Tolvaptan Samsca Tablet 15mg Otsuka Treatment of blood sodium reduction (1 blister x 10 tablets)

The concentration of natural AVP in serum can increase (average 2 - 9 PG/ml) when using Tolvaptan.

In healthy subjects when taking single doses of Samsca 60 mg, diuretic and sodium increase appear within 2-4 hours after taking the medication. The peak increases about 6 MEQ sodium serum and increased by about 9 ml/minute the ratio of urine output achieved within 4 to 8 hours after taking the drug; Therefore, the pharmacological effect is slowly compared to the concentration of tolvaptan in serum. About 60% of the peak acting on serum sodium is maintained continuously 24 hours after taking the drug, but the rate of urine output at this time is not raised anymore.

The effect of Tolvaptan in recommended doses is from 15 to 60 mg once a day to limit diuretic effects and results increase sodium concentration.

pharmacokinetics

pharmacokinetics of Tolvaptan after using single doses up to 480 mg and multi -doses up to 300 mg once a day have been surveyed on healthy people. The area under the curve (AUC) increases proportional to the dose. However, after using the dose ≥ 60 mg, CMAX increases less than the increase rate of the dose. The pharmacokinetic properties of Tolvaptan are fixed, with the stable state of the opposites S-(-) to R-(+) at about 3.

Tolvaptan is heavily connected to plasma proteins (99%) and distributed in the apparent volume of 3 l/kg. Overall, Tolvaptan is completely excreted by the path without passing the kidneys and is mainly metabolized by CYP 3A. After the oral dose, the clearance is about 4 ml/min/kg and the semi -waste time is about 12 hours. Tolvaptan's accumulation coefficient with one -time daily dose mode is 1.3 and the bottom concentration ≤ 16% of the peak concentration, suggesting the selling time of waste less than 12 hours. There is a change between the subjects of the peak and medium concentration of Tolvaptan with the percentage coefficient of the change in the range of 30 to 60%.

In patients with decreased blood sodium sodium of Tolvaptan to about 2 ml/min/kg. Medium or severe hepatic failure or congestive heart failure reduces the clearance and increased distribution of Tolvaptan, but does not change corresponding to the clinical signs. Exposure or reaction with Tolvaptan in objects with creatinine clearance between 79 to 10 ml/min and normal kidney function patients are not different.

Caution when using

Warning: Starting and reinforcing drug use in the hospital and monitoring serum sodium level

Samsca should be started and re -used in patients only in the hospital where can closely monitor sodium sodium.

The adjustment too quickly hypoglyced blood sodium (e.g. 12 MEQ/l/24 hours) can cause osmotic myelin cancellation leading to speech, mute, difficult swallowing, sleeping, emotional changes, paralysis of spasms, convulsions, coma and death. In sensitive patients including people with severe malnutrition, alcoholism, and progressive liver disease, the adjustment speed is slower than the level of blood sodium that can be recommended.

Unbelievable myelin cancellation syndrome is a risk associated with the rapid adjustment of blood sodium lower (for example, 12MEQ/l/24 hours). The osmotic myelin cancellation leads to speech, mute, difficult swallowing, sleeping, emotional changes, spastic limb paralysis, convulsions, coma or death. In sensitive patients, including those with severe malnutrition, alcoholism, and progressive liver disease, the repair speed is more slow than the blood sodium that can be recommended.

closely monitor Na+ serum concentration during treatment.

Liver damage

Tolvaptan can cause serious and fatal liver damage. In an open study with a placebo, long -lasting Tolvaptan in patients with polycystic kidney disease (ADPKD), serious liver damage has been observed for Tolvaptan.

Patients with symptoms may indicate liver damage, including fatigue, anorexia, discomfort in the upper right abdomen, dark urine or jaundice should stop treating with Tolvaptan.

Restricted use with Tolvaptan for more than 30 days to avoid liver damage. Avoid use in patients with hidden liver disease, including cirrhosis, because the ability to recover after liver damage may be impaired.

Dehydration and reduced blood volume

Treatment with Tolvaptan brings water excretion without losing electrolytes, but is compensated for each part of normal parts with the amount of drinking water. Dehydration and reduction of blood flow may occur, especially in patients who are likely to be reduced in the volume of fluids taking diuretics or patients with limited use of fluid.

Used with hypertonic salt solution

Do not recommend simultaneous use with hypertonic salt solution.

Hemorrhage or serum hyperpass drugs

Treatment with Tolvaptan is associated with a decrease in extracellular volume that can lead to increased serum potassium. Serum concentration should be monitored after starting with Tolvaptan in patients with serum potassium levels> 5MEQ/L as well as patients who are taking drugs to cause increased potassium levels in serum.

The ability to drive and operate machinery

No report.

Pregnancy

There are no complete studies and well controlled the use of samsca in pregnant women. In animal studies, there has been an open mouth, short limb, small eyes, bone deformities, fetal weight reduction, fetal bone slowly, and fetus. Samsca should only be used during pregnancy only if the possibility of benefits is more than the potential risk to the fetus.

