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FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Warning

H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P260, P263, P264, P270, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H413: May cause long lasting harmful effects to aquatic life [Hazardous to the aquatic environment, long-term hazard]

P273, and P501 (click each P-code to see the statement)

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tolvaptan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

Provide appropriate exhaust ventilation at places where dust is formed.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

Control of environmental exposure: Do not let product enter drains.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Skin protection: Handle with gloves.

Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type P95 (US) or type P1 (EU EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Body protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Tolvaptan, an arginine vasopressin (V2) receptor antagonist, may interfere with the V2 receptor agonist activity of desmopressin. In a male patient with mild von Willebrand disease, IV infusion of desmopressin 2 hours after oral administration of tolvaptan did not result in the expected increases in von Willebrand factor antigen or factor VIII activity. When the patient received desmopressin prior to initiation of tolvaptan therapy, desmopressin resulted in twofold to threefold increases in von Willebrand factor antigen, ristocetin cofactor activity, and factor VIII activity, and normalized results of the platelet function analyzer test and the activated partial thromboplastin time (aPTT). However, when the patient received desmopressin during tolvaptan therapy, desmopressin failed to increase von Willebrand factor antigen, ristocetin cofactor activity, and factor VIII activity, and effects of desmopressin on platelet function analyzer test results and aPTT were attenuated. Concomitant use of tolvaptan with V2 receptor agonists is not recommended.

In clinical studies, the incidence of hyperkalemia was approximately 1-2% higher when tolvaptan was used concomitantly with angiotensin II receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, and potassium-sparing diuretics compared with use of these drugs with placebo. Formal drug interaction studies have not been performed. Serum potassium concentrations should be monitored during concomitant therapy with tolvaptan and drugs known to increase serum potassium concentrations (e.g., angiotensin II receptor antagonists, ACE inhibitors, potassium-sparing diuretics).

Concomitant use of tolvaptan with inhibitors of the P-glycoprotein transport system (e.g., cyclosporine) may result in increased tolvaptan concentrations and may require reduction of tolvaptan dosage based on clinical response.

Concomitant use of tolvaptan with potent inducers of CYP3A (e.g., barbiturates, carbamazepine, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort (Hypericum perforatum)) may result in reduced plasma concentrations and decreased efficacy of tolvaptan. The manufacturer states that concomitant use of tolvaptan with rifampin reduces plasma tolvaptan concentrations by 85%, and other potent CYP3A inducers can be expected to produce similar results. Concomitant use of tolvaptan with CYP3A inducers should be avoided. If tolvaptan is used concomitantly with CYP3A inducers, the expected clinical effects of tolvaptan may not be observed at the recommended dosage; patient response should be monitored and the dosage adjusted accordingly.

For more Interactions (Complete) data for Tolvaptan (8 total), please visit the HSDB record page.

In prelicensure clinical trials, tolvaptan was not implicated in causing serum enzyme elevations or clinically apparent liver injury. However, instances of worsening of hepatic failure and complications of portal hypertension were reported in a small proportion of patients with cirrhosis treated with tolvaptan. These complications included variceal hemorrhage, hepatic encephalopathy and worsening of jaundice. In many trials, however, the frequency of these complications was not significantly greater than in placebo treated controls. More recently, in large registration trials of long term therapy in patients with ADPKD, serum aminotransferase elevations occurred in 4% to 5% of patients on tolvaptan, compared to only 1% of controls. Furthermore, clinically apparent liver injury occurred in approximately 0.1% of treated patients. The time to onset of illness ranged from 3 to 9 months (Case 1), but occasionally arose during long term therapy (Case 2). The clinical presentation was with the insidious development of fatigue, nausea and abdominal pain followed by dark urine, jaundice and pruritus. The pattern of serum enzyme elevations was typically hepatocellular or mixed, and liver biopsy showed an acute hepatitis with mild cholestasis. All patients recovered after stopping therapy, generally within 1 to 3 months of stopping therapy without evidence of residual injury. Immunoallergic features and autoantibodies were not found. Rapid recurrence on rechallenge was demonstrated in several patients with marked serum enzyme elevations during therapy, but patients with jaundice were not reexposed. The frequency of clinically apparent liver injury during therapy was one reason for the delay of formal approval of long term tolvaptan therapy for ADPKD. Since its approval and more wide-spread use, occasion reports of clinically apparent liver injury have continued to appear, at least one of which led to liver transplantation. Interestingly, most instances of liver injury have been reported with its use in autosomal dominant polycystic kidney disease rather than hyponatremia. Reasons for this are probably the duration of therapy, but also may relate to the slightly higher doses used to decrease progress in polycystic kidney disease.

