TOLVAP
Tolvaptan
15/ 30 mg Tablets
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Warning Tolvap 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. 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 [see Contraindications]. |
PRESENTATION
Generic Name: Tolvaptan
Strength: 15/ 30 MG
Dosage Form: Tablet
Pharmacopoeia: IP
Packing: BLISTER
Group: KHA
THERAPEUTIC INDICATIONS
TOLVAP 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).
Important Limitations
Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with TOLVAP.
It has not been established that raising serum sodium with TOLVAP provides a symptomatic benefit to patients.
DOSAGE AND ADMINISTRATION
Usual Dosage in Adults
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 TOLVAP 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 TOLVAP for more than 30 days to minimize the risk of liver injury.
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 TOLVAP should be advised that they can continue ingestion of fluid in response to thirst.
Drug Withdrawal
Following discontinuation from TOLVAP, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium and volume status.
Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors
CYP 3A Inhibitors
Tolvaptan is metabolized by CYP 3A, and use with strong CYP 3A inhibitors causes a marked
(5-fold) increase in exposure. The effect of moderate CYP 3A inhibitors on tolvaptan exposure has not been assessed. Avoid co-administration of TOLVAP and moderate CYP 3A inhibitors.
CYP 3A Inducers
Co-administration of TOLVAP with potent CYP 3A inducers (e.g., rifampin) reduces tolvaptan plasma concentrations by 85%. Therefore, the expected clinical effects of TOLVAP may not be observed at the recommended dose. Patient response should be monitored and the dose adjusted accordingly.
P-gp Inhibitors
Tolvaptan is a substrate of P-gp. Co-administration of TOLVAP with inhibitors of P-gp (e.g., cyclosporine) may necessitate a decrease in TOLVAP dose.
CONTRAINDICATIONS
Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of FDA approved REMS:
Urgent Need to Raise Serum Sodium Acutely
Inability of the Patient to Sense or Appropriately Respond to Thirst
Hypovolemic Hyponatremia
Concomitant Use of Strong CYP 3A Inhibitors
Anuric Patients
Hypersensitivity
WARNINGS AND PRECAUTIONS
Too 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 TOLVAP therapy Patients treated with TOLVAP 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 TOLVAP who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with TOLVAP and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours of therapy with TOLVAP 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.
Liver 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 post marketing 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].
Patients with symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice should discontinue treatment with TOLVAP.
Limit duration of therapy with TOLVAP 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].
Dehydration and Hypovolemia
TOLVAP 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 patients receiving TOLVAP who develop medically significant signs or symptoms of hypovolemia, interrupt or discontinue TOLVAP therapy and provide supportive care with careful management of vital signs, fluid balance and electrolytes. Fluid restriction during therapy with TOLVAP may increase the risk of dehydration and hypovolemia. Patients receiving TOLVAP should continue ingestion of fluid in response to thirst.
Co-administration with Hypertonic Saline
Drug Interactions
Other Drugs Affecting Exposure to Tolvaptan
CYP 3A Inhibitors
Tolvaptan is a substrate of CYP 3A. CYP 3A inhibitors can lead to a marked increase in tolvaptan concentrations. Do not use TOLVAP with strong inhibitors of CYP 3A and avoid concomitant use with moderate CYP 3A inhibitors.
CYP 3A Inducers
Avoid co-administration of CYP 3A inducers (e.g., rifampin, rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine, St. John's Wort) with TOLVAP, as this can lead to a reduction in the plasma concentration of tolvaptan and decreased effectiveness of TOLVAP treatment. If co- administered with CYP 3A inducers, the dose of TOLVAP may need to be increased [see Dosage and Administration, Drug Interactions].
P-gp Inhibitors
The dose of TOLVAP may have to be reduced when TOLVAP is co-administered with P-gp inhibitors, e.g., cyclosporine [see Dosage and Administration, Drug Interactions].
Hyperkalemia or Drugs that Increase Serum Potassium
Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume which could result in increased serum potassium. Serum potassium levels should be monitored after initiation of tolvaptan treatment in patients with a serum potassium >5 mEq/L as well as those who are receiving drugs known to increase serum potassium levels.
ADVERSE REACTIONS
Gastrointestinal Disorders
General Disorders and Administration Site Conditions
Metabolism and Nutrition Disorders
Renal and Urinary Disorders
Blood and Lymphatic System Disorders
Cardiac Disorders
Gastrointestinal Disorders
Metabolism and Nutrition Disorders
Musculoskeletal and Connective Tissue Disorders
Nervous System
Renal and Urinary Disorders
Reproductive System and Breast Disorders (Female)
Respiratory, Thoracic, and Mediastinal Disorders
Vascular Disorder
DRUG INTERACTIONS
Effects of Drugs on Tolvaptan
Ketoconazole and Other Strong CYP 3A Inhibitors
TOLVAP is metabolized primarily by CYP 3A. Ketoconazole is a strong inhibitor of CYP 3A and also an inhibitor of P-gp. Co-administration of TOLVAP and ketoconazole 200 mg daily results in a 5-fold increase in exposure to tolvaptan. Co-administration of TOLVAP with 400 mg ketoconazole daily or with other strong CYP 3A inhibitors (e.g., clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir and nefazodone) at the highest labeled dose would be expected to cause an even greater increase in tolvaptan exposure. Thus, TOLVAP and strong CYP 3A inhibitors should not be co-administered [see Dosage and Administration and Contraindications].
