Saptan 15

Blue, round, shallow-convex and beveled edge with engraved 15 on one side and plain on the other.
Each tablet contains Tolvaptan 15 mg.

Pharmacology: Pharmacodynamics: Tolvaptan is a selective vasopressin V₂-receptor antagonist. Antagonism of vasopressin causes an increase in urine water excretion resulting in increased free water clearance, decreased urine osmolality, and increased serum sodium concentrations.
Pharmacokinetics: Absorption: Tmax: 1.75 to 4 hours.
Bioavailability: 40%; Absolute bioavailability decreases with increasing doses. Following an oral dose of 30 mg, absolute bioavailability was 56% (range, 42% to 80%).
Effects of food: No effect.
Distribution: V_d: 3 L/kg.
Protein binding: Greater than 98%, to albumin and alpha 1-acid glycoprotein.
Metabolism: Hepatic: Almost exclusively via CYP3A.
Substrate of CYP3A.
Substrate and inhibitor of P-glycoprotein.
Inhibitor of OATPI Bl/B3 and OAT3.
Inhibitor of Breast Cancer Resistance Protein.
Excretion: Renal excretion: 40%, almost all as metabolites.
Fecal excretion: 59%, with 19% as unchanged drug.
Total body clearance: 35.6 to 38.7 L/hr; 4 mL/min/kg (healthy volunteers); 2 mL/min/kg (hyponatremic patients).
Elimination Half Life: 2.8 to 12 hours.

Hypervolemic or euvolemic hyponatremia: Treatment of clinically significant hypervolemic or euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and resistant to fluid restriction), including patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).
Important limitations: Not indicated for use when urgent treatment of hyponatremia is required to prevent or treat serious neurological symptoms. It has not been established that raising serum sodium with Tolvaptan provides symptomatic benefit.
Adjunct treatment of volume overload in heart failure: Volume overload in heart failure when adequate response is not obtained with other diuretics (e.g., loop diuretics).
Important limitations: Tolvaptan should be used in combination with other diuretics, such as loop diuretics, thiazides, and aldosterone antagonists).

Hypervolemic or euvolemic hyponatremia: Patient should be hospitalized for initiation or reinitiation of Tolvaptan therapy to evaluate therapeutic response and avoid too rapid correction of hyponatremia.
Initial: 15 mg once daily; may increase to 30 mg once daily, after at least 24 hours, to maximum of 60 mg once daily.
Avoid fluid restriction during the first 24 hours of therapy. Do not use for more than 30 days due to the risk of hepatotoxicity.
Adjunct treatment of volume overload in heart failure: Tolvaptan should be used as adjunct therapy to other diuretics (loop or thiazide diuretics, aldosterone antagonists. etc.). The usual adult dose is 15 mg once daily but it is recommended to start from 7.5 mg/day for patients whose serum sodium is less than 125 mEq/L or for whom rapid volume decrease is considered inappropriate. In order to avoid nocturnal urination, it is recommended to take Tolvaptan in the morning.
Treatment with Tolvaptan should be initiated in hospital and patients should be frequently monitored for serum sodium especially during the first day of treatment.
Renal impairment: CrCl ≥10 mL/minute: No dosage adjustment necessary.
CrCl <10 mL/minute, use not recommended.
Contraindicated in anuria.
Hepatic impairment: Avoid use with underlying liver disease, including cirrhosis; monitor closely for hepatotoxicity developing during use; discontinue use if signs/symptoms of hepatotoxicity develop (do not use for more than 30 days due to this potential risk).
Congestive heart failure: No dosage adjustment required.
Administration: Avoid fluid restriction during first 24 hours of therapy. Resume fluid restriction upon discontinuation.

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.
Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses (Thirst, dry mouth, asthenia, constipation, polyuria, and hyperglycemia are the most common adverse effects. Pyrexia was reported in Tolvaptan-treated patients during clinical efficacy trials. Severe hepatotoxicity, including development of acute liver failure requiring transplantation, has occurred during clinical trials of patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) who were being treated with Tolvaptan).
Treatment is symptomatic and supportive. There is no known antidote.
Decontamination is generally not indicated as toxicity is limited (480 mg of Tolvaptan 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.
Monitoring of patient: Monitor vital signs, fluid status, serum electrolytes and urine output after significant overdose. Monitor liver enzymes as indicated in symptomatic patients.

