Samsca

WARNING: (A) INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM (B) NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

• SAMSCA should be initiated and re-initiated in patients only in a hospital where serum 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.

• Because of the risk of hepatotoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS
  4 CONTRAINDICATIONS

  SAMSCA is contraindicated in the following conditions:

  • Patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA-approved REMS
    [see Warnings and Precautions (5.2)]
  • Unable to sense or respond to thirst
  • Hypovolemic hyponatremia
  • Taking strong CYP3A inhibitors
    [see Warnings and Precautions (5.5)]
  • Anuria
  • Hypersensitivity (e.g., anaphylactic shock, rash generalized) to tolvaptan or any components of the product
    [see Adverse Reactions (6)]

  • Use in patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA-approved REMS
  • Patients who are unable to respond appropriately to thirst
  • Hypovolemic hyponatremia
  • Concomitant use of strong CYP3A inhibitors
  • Anuria
  • Hypersensitivity

SAMSCA^® is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

• SAMSCA should be initiated and re-initiated in a hospital (
  2.1 Recommended Dosage

  Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response and because too rapid correction of hyponatremia can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.

  The usual starting dose for SAMSCA is 15 mg administered once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium. Do not administer SAMSCA for more than 30 days to minimize the risk of liver injury

  [see Warnings and Precautions (5.2)].

  During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Avoid fluid restriction during the first 24 hours of therapy. Patients receiving SAMSCA should be advised that they can continue ingestion of fluid in response to thirst

  [see Warnings and Precautions (5.1)].
  )
• The recommended starting dose is 15 mg once daily. Dosage may be increased at intervals ≥24 hr to 30 mg once daily, and to a maximum of 60 mg once daily as needed to raise serum sodium. (
  2.1 Recommended Dosage

  Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response and because too rapid correction of hyponatremia can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.

  The usual starting dose for SAMSCA is 15 mg administered once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium. Do not administer SAMSCA for more than 30 days to minimize the risk of liver injury

  [see Warnings and Precautions (5.2)].

  During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Avoid fluid restriction during the first 24 hours of therapy. Patients receiving SAMSCA should be advised that they can continue ingestion of fluid in response to thirst

  [see Warnings and Precautions (5.1)].
  )

SAMSCA is available in the following dosage forms and strengths:

• 15 mg tablets are non-scored, blue, triangular, shallow-convex, debossed with "OTSUKA" and "15" on one side.
• 30 mg tablets are non-scored, blue, round, shallow-convex, debossed with "OTSUKA" and "30" on one side.

• Pregnancy: May cause fetal harm (
  8.1 Pregnancy

  Risk Summary

  Available data with SAMSCA use in pregnant women are insufficient to determine if there is a drug-associated risk of adverse developmental outcomes. Tolvaptan did not cause any developmental toxicity in rats or in rabbits at exposures approximately 2.8 and 0.8 times, respectively, the exposure in congestive heart failure (CHF) patients at the maximum recommended human dose (MRHD) of 60 mg once daily. However, effects on embryo-fetal development occurred in both species at doses causing significant maternally toxic doses. In rats, reduced fetal weights and delayed fetal ossification occurred at 11 times the exposure in CHF patients, based on AUC. In rabbits, increased abortions, embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations occurred at approximately 1.6 times the exposure in CHF patients

  (see Data).

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.

  Data

  Animal Data

  Oral administration of tolvaptan during the period of organogenesis in Sprague-Dawley rats produced no evidence of teratogenesis at doses up to 100 mg/kg/day. Delayed ossification was seen at 1000 mg/kg, which is approximately 11 times the exposure in CHF patients at the MRHD of 60 mg (AUC_24h10271 ng*h/mL). The fetal effects are likely secondary to maternal toxicity (decreased food intake and low body weights). In a prenatal and postnatal study in rats, tolvaptan had no effect on physical development, reflex function, learning ability or reproductive performance at doses up to 1000 mg/kg/day (11 times the exposure in CHF patients at the MRHD of 60 mg).

  In rabbits, teratogenicity (microphthalmia, embryo-fetal mortality, cleft palate, brachymelia and skeletal malformations) was observed in rabbits at 1000 mg/kg (approximately 1.6 times the exposure in CHF patients at the MRHD of 60 mg dose). This dose also caused maternal toxicity (lower body weight gains and food consumption).
  )
• Lactation: Breastfeeding not recommended (
  8.2 Lactation

  Risk Summary

  There are no data on the presence of tolvaptan or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Tolvaptan is present in rat milk (

  see Data

  ). When a drug is present in animal milk, it is possible that the drug will be present in human milk, but relative levels may vary

  (see Data).

  Because of the potential for serious adverse reactions, including electrolyte abnormalities (e.g., hypernatremia), hypotension, and volume depletion in breastfed infants, advise women not to breastfeed during treatment with SAMSCA.

  Data

  In lactating rats administered radiolabeled tolvaptan, lacteal radioactivity concentrations reached the highest level at 8 hours after administration and then decreased gradually with time with a half-life of 27.3 hours. The level of activity in milk ranged from 1.5- to 15.8-fold those in maternal blood over a period of 72 hours post-dose. Increased perinatal death and decreased body weight of the offspring were observed during the lactation period and after weaning at approximately 11 times the exposure in CHF patients at the MRHD of 60 mg.
  )
• Pediatric Use: There are no studies (
  8.4 Pediatric Use

  Safety and effectiveness of SAMSCA in pediatric patients have not been established.
  )