Consumer medicine information

Samsca

Tolvaptan

BRAND INFORMATION

Brand name

Samsca

Active ingredient

Tolvaptan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Samsca.

SAMSCA®

SAMSCA®

 Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

 1. Why am I using SAMSCA?

SAMSCA contains the active ingredient tolvaptan. SAMSCA is used to treat hyponatraemia in adults, including patients who have conditions such as heart failure, and “syndrome of inappropriate antidiuretic hormone secretion” (SIADH).

For more information, see Section 1. Why am I using SAMSCA? in the full CMI.

 2. What should I know before I take SAMSCA?

Do not use if you have ever had an allergic reaction to SAMSCA or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take SAMSCA? in the full CMI.

 3. What if I am taking other medicines?

Some medicines may interfere with SAMSCA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

 4. How do I take SAMSCA?
  • Take SAMSCA once a day with or without food
  • The dose can be from 15 mg to 60 mg once a day

More instructions can be found in Section 4. How do I take SAMSCA? in the full CMI.

 5. What should I know while taking SAMSCA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking SAMSCA
  • Make sure you have access to water and continue to drink when thirsty
Things you should not do
  • Do not stop taking SAMSCA or lower the dose unless you notice side effects requiring urgent medical attention or if your doctor tells you to do so
  • Do not use SAMSCA to treat any complaint other than that directed by your doctor
  • Do not give SAMSCA to someone else even if their symptoms are the same
Driving or using machines
  • SAMSCA may occasionally make you feel dizzy or weak or you may faint for a short period
Drinking alcohol
  • Tell your doctor if you drink alcohol
Looking after your medicine
  • Store SAMSCA below 25°C and away from light and moisture
  • Do not leave it in the car on hot or cold days

For more information, see Section 5. What should I know while taking SAMSCA? in the full CMI.

 6. Are there any side effects?

Common side effects are thirst; dry mouth; making large amounts of urine and urinating often. Serious side effects include difficulty swallowing and speaking; seizures or convulsions; vomiting bright red blood; vomiting dark blood clots, or materials that looks like coffee-grounds; passing blood or stool mixed with blood; lethargy/fatigue (tiredness); mood changes; difficulty moving arms or legs, or uncontrollable movements.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

SAMSCA®

Active ingredient(s): tolvaptan (tol-vap-tan)

 Consumer Medicine Information (CMI)

This leaflet provides important information about using SAMSCA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using SAMSCA.

Where to find information in this leaflet:

1. Why am I using SAMSCA?
2. What should I know before I take SAMSCA?
3. What if I am taking other medicines?
4. How do I take SAMSCA?
5. What should I know while taking SAMSCA?
6. Are there any side effects?
7. Product details

 1. Why am I using SAMSCA?

SAMSCA contains the active ingredient tolvaptan.
SAMSCA belongs to a group of medicines called vasopressin antagonists. This means that it prevents vasopressin having its effect on water retention. This leads to a reduction in the amount of water in the body by increasing urine production and as a result it increases the concentration of sodium in your blood.

SAMSCA is used to treat hyponatraemia in adults, including patients who have conditions such as heart failure, and “syndrome of inappropriate antidiuretic hormone secretion” (SIADH). These conditions result in an inappropriate amount of the hormone vasopressin causing the sodium levels in your blood to get too low (hyponatraemia). That can lead to difficulties in concentration and memory, or in keeping your balance.

 2. What should I know before I take SAMSCA?

Warnings

Do not take SAMSCA if:

  • you are allergic to tolvaptan, any of the ingredients listed at the end of this leaflet, or any other similar medicine such as benzapine derivatives
  • Always check the ingredients to make sure you can use this medicine.
  • some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin
  • have any of the following medical conditions:
    - you cannot replace fluids by drinking
    - you cannot feel if you are thirsty
    - you have a condition which is associated with a very low blood volume
    - you are not producing or passing urine
  • you are taking the following medicine(s):
    - medicines to treat fungal infections such as ketoconazole or itraconazole
    - medicines to treat bacterial infections such as clarithromycin or telithromycin
    - medicines to treat HIV infection such as saquinavir, nelfinavir or ritonavir
    - medicines to treat depression i.e. nefazodone
  • you need to increase the sodium level in your blood right away - the safety and efficacy in these patients have not been studied

Check with your doctor if you:

  • have any other medical conditions such as:
    - you cannot drink enough water or you are fluid restricted
    - difficulties in urination or have an enlarged prostate
    - liver disease including cirrhosis
    - diabetes
    - hypothyroidism (an underactive thyroid gland)
    - hypoadrenalism (an underactive adrenal gland)
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known if SAMSCA will harm your unborn baby or if it passes into breast milk. This medicine contains sugars as lactose.

If you have been told by your doctor that you have an intolerance to some sugars, tell your doctor before taking SAMSCA.

