tolvaptan 15 mg Tablet, 10-count
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Vasopressin V2 Receptor Antagonist class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Tolvaptan (Jynarque) is used to slow the worsening of kidney function in certain patients with autosomal dominant polycystic kidney disease (ADPKD; a certain type of inherited kidney disease). Tolvaptan (Jynarque) is in a class of medications called vasopressin V2 receptor antagonists. It works by increasing the amount of water released from the body as urine and decreases the growth of cysts in the kidneys. Removing fluid from the body and slowing the growth of cysts helps to slow the worsening of kidney function. Tolvaptan is also available as a tablet (Samsca) to treat low blood levels of s...
Read the full MedlinePlus article ↗- This is a safety requirement — not just a formality. When tolvaptan raises your blood sodium levels, it has to happen gradually. If sodium goes up too fast, it can cause a rare but...
- Why do I have to start this medication in a hospital?
- Tolvaptan can cause liver damage — and with Jynarque, which is used long-term for kidney disease, that risk needs to be watched carefully. Liver blood tests check for signs of inju...
- Why do I need regular liver blood tests if I'm on Jynarque?
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💊 What it looks like
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
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UNII 3SY5LH9PMK
Anhydrous lactose is a milk sugar with no water content. It acts as a filler and binder in tablets and capsules, adding bulk and helping ingredients stick together.
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UNII D9C330MD8B
Copovidone is a synthetic polymer made by combining two types of plastic-like molecules. It acts as a binder and film-former to help hold tablet ingredients together and improve how the medicine dissolves in your body.
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UNII M28OL1HH48
Croscarmellose sodium is a plant-based substance derived from cellulose. It acts as a disintegrant, helping tablets and capsules break down quickly in the digestive system so the medicine can be absorbed.
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UNII L06K8R7DQK
A synthetic blue dye approved by the FDA for use in medications and foods. It serves as a colorant to make pills and liquids visually distinct and easier to identify.
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UNII 70097M6I30
Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
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UNII ETJ7Z6XBU4
Silicon dioxide is a naturally occurring mineral used as a glidant and anti-caking agent. It helps powder ingredients flow smoothly and prevents clumping during manufacturing and storage.
6 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $14.612 | $146.12 / 10 tablets |
| Medicaid paysCMS SDUD · 12 mo | $45.51 | $455.11 / 10 tablets |
| Medicare drug plans payPart D · Q2 2026 | $143.99 | $1,439.89 / 10 tablets |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Tolvaptan 15 mg 49884-0768-54 | Par | 10 tablets | $14.612 | AB1 | Availability likely | — |
| tolvaptan 15 mgthis 60505-4317-00 | Apotex | 10 tablets | $14.612 | AB1 | Availability likely | — |
| Tolvaptan 15 mg 72205-0130-11 | Novadoz | 10 tablets | $14.612 | AB1 | Availability likely | — |
| Tolvaptan 15 mg 72603-0932-01 | Northstar | 10 tablets | $14.612 | AB1 | Availability likely | — |
| Tolvaptan 15 mg 31722-0868-01 | Camber | 100 tablets | — | AB1 | FDA listed | — |
| Samsca 15 mg 59148-0020-50 | Otsuka | 10 tablets | — | AB1 | FDA listed | — |
| Tolvaptan 15 mg 67877-0635-01 | Ascend | 100 tablets | — | AB1 | FDA listed | — |
| Jynarque 15 mg 59148-0082-13 | Otsuka | 30 tablets | — | AB | FDA listed | — |
| Tolvaptan 15 mg 70748-0238-06 | Lupin | 30 tablets | — | AB2 | FDA listed | — |
| Tolvaptan 15 mg 67877-0915-30 | Ascend | 30 tablets | — | AB2 | FDA listed | — |
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⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
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🗺️ Medicaid utilization & spend
💊 Medicaid utilization by pack size
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
📦 Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Status |
|---|---|---|---|---|---|
| 60505-4317-00 You're viewing this | 1 BLISTER PACK in 1 CARTON (60505-4317-0) / 10 TABLET in 1 BLISTER PACK | $14.61 / ea | $146.12 | 2022-12-14 | Active |
| 60505-4317-03 | 30 TABLET in 1 BOTTLE (60505-4317-3) | — | — | 2022-12-14 | Active |
Pack size FAQ
What quantity is in NDC 60505-4317-00?
