Samsca

• Samsca^®

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

• have kidney problems and your body can not make urine.
• have liver problems.
• can not feel if you are thirsty.
• have any allergies. 
• are pregnant or breastfeeding.
• are taking desmopressin (dDAVP).

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

• See "Drug Precautions" section.
• Take Samsca exactly as prescribed by your healthcare provider.
• Take Samsca tablets by mouth once daily, with or without food..
• Do not drink grapefruit juice during treatment with Samsca. This could cause you to have too much Samsca in your blood.
• Certain medicines or illnesses may keep you from drinking fluids or may cause you to lose too much body fluid, such as vomiting or diarrhea. If you have these problems, call your healthcare provider right away.
• Do not miss or skip doses of Samsca. If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time.
• If you take too much Samsca, call your healthcare provider right away. If you take an overdose of Samsca, you may need to go to a hospital.
• If your healthcare provider tells you to stop taking Samsca, follow their instructions about limiting the amount of fluid you should drink.

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM

• 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.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have any of these signs that your hyponatremia is being reversed too quickly:

• problems with speech or muscle control;

• trouble swallowing;

• trouble moving your arms and legs;

• confusion, mood changes; or

• a seizure.

While taking tolvaptan at home, call your doctor at once if you have:

• weakness, or a light-headed feeling (like you might pass out);

• liver problems--vomiting, loss of appetite, upper stomach pain, tiredness, itching, dark urine, jaundice (yellowing of the skin or eyes); or

• dehydration symptoms--feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin.

Common side effects may include:

• dry mouth;

• increased thirst or urination;

• hunger, fruity breath odor, drowsiness, blurred vision;

• constipation; or

• weakness.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Selective arginine vasopressin (antidiuretic hormone) V2 receptor antagonist.1 2 3 4 5

• Affinity for V2 receptors 29 times that for V1A receptors.1 4 5

• Does not appear to have any affinity for V1B receptors.5

• Antagonizes effects of vasopressin at V2 receptors of distal nephron, resulting in increased free water clearance, decreased urine osmolality, and increased serum sodium concentrations.1 2 4

• Urinary sodium and potassium excretion and plasma potassium concentrations not substantially altered; plasma concentrations of endogenous arginine vasopressin may increase.1 2 4

• Does not appear to have a clinically important effect on the QTc interval.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Samsca is contraindicated in the following conditions:

Urgent Need to Raise Serum Sodium Acutely

Samsca has not been studied in a setting of urgent need to raise serum sodium acutely.

Inability of the Patient to Sense or Appropriately Respond to Thirst

Patients who are unable to auto-regulate fluid balance are at substantially increased risk of incurring an overly rapid correction of serum sodium, hypernatremia and hypovolemia.

Hypovolemic Hyponatremia

Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits.

Concomitant Use of Strong CYP 3A Inhibitors

Ketoconazole 200 mg administered with tolvaptan increased tolvaptan exposure by 5-fold. Larger doses would be expected to produce larger increases in tolvaptan exposure. There is not adequate experience to define the dose adjustment that would be needed to allow safe use of tolvaptan with strong CYP 3A inhibitors such as clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, and telithromycin.

Anuric Patients

In patients unable to make urine, no clinical benefit can be expected.

Hypersensitivity

Samsca is contraindicated in patients with hypersensitivity (e.g. anaphylactic shock, rash generalized) to tolvaptan or any component of the product [see Adverse Reactions (6.2)].

Clinical 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 Samsca. 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.

Table 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.

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) and polyuria or pollakiuria (4% tolvaptan, 1% placebo).

Gastrointestinal bleeding in patients with cirrhosis

In patients with cirrhosis treated with tolvaptan in the hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) tolvaptan-treated patients and 1 out of 57 (2%) placebo treated patients.

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 fibrillation

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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Samsca. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Neurologic: Osmotic demyelination syndrome

Investigations: Hypernatremia

Immune System Disorders: Hypersensitivity reactions including anaphylactic shock and rash generalized [see Contraindications (4.6)].

Samsca (tolvaptan) reduces the level of a hormone that regulates the balance of water and salt (sodium) in the body. High levels of this hormone can cause an imbalance that results in low sodium levels and fluid retention.

Samsca is used to treat hyponatremia (low levels of sodium in your blood) in people with heart failure, and certain hormonal imbalances.

Samsca improves urine flow without causing the body to lose too much sodium as you urinate.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Many drugs can interact with tolvaptan. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all your current medicines and any medicine you start or stop using.

Applies to tolvaptan: oral tablet

Cardiovascular

Common (1% to 10%): Intracardiac thrombus, ventricular fibrillation, orthostatic hypotension[Ref]

Gastrointestinal

Very common (10% or more): Dry mouth (up to 13%), nausea
Common (1% to 10%): Constipation, ischemic colitis, gastrointestinal bleeding, diarrhea[Ref]

General

The most frequently reported side effects included thirst, dry mouth (up to 13%), asthenia, constipation, pollakiuria or polyuria and hyperglycemia.[Ref]

Genitourinary

Common (1% to 10%): Blood in urine
Uncommon (0.1% to 1%): Urethral hemorrhage, vaginal hemorrhage[Ref]

Hematologic

Common (1% to 10%): Prolonged prothrombin time, disseminated intravascular coagulation[Ref]

Musculoskeletal

Common (1% to 10%): Rhabdomyolysis

Nervous system

Common (1% to 10%): Cerebrovascular accident, syncope, dizziness, headache
Uncommon (0.1% to 1%): Dysgeusia
Postmarketing reports: Osmotic demyelination syndrome[Ref]

Renal

Very common (10% or more): Pollakiuria and polyuria (11%)
Uncommon (0.1% to 1%): Renal impairment[Ref]

Respiratory

Common (1% to 10%): Pulmonary embolism, respiratory failure[Ref]

Metabolic

Common (1% to 10%): Hyperglycemia, anorexia, diabetic ketoacidosis, dehydration, hyperkalemia, decreased appetite, creatinine increased, hypernatremia, hypoglycemia, hyperuricemia[Ref]

Dermatologic

Common (1% to 10%): Ecchymosis, pruritus
Uncommon (0.1% to 1%): Pruritic rash[Ref]

Hepatic

Common: Alanine aminotransferase increased, aspartate aminotransferase increased, bilirubin increased

Hypersensitivity

Postmarketing reports: Hypersensitivity reactions including anaphylactic shock and generalized rash

Other

Very common (10% or more): Thirst (up to 18%)
Common (1% to 10%): Asthenia, pyrexia, malaise

Some side effects of Samsca may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.