EXPERIMENTAL: Tolvaptan is distributed into milk in rats; it is not known whether tolvaptan is distributed into human milk.

EXPERIMENTAL: ... Radioactivity was ... present in milk when (14)C-tolvaptan was administered orally to lactating rats on day 14 postpartum. Levels in milk were higher than those in plasma, peaking at 8 hr post-dose.

IDENTIFICATION AND USE: Tolvaptan is a white crystalline powder that is formulated into oral tablets. Tolvaptan is an antagonist of arginine vasopressin (antidiuretic hormone) V2 receptors. It is used to treat low sodium levels in the blood. HUMAN EXPOSURE AND TOXICITY: Tolvaptan was well tolerated in healthy subjects at single oral doses up to 480 mg and multiple doses up to 300 mg once daily for 5 days. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia. However, chronic administration of tolvaptan can cause serious and potentially fatal liver injury. In 2013, the U.S. Food and Drug Administration (FDA) determined that the drug should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially requiring liver transplant or death. In a placebo-controlled and open label extension study of chronically administered tolvaptan in patients with autosomal dominant polycystic kidney disease, cases of serious liver injury attributed to tolvaptan were observed. 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 correction of hyponatremia may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death. Slower rates of correction may be advisable in susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease. Patients with syndrome of inappropriate secretion of antidiuretic hormone or very low baseline serum sodium concentrations may be at increased risk for too rapid correction of serum sodium concentration. Tolvaptan is contraindicated in patients who are unable to sense or appropriately respond to thirst and in those with hypovolemic hyponatremia. Tolvaptan is mainly, if not exclusively, metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A; the drug also is a weak inhibitor of CYP3A and a substrate and inhibitor of the P-glycoprotein transport system. Compared with tolvaptan, metabolites of the drug have little or no antagonist activity for human V2 receptors. ANIMAL STUDIES: Tolvaptan had low acute toxicity when administered to rats and dogs. In repeated dose studies in rats and dogs, findings were generally related to the pharmacological effect of tolvaptan and consisted of increased urine volume, decreased urine osmolality and increased water consumption. Decreased body weight and alterations in hematological and clinical chemistry parameters were also seen but were reversible during a recovery period. Up to two years of oral administration of tolvaptan to male and female rats did not increase the incidence of tumors. In a fertility study in male and female rats, tolvaptan was associated with fewer corpora lutea and implants compared to controls. Oral administration of tolvaptan to pregnant rabbits during organogenesis was associated with reductions in maternal body weight gain and food consumption. Abortions, increased incidences of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia, and skeletal malformations were also observed. Tolvaptan tested negative for genotoxicity in in vitro (bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and in vivo (rat micronucleus assay) test systems.

/HUMAN EXPOSURE STUDIES/ Samsca can cause serious and potentially fatal liver injury. In a placebo-controlled and open label extension study of chronically administered tolvaptan in patients with autosomal dominant polycystic kidney disease, cases of serious liver injury attributed to tolvaptan were observed. An increased incidence of ALT greater than three times the upper limit of normal was associated with tolvaptan (42/958 or 4.4%) compared to placebo (5/484 or 1.0%). Cases of serious liver injury were generally observed starting 3 months after initiation of tolvaptan although elevations of ALT occurred prior to 3 months. Patients with symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice should discontinue treatment with Samsca. Limit duration of therapy with Samsca to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover from liver injury may be impaired

/HUMAN EXPOSURE STUDIES/ In a study in patients with creatinine clearances ranging from 10-124 mL/min administered a single dose of 60 mg tolvaptan, AUC and Cmax of plasma tolvaptan were less than doubled in patients with severe renal impairment relative to the controls. The peak increase in serum sodium was 5-6 mEq/L, regardless of renal function, but the onset and offset of tolvaptan's effect on serum sodium were slower in patients with severe renal impairment.