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What NDC number is used to bill for this package of tolvaptan 15 mg Tablet?
Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.
📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: (A) INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM (B) NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) (A) 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 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. (B) Not for use for autosomal dominant polycystic kidney disease (ADPKD) Because of the risk of hepatotoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS [see Contraindications ( 4 )] WARNING: (A) INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM (B) NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) See full prescribing information for complete boxed warning.
(A) Initiate and re-initiate in a hospital and monitor serum sodium Tolvaptan tablets 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.
(B) Not for use for autosomal dominant polycystic kidney disease (ADPKD) Because of the risk of hepatotoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS ( 4 )
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Tolvaptan 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). Tolvaptan tablets are a selective vasopressin V 2 -receptor antagonist 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) ( 1 ) Limitations of use: Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with tolvaptan tablets ( 1 ) It has not been established that tolvaptan tablets provide a symptomatic benefit to patients ( 1 ) Limitations of Use Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with tolvaptan.
It has not been established that raising serum sodium with tolvaptan provides a symptomatic benefit to patients.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Tolvaptan tablets should be initiated and re-initiated in a hospital ( 2.1 ) 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 )
2.1Recommended 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 tolvaptan 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 tolvaptan 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 tolvaptan should be advised that they can continue ingestion of fluid in response to thirst [see Warnings and Precautions ( 5.1 )].
2.2Drug Withdrawal Following discontinuation from tolvaptan, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium and volume status.
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Tolvaptan tablets are available in the following dosage forms and strength: 15 mg tablets are non-scored, blue, triangular, bevel edged biconvex tablets engraved with “APO” on one side and “TOL” over ‘15’ on other side. 30 mg tablets are non-scored, blue, round, bevel edged biconvex tablets engraved with “APO” on one side and “TOL” over ‘30’ on other side. Tablets: 15 mg and 30 mg ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Tolvaptan 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 ( 4 ) Patients who are unable to respond appropriately to thirst ( 4 ) Hypovolemic hyponatremia ( 4 ) Concomitant use of strong CYP 3A inhibitors ( 4 ) Anuria ( 4 ) Hypersensitivity ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Liver injury: Limit treatment duration to 30 days. If hepatic injury is suspected, discontinue tolvaptan tablets. Avoid use in patients with underlying liver disease ( 5.2 ) Dehydration and hypovolemia may require intervention ( 5.3 ) Avoid use with hypertonic saline ( 5.4 ) Avoid use with moderate to strong CYP 3A inhibitors ( 5.5 ) Monitor serum potassium in patients with potassium >5 mEq/L or on drugs known to increase potassium ( 5.6 ) Urinary outflow obstruction: Urinary output must be secured ( 5.7 )
5.1Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae 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 tolvaptan therapy [see Adverse Reactions (6.2) ] .
Patients treated with tolvaptan 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 tolvaptan who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with tolvaptan and consider administration of hypotonic fluid.
Fluid restriction during the first 24 hours of therapy with tolvaptan tablets 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.
5.2Liver Injury 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 occurring 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 [see Contraindications ( 4 )]. Patients with symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice should discontinue treatment with tolvaptan. Limit duration of therapy with tolvaptan to 30 days.
Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover from liver injury may be impaired [see Adverse Reactions ( 6.1 )].