 3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with SAMSCA and affect how it works. These include:

  • medicines to treat fungal infections such as ketoconazole, itraconazole or fluconazole
  • macrolide antibiotics such as clarithromycin or telithromycin or erythromycin
  • treatments for high blood pressure and chest pain such as diltiazem or verapamil
  • treatments of irregularities of heart beat and heart failure such as digoxin
  • treatments for epilepsy/seizures and some sleep disorders such as barbiturates, phenytoin or carbamazepine
  • medicines to treat tuberculosis such as rifampicin rifabutin or rifapentin
  • medicines to immunosuppressant therapy such as cyclosporine
  • treatments used to prevent or control bleeding, i.e. vasopressin analogs
  • treatments of HIV infection such as saquinavir, nelfinavir or ritonavir; and
  • medicines used to treat depression, i.e. nefazodone or St. John's Wort
  • other medicines that increase the level of sodium in your blood or which contain large amounts of salt, such as tablets that dissolve in water and indigestion remedies

These medicines may be affected by SAMSCA or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor will have more information on medicines to be careful with or avoid while taking SAMSCA.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SAMSCA.

 4. How do I take SAMSCA?

Treatment with SAMSCA should be started and re-started only in a hospital, where the sodium levels in your blood can be monitored closely.

If your doctor or pharmacist tells you to keep taking SAMSCA after you leave a hospital, it is important that you do not stop and restart SAMSCA on your own.

You may need to go back to a hospital to re-start SAMSCA. Talk to your doctor right away if you stop taking SAMSCA for any reason.

It is important to stay under the care of your doctor while taking SAMSCA and follow their instructions.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

  • Take SAMSCA once a day
  • You can take SAMSCA with or without food
  • Tablets should be swallowed without chewing and with a glass of water
  • Do not take SAMSCA with grapefruit juice
  • The dose can be from 15 mg to 60 mg once a day. Your doctor will start with a dose of 15 mg and may then increase it to a maximum of 60 mg to achieve the desired level of serum sodium.
  • Ask your doctor of pharmacist if you are unsure of the correct dose for you, they will tell you exactly how much to take
  • Follow the instructions provided and use SAMSCA until your doctor tells you to stop
  • SAMSCA should not be taken for longer than 30 days
  • If you take the wrong dose, SAMSCA may not work as well and your problem may not improve
  • Do not take more than the dose your doctor has recommended

When to take SAMSCA

  • SAMSCA should be taken the same time each day, preferably in the morning
  • This will help you remember when to take the medicine
  • Certain medicines or illnesses may keep you from drinking fluids or may cause you to lose too much body fluid, such as vomiting or diarrhoea. If you have these problems, call your doctor right away.

If you forget to take SAMSCA

SAMSCA should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember and then go back to taking your medicine as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

  • This may increase the chance of you getting an unwanted side effect

If you are not sure what to do, ask your doctor or pharmacist

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much SAMSCA

If you think that you have taken too much SAMSCA, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. Remember to take the medicine pack with you so that it is clear what you have taken.

Symptoms of an overdose may include:

  • thirst
  • dehydration
  • passing more urine than normal
  • low blood volume causing very low blood pressure
  • a rise in concentration of sodium concentration the blood

If your doctor tells you to stop taking SAMSCA, follow their instructions about limiting the amount of fluid you should drink.

 5. What should I know while taking SAMSCA?

Things you should do

Make sure you have access to water and continue to drink when thirsty.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking SAMSCA.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

Call your doctor straight away if you:

  • become pregnant while taking this medicine

Remind any doctor, dentist or pharmacist you visit that you are using SAMSCA.

Things you should not do

  • Do not use SAMSCA to treat any complaint other than that directed by your doctor
  • Do not give SAMSCA to someone else even if their symptoms are the same
  • Do not stop taking SAMSCA or lower the dose unless you notice side effects requiring urgent medical attention or if your doctor tells you to do so. This may lead to reoccurrence of your low sodium.

Drinking enough water

  • SAMSCA causes water loss because it increases your urine production. This water loss commonly results in dry mouth and thirst, and less commonly severe side effects such as kidney problems. It is therefore important that you have access to water and that you are able to drink sufficient amounts when you feel thirsty.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SAMSCA affects you.

SAMSCA may occasionally make you feel dizzy or weak or you may faint for a short period.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Store SAMSCA below 25°C and away from light and moisture.
  • Do not leave it in the car on hot or cold days. Heat, cold and dampness can destroy some medicines.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep SAMSCA in the pack until it is time to take your dose. If it is removed from the pack, it may not keep well.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking SAMSCA or it is out of date, ask your doctor what to do with any SAMSCA that is left.

Do not use this medicine after the expiry date.

 6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
General well-being related:
  • thirst
  • dry mouth
  • weakness
  • increased blood sugar levels
  • feel dizzy or faint. These may be symptoms that you have lost too much body fluid
  • loss of appetite
  • nausea
Infection related:
  • fever
Bladder related:
  • making large amounts of urine and urinating often
Speak to your doctor if you have any of these less serious side effects and they worry you.
Less serious side effectsWhat to do
Gastrointestinal related
  • constipation
  • have vomiting or diarrhoea, and cannot drink normally
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
General well-being related:
  • difficulty swallowing
  • lethargy/fatigue (tiredness)
  • mood changes
  • difficulty moving arms or legs, or uncontrollable movements
  • seizures or convulsions
Gastrointestinal related:
  • you vomit bright red blood
  • you vomit dark blood clots, or material that looks like coffee-grounds
  • you pass blood or stool mixed with blood
Speech related:
  • difficulty speaking
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

SAMSCA may affect your liver function. Therefore, please inform your doctor at any time if you have signs that could indicate potential liver problems such as:

  • unusual exhaustion
  • loss of appetite
  • pain in your right upper stomach
  • dark urine
  • jaundice (yellowing of your skin or the whites of your eyes)

During treatment with SAMSCA, your doctor may arrange blood tests to check for changes in your liver function or electrolytes (salts).