/SIGNS AND SYMPTOMS/ Single oral doses up to 480 mg and multiple doses up to 300 mg once daily for 5 days have been well tolerated in studies in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia.

/OTHER TOXICITY INFORMATION/ 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 (e.g., increases in serum sodium concentration exceeding 12 mEq/L over 24 hours) may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death. Slower rates of correction may be advisable in susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease. Patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or very low baseline serum sodium concentrations may be at increased risk for too rapid a correction of serum sodium concentration. Fluid restriction during the first 24 hours of tolvaptan therapy may increase the risk of overly rapid correction of serum sodium concentration and generally should be avoided.

/OTHER TOXICITY INFORMATION/ The U.S. Food and Drug Administration (FDA) has determined that the drug Samsca (tolvaptan) should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially requiring liver transplant or death. Samsca is used to treat low sodium levels in the blood. An increased risk of liver injury was observed in recent large clinical trials evaluating Samsca for a new use in patients with autosomal dominant polycystic kidney disease (ADPKD).

Drug Induced Liver Injury Rank (DILIrank 2.0)

Tolvaptan

vMost-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ Tolvaptan had low acute toxicity when administered to rats and dogs at 2000 mg/kg, the only findings being the presence of white material in the feces and reduced food consumption.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In /repeat-dose oral toxicity trials conducted in Sprague-Dawley rats/ the No Observed Adverse Effect Level (NOAEL) was 1000 mg/kg/day in both sexes in the 4-week and 13-week repeated oral dose toxicity trials. In the 26-week trial at doses of 30, 100 and 1000 mg/kg/day, the results showed neither overt toxicity nor target organ toxicity even at 1000 mg/kg/day. However, 3 females given 1000 mg/kg/day were euthanized in a moribund state (dehydration). Therefore, the NOAEL in this trial was estimated to be 1000 mg/kg/day in the males and 100 mg/kg/day in the females (serum drug concentration at the fourth week of administration: Cmax was 1.37 and 3.42 ug/mL and AUC(0-24) hr was 12.72 and 20.76 ug/hr/mL in the males and females, respectively). In dogs, the NOAEL was 1000 mg/kg/day in both sexes in the 4-week and 13-week administration.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In the 52-week administration trial /conducted in beagle dogs/ at doses of 30, 100 and 1000 mg/kg/day, the results showed no notable target organ toxicity even at 1000 mg/kg/day. However, one male and 2 females given 1000 mg/kg/day were sacrificed in a moribund state because of decreases in body weight and food consumption. Therefore, the NOAEL in this trial was estimated to be 100 mg/kg/day in both sexes (serum drug concentration at 52nd week of administration: Cmax was 5.46 and 6.05 ug/mL and AUC(0-24) hr was 31.45 and 42.35 ug/hr/mL in the males and females, respectively).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Although recent clinical trials have demonstrated the efficacy of the oral vasopressin (AVP) type 2 receptor (V2R) antagonist tolvaptan, its long-term effects on the myocardium and kidney in heart failure (HF) are not clear. We examined the chronic effects of tolvaptan administration on both the myocardium and kidney in a rat hypertensive HF model. Not only circulating AVP level but also myocardial AVP and V1a receptor (V1aR) expressions, renal V1aR, and V2R expressions were significantly upregulated during the transition to HF. The animals were chronically treated with low-dose or high-dose (HD) tolvaptan or vehicle from the left ventricular (LV) hypertrophic stage. Chronic tolvaptan treatment persistently increased urine volume but did not affect blood pressure. In the HD group, the animal survival significantly improved (log-rank test, P<0.01). At the HF stage, the progression of LV dysfunction was prevented and lung congestion was suppressed. Activation of atrial natriuretic peptide, endothelin-1, AVP, and V1aR mRNA levels were significantly suppressed in the LV myocardium. Meanwhile, renal histopathologic damage was ameliorated and renal function was improved in the HD group at the HF stage. Concomitantly, not only activation of aquaporin-2 but also those of V2R, V1aR, renin, and endothelin-1 in the kidney were significantly suppressed (all P<0.05). These results indicate that chronic tolvaptan treatment has beneficial effects by preventing not only the progression of LV dysfunction but also that of renal injury in hypertensive rats with HF. The underlying mechanism may be related to the suppression of myocardial and renal neurohumoral activation.