5.3Dehydration and Hypovolemia Tolvaptan therapy induces copious aquaresis, which is normally partially offset by fluid intake. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In multiple-dose, placebo-controlled trials in which 607 hyponatremic patients were treated with tolvaptan, the incidence of dehydration was 3.3% for tolvaptan and 1.5% for placebo-treated patients.
In patie…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp at 1-800-706-5575 or FDA at 1-800-FDA-1088 ( www.fda.gov/medwatch ).
6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. In multiple-dose, placebo-controlled trials, 607 hyponatremic patients (serum sodium <135 mEq/L) were treated with tolvaptan.
The mean age of these patients was 62 years; 70% of patients were male and 82% were Caucasian. One hundred eighty-nine (189) tolvaptan-treated patients had a serum sodium <130 mEq/L, and 52 patients had a serum sodium <125 mEq/L. Hyponatremia was attributed to cirrhosis in 17% of patients, heart failure in 68% and SIADH/other in 16%.
Of these patients, 223 were treated with the recommended dose titration (15 mg titrated to 60 mg as needed to raise serum sodium). Overall, over 4,000 patients have been treated with oral doses of tolvaptan in open-label or placebo-controlled clinical trials. Approximately 650 of these patients had hyponatremia; approximately 219 of these hyponatremic patients were treated with tolvaptan for 6 months or more.
The most common adverse reactions (incidence ≥5% more than placebo) seen in two 30‑day, double-blind, placebo-controlled hyponatremia trials in which tolvaptan was administered in titrated doses (15 mg to 60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. In these trials, 10% (23/223) of tolvaptan-treated patients discontinued treatment because of an adverse event, compared to 12% (26/220) of placebo-treated patients; no adverse reaction resulting in discontinuation of trial medication occurred at an incidence of >1% in tolvaptan-treated patients.
1 lists the adverse reactions reported in tolvaptan-treated patients with hyponatremia (serum sodium <135 mEq/L) and at a rate at least 2% greater than placebo-treated patients in two 30‑day, double-blind, placebo-controlled trials. In these studies, 223 patients were exposed to tolvaptan (starting dose 15 mg, titrated to 30 and 60 mg as needed to raise serum sodium). Adverse events resulting in death in these trials were 6% in tolvaptan-treated-patients and 6% in placebo-treated patients.
Table 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term Tolvaptan 15 mg/day-60 mg/day (N = 223) n (%) Placebo (N = 220) n (%) The following terms are subsumed under the referenced ADR in Table 1: Gastrointestinal Disorders Dry mouth 28 (13) 9 (4) Constipation 16 (7) 4 (2) General Disorders and Administration Site Conditions Thirst polydipsia; 35 (16) 11 (5) Asthenia 19 (9) 9 (4) Pyrexia 9 (4) 2 (1) Metabolism and Nutrition Disorders Hyperglycemia diabetes mellitus; 14 (6) 2 (1) Anorexia decreased appetite; 8 (4) 2 (1) Renal and Urinary Disorders Pollakiuria or polyuria urine output increased, micturition urgency, nocturia 25 (11) 7 (3) In a subgroup of patients with hyponatremia (N = 475, serum sodium <135 mEq/L) enrolled in a double-blind, placebo-controlled trial (mean duration of treatment was 9 months) of patients with worsening heart failure, the following adverse reactions occurred in tolvaptan-treated patients at a rate at least 2% greater than placebo: mortality (42% tolvaptan, 38% placebo), nausea (21% tolvaptan, 16% placebo), thirst (12% tolvaptan, 2% placebo), dry mouth (7% tolvaptan, 2% placebo) a…
🔄 Drug Interactions ▾
5.5Drug Interactions 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 tolvaptan tablets with strong inhibitors of CYP3A [see Contraindications ( 4 )] and avoid concomitant use with moderate CYP3A inhibitors.