Moderate CYP 3A Inhibitors
The impact of moderate CYP 3A inhibitors (e.g., erythromycin, fluconazole, aprepitant, diltiazem and verapamil) on the exposure to co-administered tolvaptan has not been assessed. A substantial increase in the exposure to tolvaptan would be expected when TOLVAP is co9 administered with moderate CYP 3A inhibitors. Co-administration of TOLVAP with moderate
CYP3A inhibitors should therefore generally be avoided [see Dosage and Administration and Warnings and Precautions].
Grapefruit Juice
Co-administration of grapefruit juice and TOLVAP results in a 1.8-fold increase in exposure to tolvaptan [see Dose and Administration and Warnings and Precautions].
P-gp Inhibitors
Reduction in the dose of TOLVAP may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response [see Dose and Administration and Warnings and Precautions].
Rifampin and Other CYP 3A Inducers
Rifampin is an inducer of CYP 3A and P-gp. Co-administration of rifampin and TOLVAP reduces exposure to tolvaptan by 85%. Therefore, the expected clinical effects of TOLVAP in the presence of rifampin and other inducers (e.g., rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine and St. John's Wort) may not be observed at the usual dose levels of TOLVAP.
The dose of TOLVAP may have to be increased [Dosage and Administration and Warnings and Precautions].
Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide
Co-administration of lovastatin, digoxin, furosemide, and hydrochlorothiazide with TOLVAP has no clinically relevant impact on the exposure to tolvaptan.
Effects of Tolvaptan on Other Drugs
Digoxin
Digoxin is a P-gp substrate. Co-administration of TOLVAP with digoxin increased digoxin
AUC by 20% and Cmax by 30%.
Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide
Co-administration of tolvaptan does not appear to alter the pharmacokinetics of warfarin, furosemide, hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone) to a clinically significant degree.
Lovastatin
TOLVAP is a weak inhibitor of CYP 3A. Co-administration of lovastatin and TOLVAP increases the exposure to lovastatin and its active metabolite lovastatin-β hydroxyacid by factors of 1.4 and 1.3, respectively. This is not a clinically relevant change.
Pharmacodynamics Interactions
Tolvaptan produces a greater 24 hour urine volume/excretion rate than does furosemide or hydrochlorothiazide. Concomitant administration of tolvaptan with furosemide or hydrochlorothiazide results in a 24 hour urine volume/excretion rate that is similar to the rate after tolvaptan administration alone.
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 1-2% 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.
As a V2-receptor antagonist, tolvaptan may interfere with the V2-agonist activity of desmopressin (dDAVP). In a male subject with mild Von Willebrand (vW) disease, intravenous infusion of dDAVP 2 hours after administration of oral tolvaptan did not produce the expected increases in vW Factor Antigen or Factor VIII activity. It is not recommended to administer TOLVAP with a V2-agonist.
USE IN SPECIFIC POPULATIONS
There is no need to adjust dose based on age, gender, race, or cardiac function [see Clinical
Pharmacology].
Pregnancy
Pregnancy Category C.
There are no adequate and well controlled studies of TOLVAP use in pregnant women. In animal studies, cleft palate, brachymelia, microphthalmia, skeletal malformations, decreased fetal weight, delayed fetal ossification, and embryo-fetal death occurred. TOLVAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryo-fetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. Rats received 2 to 162 times the maximum recommended human dose (MRHD) of tolvaptan (on a body surface area basis). Reduced fetal weights and delayed fetal ossification occurred at 162 times the MRHD. Signs of maternal toxicity (reduction in body weight gain and food consumption) occurred at 16 and 162 times the MRHD. When pregnant rabbits received oral tolvaptan at 32 to 324 times the MRHD (on a body surface area basis), there were reductions in maternal body weight gain and food consumption at all doses, and increased abortions at the mid and high doses (about 97 and 324 times the MRHD). At 324 times the MRHD, there were increased rates of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations [see Nonclinical Toxicology].
Labor and Delivery
The effect of TOLVAP on labor and delivery in humans is unknown.
Nursing Mothers
It is not known whether Tolvaptan is excreted into human milk. Tolvaptan is excreted into the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from TOLVAP, a decision should be made to discontinue nursing or TOLVAP, taking into consideration the importance of TOLVAP to the mother.
Pediatric Use
Safety and effectiveness of TOLVAP in pediatric patients have not been established.
Geriatric Use
Of the total number of hyponatremic subjects treated with TOLVAP in clinical studies, 42% were 65 and over, while 19% were 75 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.