For more Non-Human Toxicity Excerpts (Complete) data for Tolvaptan (11 total), please visit the HSDB record page.

Tolvaptan should be avoided in patients with underlying liver disease, including cirrhosis.

Tolvaptan is contraindicated in patients who are unable to sense or appropriately respond to thirst and in those with hypovolemic hyponatremia.

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 (e.g., increases in serum sodium concentration exceeding 12 mEq/L over 24 hours) may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death. Slower rates of correction may be advisable in susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease. Patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or very low baseline serum sodium concentrations may be at increased risk for too rapid a correction of serum sodium concentration. Fluid restriction during the first 24 hours of tolvaptan therapy may increase the risk of overly rapid correction of serum sodium concentration and generally should be avoided.

The U.S. Food and Drug Administration (FDA) has determined that the drug Samsca (tolvaptan) should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially requiring liver transplant or death. Samsca is used to treat low sodium levels in the blood. An increased risk of liver injury was observed in recent large clinical trials evaluating Samsca for a new use in patients with autosomal dominant polycystic kidney disease (ADPKD).

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

If overdose occurs, estimation of the severity of poisoning is an important first step. A thorough history and details of overdose should be obtained, and a physical examination should be performed. The possibility of multiple drug involvement should be considered. Treatment should involve symptomatic and supportive care, with respiratory, ECG and blood pressure monitoring and water/electrolyte supplements as needed. A profuse and prolonged aquaresis should be anticipated, which, if not matched by oral fluid ingestion, should be replaced with intravenous hypotonic fluids, while closely monitoring electrolytes and fluid balance. ECG monitoring should begin immediately and continue until ECG parameters are within normal ranges. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (>99%). Close medical supervision and monitoring should continue until the patient recovers.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tolvaptan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

C03XA01

C - Cardiovascular system

QC - Cardiovascular system

Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 receptors.

Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin.

Tolvaptan is a vasopressin antagonist that blocks the binding of arginine vasopressin (AVP) at the V2 receptors of the distal portions of the nephron. Animal pharmacology studies indicated that tolvaptan should increase excretion of water without increasing excretion of electrolytes (aquaresis) and thus offer a means of correcting serum sodium concentration by inducing excretion of water without loss of serum electrolytes. Tolvaptan is about 29 times more selective for V2 receptors than for V1a receptors with virtually no binding to V1b receptors.

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times greater than for the V1a-receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V2-receptors compared with tolvaptan. Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan administration.

Terminal half life, oral dose = 12 hours.

After IV administration, a half-life was estimated to be 3.5 hours, but it is suggested that this value most likely represents a distribution half-life and not a true elimination half-life.

The terminal phase half-life is about 12 hours.

Although tolvaptan is poorly soluble in water, following single dose of 30-480 mg, it is absorbed rapidly with a median time to peak plasma concentrations of about 2 hours (range of 1-12 hours) in healthy subjects. The mean (SD) of elimination half life is 7.8 (4.9) hours.

Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive.

Repeated dosing of female rats reduced systemic exposure to tolvaptan. Analysis of the serum samples for metabolites DM-4103 and DM-4107 revealed increases in the concentrations of these metabolites following repeated dosing, and explained the reduction in serum tolvaptan concentrations. Furthermore, tolvaptan was shown to induce hepatic drug-metabolising enzymes (cytochrome b5 content and aminopyrine N-demethylase activity) in female rats after 7 days dosing at 300 mg/kg/day. Tolvaptan was both a substrate for, and inhibitor of, MDR1-mediated transport.

