Tolvaptan

Common name: Tolvaptan tablets

Trade name: Sumika

All names: Tolvaptan tablets, Sumika, Tolvaptan

Indications:

This product is used for Treatment of clinically apparent hypervolemic and euvolemic hyponatremia (serum sodium concentration <125 mEq/L, or hyponatremia that is subtle but symptomatic and refractory to fluid restriction therapy), including patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Important Restrictions: Patients who require an urgent increase in serum sodium to prevent or treat severe neurological symptoms should not be treated with this product. The symptomatic benefit of increasing serum sodium concentrations with this product has not been established.

Usage and Dosage:

1. Common adult dosage:

In order to evaluate the therapeutic effect of this product, and correcting hyponatremia too quickly may cause It acts as an osmotic demyelinating agent, leading to dysarthria, mutism, dysphagia, drowsiness, affective changes, tonic quadriplegia, seizures, coma and death. Therefore, the patient's initial medication and re-medication should be hospitalized.

The usual starting dose of this product is 15mg, once a day, and can be taken before or after meals. After taking the medicine for at least 24 hours, the dosage can be increased to 30 mg once a day. Depending on the serum sodium concentration, the maximum dose can be increased to 60 mg, once daily. Changes in serum electrolytes and blood volume should be monitored frequently during initial administration and dose increase, and fluid restriction should be avoided during the first 24 hours of treatment. Patients taking this product should drink water when thirsty.

2. Suspension of drug treatment:

After the patient stops taking this product, the patient should be instructed to limit fluid intake again, and changes in serum sodium concentration and blood volume should be detected.

If serum sodium levels are appropriately improved, consideration should be given to replacing tolvaptan treatment with other treatments or adding other treatments to tolvaptan. Patients who experience modest improvement in serum sodium levels should have their underlying medical conditions and serum sodium levels regularly monitored to evaluate the need for further treatment with tolvaptan. In the case of hyponatremia, the duration of treatment depends on the underlying disease and its treatment. Treatment with tolvaptan is expected to be continued until the underlying disease is appropriately treated or hyponatremia is no longer a clinical problem.

3. Special groups:

This product does not need to be adjusted according to the patient's age, gender, race, cardiac function, mild or moderate liver function impairment.

Reduced renal function: Patients with mild to toxic renal insufficiency (creatinine clearance 10~79ml/min) do not need to adjust the dosage, because the plasma concentration of tolvaptan will not increase. Tolvaptan has not been evaluated in patients with creatinine clearance <10 ml/min or who are undergoing dialysis. No benefit is expected in patients with anuria.

4. Combined use with CYP3A inhibitors, CYP3A inducers and P-glycoprotein inhibitors:

CYP3A inhibitors: Since tolvaptan is metabolized by CYP3A, when combined with a strong CYP3A inhibitor, the plasma concentration of tolvaptan can be significantly increased (increased by 5 times). The effect of use with moderate CYP3A inhibitors on tolvaptan exposure has not been evaluated. Avoid the combined use of this product and moderate CYP3A enzyme inhibitors.

CYP3A inducers: The combined use of this product with strong CYP3A inducers (such as rifampicin) can reduce the plasma drug concentration of tolvaptan by 85%. Therefore, the expected clinical efficacy of this product may not be obtained at the recommended dose. Dosage should be adjusted based on patient responsiveness.

P glycoprotein inhibitor: Tolvaptan is a substrate of P glycoprotein. When this product is combined with P glycoprotein inhibitors (cyclosporine A, etc.), the dosage of this product needs to be reduced.

Specification:

15mg ; 30mg

Adverse reactions:

Thirst, dry mouth, fatigue, constipation, frequent or polyuria, high blood sugar, heart failure, cirrhosis, nausea

Contraindications:

1. Urgent need to rapidly increase serum sodium concentration

The effect of this product on urgently needed to rapidly increase serum sodium concentration has not been studied.

2. Patients who are not sensitive to thirst or respond normally to oral intake

For patients who cannot adjust their own body fluid balance independently, the risk of rapid correction of serum sodium, hypernatremia, and hypovolemia will increase.

3. Hypovolemic hyponatremia

There is a risk of worsening the hypovolemic condition, including complications of hypotension and renal failure, which may cause more harm than good.