7 DRUG INTERACTIONS Avoid concomitant use with: Moderate CYP3A inhibitors (7.1) Strong CYP3A inducers (7.1) V2-receptor antagonists (7.3) Monitor serum potassium during concomitant therapy with ( 7.2 ) Angiotensin receptor blockers Angiotensin converting enzyme inhibitors Potassium sparing diuretics
7.1CYP3A Inhibitors and Inducers Strong CYP3A Inhibitors Tolvaptan AUC was 5.4 times as large and C max 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 tolvaptan tablets are co-administered with moderate CYP3A inhibitors. Avoid co-administration of tolvaptan tablets with moderate CYP3A inhibitors [see Warnings and Precautions ( 5.5 )]. Patients should avoid grapefruit juice beverages while taking tolvaptan tablets [see Clinical Pharmacology ( 12.3 )] .
Strong CYP3A Inducers Co-administration of tolvaptan tablets with strong CYP3A inducers reduces exposure to tolvaptan tablets [see Clinical Pharmacology ( 12.3 )] . Avoid concomitant use of tolvaptan tablets with strong CYP3A inducers.
7.2Angiotensin Receptor Blockers, Angiotensin Converting Enzyme Inhibitors and Potassium Sparing Diuretics Although specific interaction studies were not performed, in clinical studies tolvaptan was used concomitantly with beta-blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics. Adverse reactions of hyperkalemia were approximately 1 to 2% higher when tolvaptan was administered with angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics compared to administration of these medications with placebo.
Serum potassium levels should be monitored during concomitant drug therapy.
7.3V 2 -Receptor Agonist As a V 2 -receptor antagonist, tolvaptan may interfere with the V 2 -agonist activity of desmopressin (dDAVP). Avoid concomitant use of tolvaptan tablets with a V 2 -agonist.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm ( 8.1 ) Lactation: Breastfeeding not recommended ( 8.2 ) Pediatric Use: There are no studies ( 8.4 )
8.1Pregnancy Risk Summary Available data with tolvaptan tablet 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 24h 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 1,000 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 1,000 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).
8.2Lactation 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 tolvaptan tablets. 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.
8.4Pediatric Use Safety and effectiveness of tolvaptan in pediatric patients have not been established.
8.5Geriatric Use Of the total number of hyponatremic subjects treated with tolvaptan in clinical studies, 42% were 65 years old and over, while 19% were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and y…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Available data with tolvaptan tablet 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 24h 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 1,000 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 1,000 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).
🧒 Pediatric Use ▾
8.4Pediatric Use Safety and effectiveness of tolvaptan in pediatric patients have not been established.
🧓 Geriatric Use ▾
8.5Geriatric Use Of the total number of hyponatremic subjects treated with tolvaptan in clinical studies, 42% were 65 years old and over, while 19% were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Increasing age has no effect on tolvaptan plasma concentrations.
🆘 Overdosage ▾
10 OVERDOSAGE Single oral doses up to 480 mg (8 times the maximum recommended daily dose) and multiple doses up to 300 mg once daily for 5 days have been well tolerated in studies in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia.
No mortality was observed in rats or dogs following single oral doses of 2000 mg/kg (maximum feasible dose). A single oral dose of 2000 mg/kg was lethal in mice, and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia. In patients with suspected tolvaptan tablets overdosage, assessment of vital signs, electrolyte concentrations, ECG and fluid status are recommended.
Continue replacement of water and electrolytes until aquaresis abates. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (>98%).
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Tolvaptan is a selective vasopressin V 2 -receptor antagonist with an affinity for the V 2 -receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2 -receptor is 29 times greater than for the V 1a -receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations.
Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V 2 -receptors compared with tolvaptan.
12.2Pharmacodynamics In healthy subjects receiving a single dose of tolvaptan 60 mg, the onset of the aquaretic and sodium increasing effects occurs within 2 to 4 hours post-dose. A peak effect of about a 6 mEq increase in serum sodium and about 9 mL/min increase in urine excretion rate is observed between 4 and 8 hours post-dose; thus, the pharmacological activity lags behind the plasma concentrations of tolvaptan. About 60% of the peak effect on serum sodium is sustained at 24 hours post-dose, but the urinary excretion rate is no longer elevated by this time.