Tolvaptan is extensively metabolized in all species investigated. In vitro studies with rat liver supernatant produced a number of metabolites of tolvaptan. Hydroxylation of the benzazepine ring produced metabolites DM-4110, DM-4111 and DM-4119. Cleavage of the bond between the 1 and 2 positions of the benzazepine ring produced metabolites DM-4103, DM-4104, DM-4105 and DM- 4107. Oxidation of the hydroxyl group at the 5 position in the benzazepine ring produced MOP-21826.

Tolvaptan is mainly, if not exclusively, metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A; the drug also is a weak inhibitor of CYP3A and a substrate and inhibitor of the P-glycoprotein transport system. Compared with tolvaptan, metabolites of the drug have little or no antagonist activity for human V2 receptors.

Tolvaptan is metabolized extensively in humans by the CYP3A4/5 system with seven metabolites (DM-4103, DM-4104, DM-4105, DM-4107, DM-4110, DM-4111, DM-4119) detected in the plasma, urine, and faeces of all subjects in a 14C mass balance study. After administration of (14)C-tolvaptan, 13 metabolites were identified in human plasma. Tolvaptan and identified metabolites accounted for about 70% of administered radioactivity. The predominant metabolite, with >50% of the total dose using the mass balance approach was DM-4103. The terminal elimination half-life of DM-4103 is approximatley 183 hours and after multiple dosing DM-4103 shows accumulation by day 28, but this appears pharmacologically inactive in the concentrations achieved using clinically relevant doses. Only 3% of the radioactivity was due to unchanged tolvaptan in the plasma.

21G72T1950

TOLVAPTAN

Established Pharmacologic Class [EPC] - Vasopressin V2 Receptor Antagonist

Mechanisms of Action [MoA] - Vasopressin V2 Receptor Antagonists

Tolvaptan is a Vasopressin V2 Receptor Antagonist. The mechanism of action of tolvaptan is as a Vasopressin V2 Receptor Antagonist.

TOLVAPTAN

Tmax, Healthy subjects: 2 - 4 hours; Cmax, Healthy subjects, 30 mg: 374 ng/mL; Cmax, Healthy subjects, 90 mg: 418 ng/mL; Cmax, heart failure patients, 30 mg: 460 ng/mL; Cmax, heart failure patients, 90 mg: 723 ng/mL; AUC(0-24 hours), 60 mg: 3.71 μg·h/mL; AUC(∞), 60 mg: 4.55 μg·h/mL; The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan.

Fecal- very little renal elimination (<1% is excreted unchanged in the urine)

Healthy subjects: 3L/kg; slightly higher in heart failure patients.

4 mL/min/kg (post-oral dosing).

In a study in patients with creatinine clearances ranging from 10-124 mL/min administered a single dose of 60 mg tolvaptan, AUC and Cmax of plasma tolvaptan were less than doubled in patients with severe renal impairment relative to the controls. The peak increase in serum sodium was 5-6 mEq/L, regardless of renal function, but the onset and offset of tolvaptan's effect on serum sodium were slower in patients with severe renal impairment.

In healthy subjects the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been examined. Area under the curve (AUC) increases proportionally with dose. After administration of doses > or = 60 mg, however, Cmax increases less than proportionally with dose. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Food does not impact the bioavailability of tolvaptan. In vitro data indicate that tolvaptan is a substrate and inhibitor of P-gp. Tolvaptan is highly plasma protein bound (99%) and distributed into an apparent volume of distribution of about 3 L/kg. Tolvaptan is eliminated entirely by non-renal routes and mainly, if not exclusively, metabolized by CYP 3A. After oral dosing, clearance is about 4 mL/min/kg and the terminal phase half-life is about 12 hours. The accumulation factor of tolvaptan with the once-daily regimen is 1.3 and the trough concentrations amount to > or = 16% of the peak concentrations, suggesting a dominant half-life somewhat shorter than 12 hours. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.

Vasopressin V2 Receptor Antagonist

MEDICATION