In studies for embryo development, rats and pregnant rabbits are given Tolvaptan oral during the organization of the organ. Rats are given Tolvaptan at 2 - 162 times the maximum dose recommended for humans (MRHD) (on the basis of body surface area). Reducing fetal weight and bone slowdown of pregnancy occurs 162 times higher than MRHD. Signs of toxicity in rats and mother rabbits (reducing body weight gain and food consumption) occur 16 and 162 times higher than MRHD. When pregnant rabbits take Tolvaptan 32 to 3 times MRHD (on the basis of the body surface area), reduce the weight gain of the mother's body and food consumption in all doses, and increase miscarriage in the average and high doses (about 97 and 324 times the MRHD). At 324 times the dose of MRHD, there is an increase in the rate of fetus, small eyes, open eyelids, cleft palate, short limb and bone defects.

labor and childbirth

The effect of samsca on labor and childbirth in humans has not been well known.

The period of breastfeeding

It is unknown whether Samsca will be excreted in breast milk or not. Tolvaptan is excreted in the milk of breastfeeding mice. Because there are many drugs excreted in breast milk and because of the potential of serious adverse reactions in young breastfed children from Samsca, it is necessary to decide to stop breastfeeding or stop using Samsca, considering the importance of Samsca with the mother.

Drug interaction

The impact of drugs on Tolvaptan

Ketoconazole and strong CYP 3A inhibitors: Samsca is metabolized mainly by CYP 3A. Ketoconazole is a strong CYP 3A inhibitor and also inhibits P-GP. Simultaneous use of samsca and ketoconazole 200mg daily increases 5 times in contact with Tolvaptan. Simultaneous use of samsca and 400 mg ketoconazole daily or with other powerful CYP 3A inhibitors (such as Clarithromycin, Itraconazole, Telithromycin, Saquinavir, Nelfinavir, Ritonavir and Nefazodon) at the highest dose on the label that is expected to increase to increase Tolvaptan exposure. Therefore, Samsca should not be used simultaneously with strong CYP 3A inhibitors.

Average CYP 3A inhibitors: The impact of medium CYP 3A inhibitors (such as erythromycin, fluconazole, aprepitant, diltiazem and verapamil) to contact when used in combination with not evaluated Tolvaptan. Significant increase in contact with Tolvaptan when using Samsca combination with medium CYP 3A inhibitors. Therefore, avoid combining Samsca with medium CYP 3A inhibitors.

Grapefruit juice: Using a combination of samsca and grapefruit juice, it increases 1.8 times in contact with Tolvaptan.

P-GP inhibitors: Samsca dose should be reduced in patients treated in combination with P-GP inhibitors such as cyclosporin based on clinical response.

Rifampicin and other CYP 3A induction substances: Rifampicin is a CYP 3A and P-GP induction. Use a combination of rifampicin and samsca to reduce Tolvaptan exposure 85%. Therefore, Samsca's expected clinical effect in Rifampicin and other boosters (such as Rifabutin, Rifapentin, Barbiturates, Phenytoin, Carbamazepin and St. John’s Wort) may not be achieved at the usual Samsca dose. Samsca's dose may be increased.

lovastatin, digoxin, furosemid, and hydrochlorothiazide: Use a combination of lovastatin, digoxin, furosemid, and hydrochlorothiazid with samsca that does not have a clinical impact on the use of Tolvaptan.

The impact of Tolvaptan on other drugs

Digoxin: Digoxin is a P-GP substrate. Using a combination of samsca with digoxin increases the digoxin of digoxin to 20% and cmax of digoxin to 30%.

Warfarin, Amiodaron, Furosemid, and Hydrochlorothiazide: simultaneously use Tolvaptan with Warfarin, Furosemid, Hydrochlorothiazid, or Amiodaron (or its active metabolites, Desethylamiodaron) does not change the pharmacokinetics of these substances to these substances to the significant clinical level.

lovastatin: Samsca is a weak inhibitor CYP 3A. Use a combination of lovastatin and samsca to increase the levels of lovastatin and metabolites with lovastatin-β hydroxyacids respectively 1.4 and 1.3 times. There is no corresponding change in terms of clinical.

Pharmacological interaction: Samsca produces a larger rate between the volume of urine 24 hours/amount of urine output compared to the dose of Furosemid or hydrochlorothiazid. Use a combination of Tolvaptan with Furosemid or Hydrochlorothiazid to produce the rate of 24 -hour urine volume/amount of urine output is similar to the ratio after using Tolvaptan alone.

Although specific interactive studies have not been conducted, in the Tolvaptan clinical studies are used simultaneously with beta blockers, angiotensin receptor blockers, angiotensin transfer enamel inhibitors and potassium diuretic. Unwanted effects of increased potassium is about 1-2% high when using Tolvaptan with angiotensin receptor blockers, angiotensin transferring enamel inhibitors and potassium diuretic compared to when used with placebo. Monitoring potassium levels should be monitored during combined drug treatment.

Like a V2 receptor antagonist, Tolvaptan may hinder the operator of Desmopressin (DDAVP). In men with mild Von Willebrand (VW), DDAVP intravenous infusion 2 hours after taking Tolvaptan does not increase the VW antigen factor or VIII operating factor. It is not recommended to use Tolvaptan with the owner of V2.