thirst occurred in 16% of the patients in the tolvaptan group (n=223), and 5% of the patients in the placebo group (n=220) (Prod Info SAMSCA(TM) oral tablets, 2009; Schrier et al, 2006).
    2) In a subgroup of patients with hyponatremia (less than 135 mEq/L) and worsening heart failure included in a double-blind, placebo-controlled trial for a mean duration of 9 months (n=475), thirst occurred in 12% of the patients in the tolvaptan group and 2% of the patients in the placebo group (Prod Info SAMSCA(TM) oral tablets, 2009).
    3) In a double-blind, randomized, trial, 31.3%, 40.3%, and 24.6% of patients in the tolvaptan 30-mg (n=64), 45-mg (n=62), and 60-mg groups (n=61), respectively, experienced increased thirst compared with 4.8% of the patients in the placebo group (n=62) (Gheorghiade et al, 2003).

Reproductive

    3.20.1) SUMMARY
    A) Conivaptan and tolvaptan are both classified as pregnancy category C. There have been no reports of teratogenicity with conivaptan administration during animal studies; however, teratogenic effects (ie, cleft palate, brachymelia, microphthalmia, skeletal malformations) were reported in animals following tolvaptan administration.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) TOLVAPTAN
    a) RABBITS: Oral administration of tolvaptan at a dosage of 1000 mg/kg/day (324 times the maximum recommended human dose (MRHD)) to pregnant rabbits during organogenesis resulted in a variety of teratogenic effects including fetal microphthalmia, open eyelids, cleft palate, brachymelia, and skeletal malformations (Prod Info SAMSCA(TM) oral tablets, 2009). An increased incidence of embryo-fetal death was also observed at this dose.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Conivaptan and tolvaptan are classified by their manufacturers as FDA pregnancy category C (Prod Info SAMSCA(TM) oral tablets, 2009; Prod Info VAPRISOL(R) injection, 2007).
    B) ANIMAL STUDIES
    1) CONIVAPTAN
    a) RATS: Female rats administered conivaptan intravenous bolus dosages of 2.5 mg/kg/day (systemic exposures less than the therapeutic dose) before mating and through day 7 of gestation experienced prolonged diestrus, decreased fertility, and increased implantation loss. Pregnant rats administered intravenous dosages up to 2.5 mg/kg/day from gestation day 7 through 17 experienced no adverse maternal or fetal effects. When the same dose was given gestation day 7 through lactation day 20, the pups showed decreased neonatal viability, weaning indices, delayed growth and physical development, and delayed reflex development. Lower dosages of 0.5 and 1.25 mg/kg/day administered during the same time period did not adversely affect the pups. The dams were not adversely affected in any of these three groups (Prod Info VAPRISOL(R) injection, 2007).
    b) RABBITS: Intravenous dosages of 3, 6, or 12 mg/kg/day administered to pregnant rabbits from gestation day 6 through 18 did not adversely affect the fetuses, but maternal toxicity was observed in all groups. This dose represents systemic exposures less than the therapeutic dose (Prod Info VAPRISOL(R) injection, 2007).
    2) TOLVAPTAN
    a) RATS: Reductions in maternal body weight gain and food consumption were reported in pregnant rats who were given tolvaptan orally at dosages of 100 and 1000 mg/kg/ day during organogenesis. Reduced fetal weight and delayed ossification of fetuses were also noted following maternal oral administration of 1000 mg/kg/day (162 times the MRHD) during organogenesis (Prod Info SAMSCA(TM) oral tablets, 2009).
    b) RABBITS: Reductions in maternal body weight gain and food consumption were observed following oral administration of tolvaptan to pregnant rabbits during organogenesis at dosages of 100, 300, and 1000 mg/kg/day. Abortions were also noted at the 300 and 1000 mg/kg/day doses (approximately 97 and 324 times the MRHD, respectively) (Prod Info SAMSCA(TM) oral tablets, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) LACK OF INFORMATION: It is unknown whether conivaptan or tolvaptan are excreted into human breast milk (Prod Info SAMSCA(TM) oral tablets, 2009; Prod Info VAPRISOL(R) injection, 2007).
    B) ANIMAL STUDIES
    1) CONIVAPTAN
    a) There are no literature reports describing the use of conivaptan during human lactation. When administered intravenously to lactating rats, conivaptan is detected in milk and the neonate. Maximum levels were reached in milk one hour post dose, reaching concentrations 3 times greater than maternal plasma concentrations. Intravenous dosage of 2.5 mg/kg/day, representing systemic exposures less than the therapeutic dose based on AUC comparisons, increased peripartum pup mortality (Prod Info VAPRISOL(R) injection, 2007).
    2) TOLVAPTAN
    a) Tolvaptan is excreted into the milk of lactating rats (Prod Info SAMSCA(TM) oral tablets, 2009).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) CONIVAPTAN
    a) Prolonged diestrus, decreased fertility, and increased pre- and post-implantation loss were reported in female rats who were given an intravenous bolus dose of conivaptan, 15 days before mating through gestation day 7, at a dosage of 2.5 mg/kg/day (Prod Info VAPRISOL(R) injection, 2007).
    2) TOLVAPTAN
    a) Oral administration of tolvaptan to male and female rats at a dosage of 1000 mg/kg/day was associated with significantly fewer corpora lutea and implants as compared with controls (Prod Info SAMSCA(TM) oral tablets, 2009).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) CONIVAPTAN
    a) Following conivaptan administration at dosages up to 30 mg/kg/day in mice and rats (6 times and 2 times the maximum recommended human dose, respectively), the incidence of tumors did not increase (Prod Info VAPRISOL(R) injection, 2007).
    2) TOLVAPTAN
    a) Following 2-year oral administration of tolvaptan to male and female rats at dosages up to 1000 mg/kg/day (162 times the maximum recommended human dose (MRHD) on a body surface area basis) and to male mice and female mice at dosages of 60 mg/kg/day (5 times the MRHD) and 100 mg/kg/day (8 times the MRHD), respectively, the incidence of tumors did not increase (Prod Info SAMSCA(TM) oral tablets, 2009).