Use in Patients with Hepatic Impairment
Moderate and severe hepatic impairment do not affect exposure to tolvaptan to a clinically relevant extent. Avoid use of tolvaptan in patients with underlying liver disease.
Use in Patients with Renal Impairment
No dose adjustment is necessary based on renal function. There are no clinical trial data in patients with CrCl <10 mL/min, and, because drug effects on serum sodium levels are likely lost at very low levels of renal function, use in patients with a CrCl <10 mL/min is not recommended. No benefit can be expected in patients who are anuric [see Contraindications and Clinical Pharmacology].
Use in Patients with Congestive Heart Failure
The exposure to tolvaptan in patients with congestive heart failure is not clinically relevantly increased. No dose adjustment is necessary.
OVERDOSAGE
Single oral doses up to 480 mg 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.
The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. 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 locomotors activity, staggering gait, tremor and hypothermia.
If overdose occurs, estimation of the severity of poisoning is an important first step. A thorough history and details of overdose should be obtained, and a physical examination should be performed. The possibility of multiple drug involvement should be considered.
Treatment should involve symptomatic and supportive care, with respiratory, ECG and blood pressure monitoring and water/electrolyte supplements as needed. A profuse and prolonged aquaresis should be anticipated, which, if not matched by oral fluid ingestion, should be replaced with intravenous hypotonic fluids, while closely monitoring electrolytes and fluid balance.
ECG monitoring should begin immediately and continue until ECG parameters are within normal ranges. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (>99%). Close medical supervision and monitoring should continue until the patient recovers.
CLINICAL PHARMACOLOGY
Mechanism of Action
Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times greater than for the V1a-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 V2-receptors compared with tolvaptan.
Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan administration.
Pharmacokinetics
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. Area under the curve (AUC) increases proportionally with dose. After administration of doses ≥60 mg, however, Cmax increases less than proportionally with dose. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3.
The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Food does not impact the bioavailability of tolvaptan. In vitro data indicate that tolvaptan is a substrate and inhibitor of P-gp. Tolvaptan is highly plasma protein bound (99%) and distributed into an apparent volume of distribution of about 3 L/kg. Tolvaptan is eliminated entirely by non-renal routes and mainly, if not exclusively, metabolized by CYP 3A. After oral dosing, clearance is about 4 mL/min/kg and the terminal phase half-life is about 12 hours. The accumulation factor of tolvaptan with the once-daily regimen is 1.3 and the trough concentrations amount to ≤16% of the peak concentrations, suggesting a dominant half-life somewhat shorter than 12 hours. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.
In patients with hyponatremia of any origin the clearance of tolvaptan is reduced to about 2 mL/min/kg. Moderate or severe hepatic impairment or congestive heart failure decrease the clearance and increase the volume of distribution of tolvaptan, but the respective changes are not clinically relevant. Exposure and response to tolvaptan in subjects with creatinine clearance ranging between 79 and 10 mL/min and patients with normal renal function are not different.
In a study in patients with creatinine clearances ranging from 10-124 mL/min administered a single dose of 60 mg tolvaptan, AUC and Cmax of plasma tolvaptan were less than doubled in patients with severe renal impairment relative to the controls. The peak increase in serum sodium was 5-6 mEq/L, regardless of renal function, but the onset and offset of tolvaptan's effect on serum sodium were slower in patients with severe renal impairment [see Use in Special Populations].
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Up to two years of oral administration of tolvaptan to male and female rats at doses up to 1000 mg/kg/day (162 times the maximum recommended human dose [MRHD] on a body surface area basis), to male mice at doses up to 60 mg/kg/day (5 times the MRHD) and to female mice at doses up to 100 mg/kg/day (8 times the MRHD) did not increase the incidence of tumors.
Tolvaptan tested negative for genotoxicity in in vitro (bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and in vivo (rat micronucleus assay) test systems.
In a fertility study in which male and female rats were orally administered tolvaptan at 100, 300 or 1000 mg/kg/day, the highest dose level was associated with significantly fewer corpora lutea and implants than control.
Reproductive and Developmental Toxicology
In pregnant rats, oral administration of tolvaptan at 10, 100 and 1000 mg/kg/day during organogenesis was associated with a reduction in maternal body weight gain and food consumption at 100 and 1000 mg/kg/day, and reduced fetal weight and delayed ossification of fetuses at 1000 mg/kg/day (162 times the MRHD on a body surface area basis). Oral administration of tolvaptan at 100, 300 and 1000 mg/kg/day to pregnant rabbits during organogenesis was associated with reductions in maternal body weight gain and food consumption at all doses, and abortions at mid- and high-doses. At 1000 mg/kg/day (324 times the MRHD), increased incidences of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations were observed. There are no adequate and well-controlled studies of TOLVAP in pregnant women. TOLVAP should be used in pregnancy only if the potential benefit justifies the risk to the fetus.
Storage and Handling
Store at 25 °C (77 °F), excursions permitted between 15 °C and 30 °C (59 °F to 86 °F) controlled Room Temperature. Keep out of reach of children.