Drug Safety-related Labeling Changes (SrLC)

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SAMSCA (NDA-022275)

(TOLVAPTAN)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/22/2021 (SUPPL-17)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

SAMSCA is contraindicated in the following conditions:

  • Patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA-approved REMS  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

5 Warnings and Precautions

5.5 Drug Interactions

Additions and/or revisions underlined:

Tolvaptan is a substrate of CYP3A. Moderate to strong CYP3A inhibitors can lead to a marked increase in tolvaptan concentrations [see Drug Interactions (7.1)]. Do not use SAMSCA with strong inhibitors of CYP3A [see Contraindications (4)] and avoid concomitant use with moderate CYP3A inhibitors.

Newly added subsection:

5.7 Acute Urinary Retention with Outflow Obstruction

Patients with partial obstruction of urinary outflow, for example, patients with prostatic hypertrophy or impairment of micturition, have an increased risk of developing acute retention. Do not administer tolvaptan in patients with uncorrected urinary outflow obstruction.

7 Drug Interactions

7.1 CYP3A Inhibitors and Inducers

Strong CYP3A Inhibitors

Tolvaptan's AUC was 5.4 times as large and Cmax was 3.5 times as large after co-administration of tolvaptan and 200 mg ketoconazole  [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. Larger doses of the strong CYP3A inhibitor would be expected to produce larger increases in tolvaptan exposure. Concomitant use of tolvaptan with strong CYP3A inhibitors is contraindicated [see Contraindications (4)].

Moderate CYP3A Inhibitors

A substantial increase in the exposure to tolvaptan would be expected when SAMSCA is co-administered with moderate CYP3A inhibitors. Avoid co-administration of SAMSCA with moderate CYP3A inhibitors [see Warnings and Precautions (5.5)].

Patients should avoid grapefruit juice beverages while taking SAMSCA [see Clinical Pharmacology (12.3)].

Strong CYP3A Inducers

Co-administration of SAMSCA with strong CYP3A inducers reduces exposure to SAMSCA [see Clinical Pharmacology (12.3)]. Avoid concomitant use of SAMSCA with strong CYP3A inducers.

Additions and/or revisions underlined:

7.2 Angiotensin Receptor Blockers, Angiotensin Converting Enzyme Inhibitors and Potassium Sparing Diuretics

Although specific interaction studies were not performed, in clinical studies, tolvaptan was used concomitantly …

7.3 V2-Receptor Agonist

As a V2-receptor antagonist, tolvaptan may interfere with the V2-agonist activity of desmopressin (dDAVP). Avoid concomitant use of SAMSCA with a V2-agonist.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

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 (AUC24h 10271 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).

8.2 Lactation

(PLLR conversion; additions and/or revisions underlined):

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What should I tell my healthcare provider before taking SAMSCA?

Tell your healthcare provider about all your medical conditions, including if you:

    • had an allergic reaction in the past to tolvaptan or to any of the other ingredients of this medicine. See the end of this Medication Guide for a list of the ingredients in SAMSCA.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Pregnancy

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise patients not to breastfeed an infant if they are taking SAMSCA [see Use in Specific Populations (8.2)].

04/23/2018 (SUPPL-16)

Approved Drug Label (PDF)

Boxed Warning

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

4 Contraindications

Addition of the following subsection:

4.1 Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of FDA approved REMS

Tolvaptan can cause serious and potentially fatal liver injury. Tolvaptan should not be prescribed or used outside of the FDA-approved Risk Evaluation and Mitigation Strategy (REMS) for ADPKD patients.

5 Warnings and Precautions

5.2 Liver Injury

Additions and/or revisions underlined:

Tolvaptan can cause serious and potentially fatal liver injury. In placebo-controlled studies and an open label extension study of chronically administered tolvaptan in patients with ADPKD, cases of serious liver injury attributed to tolvaptan, generally occuring during the first 18 months of therapy, were observed. In postmarketing experience with tolvaptan in ADPKD, acute injury resulting in liver failure requiring liver transplantation has been reported. Tolvaptan should not be used to treat ADPKD outside of the FDA-approved risk evaluation and mitigation strategy (REMS) for ADPKD patients … Patients with symptoms that may indicate liver injury …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What is the most important information I should know about SAMSCA?

Addition of the following:

3) If you have autosomal dominant polycystic kidney disease (ADPKD), do not use SAMSCA because you should receive the medicine (tolvaptan) through a program that ensures laboratory monitoring of your liver.

06/01/2017 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae

(additions underlined)

Osmotic demyelination syndrome is a risk associated with too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. In controlled clinical trials in which tolvaptan was administered in titrated doses starting at 15 mg once daily, 7% of tolvaptan-treated subjects with a serum sodium <130 mEq/L had an increase in serum sodium greater than 8 mEq/L at approximately 8 hours and 2% had an increase greater than 12 mEq/L at 24 hours. Approximately 1% of placebo-treated subjects with a serum sodium <130 mEq/L had a rise greater than 8 mEq/L at 8 hours and no patient had a rise greater than 12 mEq/L/24 hours. Osmotic demyelination syndrome has been reported in association with SAMSCA therapy [see Adverse Reaction. Patients treated with SAMSCA should be monitored to assess serum sodium concentrations and neurologic status, especially during initiation and after titration. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours of therapy with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided. Co-administration of diuretics also increases the risk of too rapid correction of serum sodium and such patients should undergo close monitoring of serum sodium.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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