Genotoxicity

    A) Conivaptan is not mutagenic or clastogenic according to the Ames text with S. typhimurium and E. coli, in human peripheral blood lymphocytes, or the in vivo rat micronucleus assay (Prod Info VAPRISOL(R) injection, 2007).
    B) Tolvaptan is not genotoxic according to the in vitro bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells and the in vivo rat micronucleus assay (Prod Info SAMSCA(TM) oral tablets, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, fluid status, serum electrolytes and urine output after significant overdoses.
    B) Conivaptan and tolvaptan plasma levels are not widely available or useful in guiding therapy after overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with deliberate ingestions demonstrating severe fluid and electrolyte imbalance should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with inadvertent overdose can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Monitor vital signs, fluid status, serum electrolytes and urine output after significant overdoses.
    B) Conivaptan and tolvaptan plasma levels are not widely available or useful in guiding therapy after overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not indicated as toxicity is limited.
    6.5.3) TREATMENT
    A) SUPPORT
    1) In case of overdose, treatment is symptomatic and supportive. There is no antidote available.
    B) MONITORING OF PATIENT
    1) Monitor vital signs, fluid status, serum electrolytes, and urine output after significant overdose.

Enhanced Elimination

    A) ENHANCED ELIMINATION
    1) Due to high protein binding (99%), hemodialysis and hemoperfusion are NOT likely to be beneficial.