Doses above 60 mg tolvaptan do not increase aquaresis or serum sodium further. The effects of tolvaptan in the recommended dose range of 15 to 60 mg once daily appear to be limited to aquaresis and the resulting increase in sodium concentration. Plasma concentrations of native AVP may increase (avg.
2 to 9 pg/mL) with tolvaptan administration. Cardiac Electrophysiology No prolongation of the QT interval was observed with tolvaptan following multiple doses of 300 mg/day for 5 days. In a parallel-arm, double-blind (for tolvaptan and placebo), placebo- and positive-controlled, multiple dose study of the effect of tolvaptan on the QTc interval, 172 healthy subjects were randomized to tolvaptan 30 mg, tolvaptan 300 mg, placebo, or moxifloxacin 400 mg once daily.
At both the 30 mg and 300 mg doses, no significant effect of administering tolvaptan on the QTc interval was detected on Day 1 and Day 5. At the 300 mg dose, peak tolvaptan plasma concentrations were approximately 4‑fold higher than the peak concentrations following a 30 mg dose. Moxifloxacin increased the QT interval by 12 ms at 2 hours after dosing on Day 1 and 17 ms at 1 hour after dosing on Day 5, indicating that the study was adequately designed and conducted to detect tolvaptan's effect on the QT interval, had an effect been present.
12.3Pharmacokinetics In healthy subjects, the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been examined. In hyponatremia subjects, single and multiple doses up to 60 mg have been studied. Absorption In healthy subjects, peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose.
Peak concentrations increase less than dose proportionally with doses greater than 240 mg. The absolute bioavailability of tolvaptan decreases with increasing doses. The absolute bioavailability of tolvaptan following an oral dose of 30 mg is 56% (range 42 to 80%).
Co-administration of 90 mg tolvaptan with a high-fat meal (~1000 calories, of which 50% are from fat) doubles peak concentrations but has no effect on the AUC of tolvaptan; tolvaptan may be administered with or without food. Distribution Tolvaptan binds to both albumin and α1-acid glycoprotein and the overall protein binding is >98%; binding is not affected by disease state. The volume of distribution of tolvaptan is about 3 L/kg.
The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. When administered as multiple once-daily 300 mg doses to healthy subjects or to patients with congest…
🧬 Mechanism of Action ▾
12.1Mechanism of Action Tolvaptan is a selective vasopressin V 2 -receptor antagonist with an affinity for the V 2 -receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V 2 -receptor is 29 times greater than for the V 1a -receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations.
Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V 2 -receptors compared with tolvaptan.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Tolvaptan Tablets are available in the following strength and package. Tolvaptan Tablets 15 mg are non-scored, blue, triangular, bevel edged biconvex tablets engraved with “APO” on one side and “TOL” over ‘15’ on other side. Blister of 10 tablets NDC 60505-4317-0 Tolvaptan Tablets 30 mg are non-scored, blue, round, bevel edged biconvex tablets engraved with "APO" on one side and "TOL" over ‘30’ on other side.
Blister of 10 tablets NDC 60505-4318-0 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children.
📦 Storage and Handling ▾
Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children.
📋 Description ▾
11 DESCRIPTION Tolvaptan tablets contain tolvaptan, a selective vasopressin V 2 -receptor antagonist in tablets for oral use available in 15 mg or 30 mg strengths. Tolvaptan is 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1 H -1-benzazepine. The empirical formula is C 26 H 25 ClN 2 O 3.
Molecular weight is 448.95 g/mol. The chemical structure is: Tolvaptan tablets for oral use contain 15 mg or 30 mg of tolvaptan. Inactive ingredients include anhydrous lactose, colloidal silicon dioxide, copovidone, croscarmellose sodium, indigotine al lake 12-14% and magnesium stearate.