History, signs or symptoms of significant liver impairment or injury, excluding uncomplicated polycystic liver disease.
Anuria; no clinical benefit expected.
Concomitant use with strong CYP3A inhibitors (eg, clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, telithromycin).
Fluid balance, inability to autoregulate; increased risk of too-rapid correction of serum sodium, hypernatremia, and hypovolemia.
Hypersensitivity (eg, anaphylactic shock or generalized rash) to Tolvaptan or any component of the product.
Hypovolemic hyponatremia; risks associated with worsening hypovolemia (eg, hypotension and renal failure) outweigh possible benefits.
Urgent need to raise serum sodium acutely; not studied for this use.
Uncorrected urinary outflow obstruction.
Unable to sense or respond to thirst.
Uncorrected abnormal blood sodium concentrations.

Initiate and re-initiate in a hospital and monitor serum sodium.
Tolvaptan should be initiated and re-initiated in patients only in a hospital where scrum sodium can be monitored closely.
Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.
Potent aquaresis (free water clearance), especially in normonatremic patients treated with Tolvaptan for heart failure, may induced hypernatremia which can lead to disturbed consciousness. If serum sodium increases above normal range, Tolvaptan should be discontinued, serum sodium should be carefully monitored and appropriate measures should be taken if necessary.

Concomitant use: Avoid use of CYP3A inducers and moderate CYP3A inhibitors.
Not recommended for use with hypertonic saline.
Endocrine and metabolic: Too rapid serum sodium correction can cause serious neurologic sequelae.
Dehydration may occur, particularly in volume-depleted patients receiving diuretics or fluid-restricted patients; interrupt or discontinue use if suspected. Monitoring recommended.
Hyperkalemia, pre-existing, or drugs that increase serum potassium may further increase serum potassium; monitoring recommended.
Hypovolemia may occur, particularly in volume-depleted patients receiving diuretics or fluid-restricted patients; monitoring recommended; interrupt or discontinue use if suspected.
Hypernatremia may occur; monitoring recommended.
Neurologic: Serious neurologic conditions and osmotic demyelination syndrome may occur; increased risk in very low baseline sodium levels, concomitant use of diuretics, and conditions such as severe malnutrition, alcoholism, or advanced liver disease; avoid use if patient is fluid restricted during first 24 hours of therapy; monitoring recommended, especially during initiation and dose titration; interrupt or discontinue use if occurs.
Hepatic: Avoid use in liver disease (eg, cirrhosis); may impair liver injury recovery.
Serious and potentially fatal liver injury has been reported; limit Tolvaptan therapy to 30 days to minimize liver injury risk; liver function tests recommended if symptomatic; discontinue use if suspected; reinstitute therapy only if liver injury is unrelated to Tolvaptan.
Renal: Use not recommended if CrCl is less than 10 mL/min.

Pregnancy: There are insufficient human data regarding the use of Tolvaptan in pregnant women to determine the risk of adverse developmental outcomes; however, Tolvaptan use during pregnancy may cause fetal harm. Advise pregnant women of the potential for fetal harm if Tolvaptan is used during pregnancy. Administer Tolvaptan during pregnancy only if the potential maternal benefit outweighs the potential fetal risk.
Lactation: It is unknown whether Tolvaptan is present in human milk, effects milk production, or impacts the breastfed infant. Due to the risk of serious adverse effects to the infant, including hepatotoxicity, hypernatremia, hypotension, and volume depletion, advise women to avoid breastfeeding during Tolvaptan therapy.

Common: Endocrine metabolic: Hypernatremia (0.7% to 25.6%).
Gastrointestinal: Diarrhea (13.3%), Increased thirst (12% to 63.7%), Nausea (8% to 21%), Xerostomia (7% to 23%).
Hepatic: ALT/SGPT level raised, Serum bilirubin raised.
Musculoskeletal: Asthenia (9%).
Neurologic: Dizziness (4.8% to 11.3%).
Renal: Increased frequency of urination (69.5%), Polyuria (4% to 24%).
Other: Fatigue ( 13.6%).
Serious: Cardiovascular: Hypovolemia.
Gastrointestinal: Gastrointestinal hemorrhage (in cirrhotic patients (10%)).
Hepatic: Acute hepatic failure, Injury of liver.
Neurologic: Osmotic demyelination syndrome.

Avoid concomitant use of Tolvaptan and moderate CYP3A inhibitors (eg, aprepitant, erythromycin, fluconazole, verapamil).
Concomitant use of Tolvaptan and strong CYP3A inhibitors (eg, ketoconazole, clarithromycin, ritonavir, saquinavir) is contraindicated.
Avoid concomitant use of Tolvaptan and strong CYP3A inducers (eg, rifampin, barbiturates, phenytoin, carbamazepine, St. John's Wort). If concurrent use is necessary, monitor patient response and increase Tolvaptan dose as necessary.
Dose reduction of Tolvaptan may be necessary when concurrent use with P-gp inhibitors (eg, cyclosporine, quinidine).

Store below 30°C.

Diuretics

C03XA01 - tolvaptan ; Belongs to the class of vasopressin antagonists. Used as diuretics.

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