Range Of Toxicity

Summary

    A) TOXICITY: Overdose data are limited. Tolvaptan administration of single oral doses up to 480 mg and multiple dosing up to 300 mg once daily for 5 days were well tolerated in healthy subjects. Conivaptan administration of a 20 mg loading dose followed by a continuous intravenous infusion of 80 mg/day for 4 days or 120 mg/day for 2 days were also well tolerated.
    B) THERAPEUTIC DOSE: CONIVAPTAN: The loading dose is 20 mg administered intravenously over 30 minutes, following by a continuous infusion of 20 mg/24 hours. The dose may be increased up to a maximum daily dose of 40 mg and up to 4 days of therapy. TOLVAPTAN: Initial dose: 15 mg orally once daily. After 24 hours, the dose may be increased to 30 mg once daily, up to a maximum dose of 60 mg once daily.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) CONIVAPTAN: Initially, the recommended loading dose is 20 mg administered intravenously over 30 minutes, following by a continuous intravenous infusion of 20 mg/24 hours. The dose may be increased up to a maximum daily dose of 40 mg. The total duration of therapy should not exceed 4 days (Prod Info VAPRISOL(R) injection, 2007).
    2) TOLVAPTAN: The recommended starting dose is 15 mg orally once daily. After 24 hours, the dose may be increased to 30 mg once daily, up to a maximum dose of 60 mg once daily (Prod Info SAMSCA(TM) oral tablets, 2009).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info SAMSCA(TM) oral tablets, 2009; Prod Info VAPRISOL(R) injection, 2007).

Maximum Tolerated Exposure

    A) CONIVAPTAN: Intravenous administration of a 20 mg loading dose on day 1, followed by a continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in patients with congestive heart failure were well tolerated. Only adverse effects related to conivaptan therapy (e.g. hypotension, thirst) occurred more frequently at the higher doses. There was no evidence of development of new toxicities (Prod Info VAPRISOL(R) injection, 2007).
    B) TOLVAPTAN: Oral single doses up to 480 mg and multiple dosing up to 300 mg once daily for 5 days were well-tolerated by healthy subjects (Prod Info SAMSCA(TM) oral tablets, 2009).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) TOLVAPTAN: Greater than 2000 mg/kg (Prod Info SAMSCA(TM) oral tablets, 2009)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Conivaptan and tolvaptan are arginine vasopressin (AVP) receptor antagonists. Conivaptan is a dual antagonist of both V1a and V2 receptors, although its AVP effects are mediated through the V2 receptors. Tolvaptan a selective antagonist with an affinity for the V2 receptor that is 29 times greater than the V1a receptor. The V2 receptors are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors assist in maintaining plasma osmolality within the normal range. Antagonism of AVP in the renal collecting ducts produces an increase in urine flow, increase in net fluid loss, and a decrease in urine osmolality, resulting in the excretion of free water, with corresponding increases in plasma osmolality and serum sodium without increasing the renal elimination of sodium (Prod Info SAMSCA(TM) oral tablets, 2009; Prod Info VAPRISOL(R) injection, 2007).

Physicochemical

Physical Characteristics

    A) CONIVAPTAN HYDROCHLORIDE: Conivaptan hydrochloride is a white to off-white or pale orange-white powder that is very slightly soluble in water (Prod Info VAPRISOL(R) injection, 2007).

Molecular Weight

    A) CONIVAPTAN HYDROCHLORIDE: 535.04 (Prod Info VAPRISOL(R) injection, 2007)
    B) TOLVAPTAN: 448.94 (Prod Info SAMSCA(TM) oral tablets, 2009)

References

General Bibliography

    1) Burnier M, Fricker AF, Hayoz D, et al: Pharmacokinetic and pharmacodynamic effects of YM087, a combined V1/V2 vasopressin receptor antagonist in normal subjects. Eur J Clin Pharmacol 1999; 55(9):633-637.
    2) Gheorghiade M, Niazi I, Ouyang J, et al: Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation 2003; 107(21):2690-2696.
    3) Martinez-Castelao A: Conivaptan. Curr Opin Investig Drugs 2002; 3(1):89-95.
    4) Product Information: SAMSCA(TM) oral tablets, tolvaptan oral tablets. Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan, 2009.
    5) Product Information: VAPRISOL(R) injection, conivaptan hcl injection. Astellas Pharma US,Inc, Deerfield, IL, 2007.
    6) Schrier RW, Gross P, Gheorghiade M, et al: Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia. N Engl J Med 2006; 355(20):2099-2112.