Chemical Structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION As a part of patient counseling, healthcare providers must review the tolvaptan tablets Medication Guide with every patient [see FDA-Approved Medication Guide]. 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 tolvaptan tablets [see Use In Specific Populations ( 8.2 )]. Rx Only APOTEX INC. Tolvaptan Tablets 15 mg and 30 mg Manufactured by: Manufactured for: Apotex Inc.
Toronto, Ontario, Canada M9L 1T9 Apotex Corp. Weston, Florida 33326 Rev. 4
💬 Medication Guide ▾
MEDICATION GUIDE Tolvaptan (tol vap' tan) Tablets Read the Medication Guide that comes with Tolvaptan Tablets before you take it and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Share this important information with members of your household. What is the most important information I should know about tolvaptan tablets ? 1) Tolvaptan tablets may make the salt (sodium) level in your blood rise too fast.
This can increase your risk of a serious condition called osmotic demyelination syndrome (ODS). ODS can lead to coma or death. ODS can also cause new symptoms such as: trouble speaking swallowing trouble or feeling like food or liquid gets stuck while swallowing drowsiness confusion mood changes trouble controlling body movement (involuntary movement) and weakness in muscles of the arms and legs seizures You or a family member should tell your healthcare provider right away if you have any of these symptoms even if they begin later in treatment.
Also tell your healthcare provider about any other new symptoms while taking tolvaptan tablets. You may be more at risk for ODS if you have: liver disease not eaten enough for a long period of time (malnourished) very low sodium level in your blood been drinking large amounts of alcohol for a long period of time (chronic alcoholism) To lessen your risk of ODS while taking tolvaptan tablets: Treatment with tolvaptan tablets should be started and re-started only in a hospital, where the sodium levels in your blood can be checked closely.
Do not take tolvaptan tablets if you cannot tell if you are thirsty. To prevent losing too much body water (dehydration), have water available to drink at all times while taking tolvaptan tablets. Unless your healthcare provider tells you otherwise, drink when you are thirsty.
If your healthcare provider tells you to keep taking tolvaptan tablets after you leave a hospital, it is important that you do not stop and re-start tolvaptan tablets on your own. You may need to go back to a hospital to re-start tolvaptan tablets. Talk to your healthcare provider right away if you stop taking tolvaptan tablets for any reason.
It is important to stay under the care of your healthcare provider while taking tolvaptan tablets and follow their instructions. 2) Tolvaptan tablets may cause liver problems, including life-threatening liver failure. Tolvaptan tablets should not be taken for more than 30 days.
Tell your doctor right away if you develop or have worsening of any of these signs and symptoms of liver problems: Loss of appetite, nausea, vomiting Fever, feeling unwell, unusual tiredness Itching Yellowing of the skin or the whites of the eyes (jaundice) Unusual darkening of the urine Right upper stomach area pain or discomfort 3) If you have autosomal dominant polycystic kidney disease (ADPKD), do not use Tolvaptan tablets because you should receive the medicine (tolvaptan) through a program that ensures laboratory monitoring of your liver.
What are tolvaptan tablets ? Tolvaptan tablets are a prescription medicine used to help increase low sodium levels in the blood, in adults with conditions such as heart failure, and certain hormone imbalances. Tolvaptan tablets helps raise salt levels in your blood by removing extra body water as urine.
It is not known if tolvaptan tablets are safe or works in children. Who should not take tolvaptan tablets ? Do not take tolvaptan tablets if: you are allergic to tolvaptan or any of the ingredients in tolvaptan tablets.
See the end of this Medication Guide for a complete list of ingredients in tolvaptan tablets. the sodium level in your blood must be increased right away. you cannot replace fluids by drinking or you cannot feel if you are thirsty. you are dizzy, faint, or your kidneys are not working normally because you have lost too much body fluid. you take certain medicines.…