4. Combined use with strong CYP3A inhibitors

After combined use with ketoconazole 200 mg, the exposure of tolvaptan increased 5-fold. Tolvaptan exposure may further increase if the dose is increased, and there is insufficient experience to determine how to safely adjust the dose of tolvaptan when used concomitantly with strong CYP3A inhibitors such as clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nifenavir, saquinavir, nefazodone, and telithromycin.

5. Patients with anuria

For patients who cannot produce urine, clinical benefit cannot be expected.

6. Those who are allergic to any component of this product

7. Patients with hypernatremia

Notes:

1. Correcting the serum sodium concentration too quickly will lead to serious neurological sequelae:

Correcting serum concentrations of hyponatremia too quickly (>12 mEq/L/24 hours) carries the risk of developing osmotic demyelination syndrome, which can cause dysarthria, mutism, dysphagia, somnolence, affective changes, spastic quadriplegia, seizures, coma, and death. For patients prone to osmotic demyelination such as severe malnutrition, alcoholism, and advanced liver disease, it is recommended to slow down the correction of serum sodium. In a dose-escalation controlled clinical trial of tolvaptan with a starting dose of 15 mg once daily, 7% of subjects in the tolvaptan group with serum sodium <130 mEq/L had an increase in serum sodium concentration of more than 8 mEq/L 8 hours after taking the drug; 2% of subjects in the tolvaptan group had an increase in serum sodium concentration of more than 12 mEq/L 24 hours after taking the drug. In the placebo group, 1% of subjects with serum sodium concentrations <130 mEq/L had serum sodium concentrations that increased by more than 8 mEq/L 8 hours after taking the medication, but no subject had serum sodium concentrations that increased by more than 12 mEq/L 24 hours after taking the medication. Although osmotic demyelinating syndrome and associated neurologic sequelae were not seen in these studies, CPP symptoms have been reported with rapid correction of serum sodium concentrations. For patients taking this product, especially at the beginning of taking the drug and after increasing the dose, attention should be paid to observing the serum sodium concentration and neurological symptoms. Patients with SIADH or very low serum sodium concentrations are at higher risk if their serum sodium concentrations are corrected too quickly. For patients whose serum sodium concentration rises too quickly while taking this product, the medication needs to be stopped or interrupted, and hypotonic fluids should be considered. Restricting fluid intake within 24 hours of taking this product may cause serum sodium concentrations to correct too quickly, and such restrictions should generally be avoided.

2. Liver damage:

In studies of long-term, high-dose use of tolvaptan - the indications for which are different from those recorded in this package insert, liver damage caused by tolvaptan has been observed. In the study, three patients taking tolvaptan were observed to have clinically significant increases in serum alanine aminotransferase (ALT) (greater than 3 times the upper limit of normal) and increased serum total bilirubin (greater than 2 times the upper limit of normal). In addition, significant elevations in ALT were observed in 4.4% (42/985) of the patients in the tolvaptan group compared with 1.0% (5/484) of the placebo group. The vast majority of liver enzyme abnormalities are detected within 18 months of starting treatment. Most of these elevated markers gradually improved after stopping tolvaptan. These findings suggest that tolvaptan may cause irreversible and fatal liver injury.

In other studies of tolvaptan, including those used to obtain the indications in this labeling, no greater incidence of liver injury was found than with placebo. However, these results do not exclude the risk of fatal liver injury in patients receiving tolvaptan for this indication.

To reduce the risk of significant or irreversible liver injury, hepatic transferase and bilirubin should be monitored with blood tests before starting tolvaptan, monthly for 18 months after use, and periodically thereafter (e.g., every 3 to 6 months). If a patient taking tolvaptan reports symptoms such as fatigue, anorexia, epigastric discomfort, abnormally dark urine, or jaundice that may indicate liver damage or worsening of liver damage, liver function testing should be performed immediately. If hepatic injury or worsening of hepatic injury is suspected, tolvaptan should be discontinued immediately, appropriate treatment should be instituted, and the cause of the occurrence should be investigated. Tolvaptan should not be re-administered to patients who have developed hepatic impairment unless it is determined that the occurrence of hepatic impairment is not related to the use of tolvaptan.

