SAMSCA®
(tolvaptan)
The following adverse reactions occurred in < 2% of hyponatremic patients treated with SAMSCA and at a rate greater than placebo in double-blind placebo-controlled trials (N = 607 tolvaptan; N=518 placebo) or in < 2% of patients in an uncontrolled trial of patients with hyponatremia (N = 111) and are not mentioned elsewhere in the label: Blood and Lymphatic System Disorders: Disseminated intravascular coagulation; Cardiac Disorders: Intracardiac thrombus, ventricular fi brillation; Investigations: Prothrombin time prolonged; Gastrointestinal Disorders: Ischemic colitis; Metabolism and Nutrition Disorders: Diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis; Nervous System: Cerebrovascular accident; Renal and Urinary Disorders: Urethral hemorrhage; Reproductive System and Breast Disorders (female): Vaginal hemorrhage; Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure; Vascular disorder: Deep vein thrombosis.
DRUG INTERACTIONS: Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP 3A Inhibitors: SAMSCA is metabolized primarily by CYP 3A. Ketoconazole is a strong inhibitor of CYP 3A and also an inhibitor of P-gp. Co- administration of SAMSCA and ketoconazole 200 mg daily results in a 5-fold increase in exposure to tolvaptan. Co-administration of SAMSCA with 400 mg ketoconazole daily or with other strong CYP 3A inhibitors (e.g., clarithromycin, itraconazole, telithromycin, saquinavir, nel navir, ritonavir and nefazodone) at the highest labeled dose would be expected to cause an even greater increase in tolvaptan exposure. Thus, SAMSCA and strong CYP 3A inhibitors should not be co-administered [see Dosage and Administration (2.4) and Contraindications (4.4)].
Moderate CYP 3A Inhibitors: The impact of moderate CYP 3A inhibitors (e.g., erythromycin, uconazole, 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 SAMSCA is co-administered with moderate CYP 3A inhibitors. Co-administration of SAMSCA with moderate CYP3A inhibitors should therefore generally be avoided [see Dosage and Administration (2.4) and Warnings and Precautions (5.5)]. Grapefruit Juice: Co-administration of grapefruit juice and SAMSCA results in a 1.8-fold increase in exposure to tolvaptan [see Dose and Administration (2.4) and Warnings and Precautions (5.5)]. P-gp Inhibitors: Reduction in the dose of SAMSCA may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response [see Dose and Administration (2.4) and Warnings and Precautions (5.5)]. Rifampin and Other CYP 3A Inducers: Rifampin is an inducer of CYP 3A and P-gp. Co- administration of rifampin and SAMSCA reduces exposure to tolvaptan by 85%. Therefore, the expected clinical effects of SAMSCA 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 SAMSCA. The dose of SAMSCA may have to be increased [Dosage and Administration (2.4) and Warnings and Precautions (5.5)]. Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide: Co-administration of lovastatin, digoxin, furosemide, and hydrochlorothiazide with SAMSCA has no clinically relevant impact on the exposure to tolvaptan. Effects of Tolvaptan on Other Drugs: Digoxin: Digoxin is a P-gp substrate and SAMSCA is a P-gp inhibitor. Co-administration of SAMSCA and digoxin results in a 1.3-fold increase in the exposure to digoxin. 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 signi cant degree. Lovastatin: SAMSCA is a weak inhibitor of CYP 3A. Co-administration of lovastatin and SAMSCA increases the exposure to lovastatin and its active metabolite lovastatin- hydroxyacid by factors of 1.4 and 1.3, respectively. This is not a clinically relevant change. Pharmacodynamic 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 speci c 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. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category C. There are no adequate and well controlled studies of SAMSCA use in pregnant women.
In animal studies, cleft palate, brachymelia,
microphthalmia, skeletal malformations, decreased fetal weight, delayed fetal ossi cation, and embryo-fetal death occurred. SAMSCA should be used during pregnancy only if the potential bene t justi es 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 ossi cation 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),
SAMSCA®
(tolvaptan)
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 (13.3)].
Labor and Delivery: The effect of SAMSCA on labor and delivery in humans is unknown. Nursing Mothers: It is not known whether SAMSCA 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 SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother. Pediatric Use: Safety and effectiveness of SAMSCA in pediatric patients have not been established. Geriatric Use: Of the total number of hyponatremic subjects treated with SAMSCA 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 identi ed 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. No dose adjustment of tolvaptan is necessary.
Use in Patients with Renal Impairment: Exposure and response to tolvaptan are similar in patients with a creatinine clearance 10-79 mL/min and in patients without renal impairment. No dose adjustment is necessary. Exposure and response to tolvaptan in patients with a creatinine clearance < 10 mL/min or in patients on chronic dialysis have not been studied. No bene t can be expected in patients who are anuric [see Contraindications (4.5)]. 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 speci c 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 locomotor activity, staggering gait, tremor and hypothermia. If overdose occurs, estimation of the severity of poisoning is an important rst 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 uid ingestion, should be replaced with intravenous hypotonic uids, while closely monitoring electrolytes and uid 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 af nity for human plasma protein (> 99%). Close medical supervision and monitoring should continue until the patient recovers. PATIENT COUNSELING INFORMATION: As a part of patient counseling, healthcare providers must review the SAMSCA Medication Guide with every patient [see FDA-Approved Medication Guide (17.3)]. Concomitant Medication: Advise patients to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs since there is a potential for interactions. Strong and Moderate CYP 3A inhibitors and Pg-p inhibitors: Advise patients to inform their physician if they use strong (e.g., ketoconazole, itraconazole, clarithromycin, telithromycin, nel navir, saquinavir, indinavir, ritonavir) or moderate CYP 3A inhibitors (e.g., aprepitant, erythromycin, diltiazem, verapamil, uconazol) or P-gp inhibitors (e.g., cyclosporine) [see Dosage and Administration (2.4), Contraindications (4.4), Warnings and Precautions (5.5) and Drug Interactions (7.1)]. Nursing: Advise patients not to breastfeed an infant if they are taking SAMSCA [see Use In Specifi c Populations (8.3)].
For more information about SAMSCA, call 1-877-726-7220 or go to
www.samsca.com.
Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850
US Patent Nos.: 5,258,510 and 5,753,677. SAMSCA is a trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
0708L-0023B © 2010 Otsuka Pharmaceutical Co., Ltd.
Rev. 05/2009
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