3. Gastrointestinal bleeding in patients with cirrhosis:

In clinical trials with patients with hyponatremia, patients with cirrhosis took tolvaptan. Gastrointestinal bleeding occurred in 6 out of 63 patients (10%) in the tolvaptan group and in 1 out of 53 patients (2%) in the placebo group. For patients with cirrhosis, this product can only be used when it is judged that the benefits of treatment outweigh the risks.

4. Dehydration and decreased blood volume:

After taking tolvaptan tablets, obvious drainage and diuretic effects may occur. Generally, drinking water can weaken its effect. Especially for patients who are taking diuretics or restricting fluid intake and may have reduced blood volume, taking tolvaptan tablets may cause dehydration and fluid loss. In a controlled clinical trial in which patients with hyponatremia continuously took tolvaptan or placebo, the incidence of dehydration was 3.3% in the tolvaptan group (607 patients) and 1.5% in the placebo group. For patients who develop medically significant signs or symptoms of hypovolemia after taking this product, medication should be interrupted or stopped, and vital signs, fluid balance, and electrolytes should be closely monitored, and auxiliary treatment should be provided. Restricting fluid intake while taking this product increases the risk of dehydration and loss of fluid volume, and patients taking this product should continue to drink water when thirsty.

5. Combined application of hypertonic saline:

There is no experience in the combined application of this product and hypertonic saline, and combined application with hypertonic saline is not recommended.

6. Hyperkalemia or drugs that increase serum potassium concentration:

After taking tolvaptan, the sharp decrease in extracellular fluid volume may lead to an increase in serum potassium concentration. In patients taking medications that increase serum potassium concentrations or in patients with serum potassium concentrations >mEq/L, serum potassium concentrations should be monitored after initiation of medication.

7. Difficulty urinating:

Urine output must be ensured. Some patients with difficulty urinating, such as patients with prostatic hypertrophy or urinary disorders, are at increased risk of acute urinary retention.

8. Diabetes:

Diabetic patients with elevated blood sugar concentrations (for example, more than 300 mg/dl) may suffer from pseudohyponatremia. This condition should be ruled out before and during treatment with tolvaptan.

Tolvaptan may cause hyperglycemia. Therefore, patients with diabetes receiving tolvaptan should be managed with caution, especially those with poorly controlled type 2 diabetes.

9. Lactose and galactose intolerance:

Samsca contains the excipient lactose. Patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this product.

10. Embryo-fetal toxicity:

There are currently no adequate and well-controlled studies on the use of tolvaptan tablets in pregnant women. In animal experiments, cleft palate, short limbs, microphthalmia, skeletal deformities, reduced fetal weight, delayed ossification, and embryonic death occurred. This product has not been tested in pregnant women. Regarding whether tolvaptan can be used by pregnant women, this product can only be used during pregnancy after it is determined that the benefits of treatment outweigh the risks to the fetus.

The effect of this product on human labor and delivery is unclear.

It is not clear whether this product is distributed in breast milk. When tolvaptan is administered orally to lactating rats, tolvaptan is excreted in breast milk. Since many drugs can be excreted in human milk, and tolvaptan may cause serious adverse reactions to nursing infants, the mother should decide to take tolvaptan or stop breastfeeding as needed.

Storage:

Shade light, seal and store

Mechanism of action:

A vasopressin V2 receptor antagonist (non-peptide AVP2 receptor antagonist), which can increase the concentration of sodium ions in the plasma and help excess water be excreted in the urine. Enhances the kidneys' ability to process water. Cyclic adenosine monophosphate (cAMP) accumulates in polycystic kidney cells, which promotes cyst growth by stimulating cyst fluid secretion and lining cell proliferation. Tolvaptan is a type 2 vasopressin receptor antagonist that inhibits cAMP production and accumulation. Tolvaptan has shown good efficacy in various PKD animal model studies.

Safety and efficacy:

In a trial, the effect of oral tolvaptan tablets was observed in 38 patients with fluid retention and hyponatremia caused by congestive heart failure, liver failure with ascites formation, chronic renal insufficiency or inappropriate antidiuretic hormone secretion. Results: Those who took tolvaptan tablets had a significant increase in blood sodium concentration and blood osmotic pressure. Conclusion: Tolvaptan tablets can show a good effect on increasing serum sodium concentration and have obvious curative effect on patients with hyponatremia. There are no serious complications and adverse reactions, and it is simple and safe in clinical application.