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

 7. Product details

This medicine is only available with a doctor's prescription.

What SAMSCA contains

Active ingredient
(main ingredient)
  • tolvaptan
Other ingredients
(inactive ingredients)
  • maize starch
  • hyprolose
  • lactose monohydrate
  • magnesium stearate
  • microcrystalline cellulose
  • indigo carmine aluminium lake
Potential allergenssugars as lactose

SAMSCA tablets contain 15 mg of tolvaptan.

Do not take this medicine if you are allergic to any of these ingredients.

What SAMSCA looks like

SAMSCA is supplied as 15 mg tablets in a PVC/aluminium perforated unit dose blister pack of 10 tablets.

The 15 mg tablet is blue, triangular, shallow-convex, debossed with “OTSUKA” and “15” on one side.

(Aust R 176602).

Who distributes SAMSCA

Otsuka Australia Pharmaceutical Pty Ltd
Suite 2.03, Level 2
9 Help Street
Chatswood NSW 2067

This leaflet was prepared in June 2022.

SAMSCA® is a registered trademark of Otsuka Pharmaceutical Co., Ltd.

Published by MIMS August 2022

BRAND INFORMATION

Brand name

Samsca

Active ingredient

Tolvaptan

Schedule

S4

 

1 Name of Medicine

Tolvaptan.

2 Qualitative and Quantitative Composition

Samsca tablets for oral use contain 15 mg or 30 mg of tolvaptan.
Excipients with known effect: sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Samsca is supplied as 15 mg and 30 mg tolvaptan tablets.
The 15 mg tablet is blue, triangular, shallow-convex, debossed with "OTSUKA" and "15" on one side.
The 30 mg tablet is blue, round, shallow-convex, debossed with "OTSUKA" and "30" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Samsca is indicated for the treatment of clinically significant hypervolaemic or euvolaemic hyponatraemia (serum sodium less than 125 mmol/L, or less marked hyponatraemia 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 Samsca. It has not been established that raising serum sodium with Samsca provides a symptomatic benefit to patients.

4.2 Dose and Method of Administration

Due to the need for a dose titration phase with close monitoring of serum sodium and volume status, treatment with Samsca should be initiated and reinitiated in hospital.
Treatment with Samsca should be initiated at a dose of 15 mg, orally, once daily. The dose may be increased to a maximum of 60 mg once daily as tolerated to achieve the desired level of serum sodium. Increase from the starting dose should be done incrementally (first to 30 mg and then to 60 mg if required) at intervals ≥ 24 hours. During titration, patients should be monitored for serum sodium and volume status.
For patients with an appropriate increase in serum sodium, the underlying disease and serum sodium levels should be monitored at regular intervals to evaluate further need of Samsca treatment. Do not administer Samsca for more than 30 days to minimise the risk of liver injury (see Section 4.4 Special Warnings and Precautions for Use).
Samsca tablets should be taken orally, preferably in the morning, without regard to meals. Tablets should be swallowed without chewing with a glass of water.
Samsca tablets should not be taken with grapefruit juice.

Patient monitoring.

In patients receiving Samsca who develop too rapid a rise in serum sodium, treatment with Samsca should be discontinued or interrupted and administration of hypotonic fluids should be considered. 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.

Hyperkalaemia or drugs that increase serum potassium.

Serum potassium levels should be monitored after initiation of Samsca treatment in patients with a serum potassium > 5 mmol/L as well as those who are receiving drugs known to increase serum potassium levels.

Drug withdrawal.

Following discontinuation of Samsca, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium and volume status.

4.3 Contraindications

Samsca is contraindicated in:
Patients hypersensitive to the active substance, benzazepine derivatives or any of the excipients.
Patients who are unable to sense or appropriately respond to thirst.
Patients suffering from hypovolaemic hyponatraemia.
Patients with anuria.
Urgent need to raise serum sodium acutely. Samsca has not been studied in a setting of urgent need to raise serum sodium acutely.
Ketoconazole and other strong CYP3A inhibitors. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

4.4 Special Warnings and Precautions for Use

Heart failure.

Efficacy of Samsca for the treatment of heart failure has not been established.

Hypothyroidism and hypoadrenalism.

Patients should be screened and treated for hypothyroidism and hypoadrenalism before treatment with Samsca.

Liver injury.

Drug induced liver injury has been observed in clinical trials investigating a different indication with long-term use of Samsca at higher doses than for the approved indication. In a placebo controlled and open label extension study of chronically administered tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD) clinically significant increases (greater than 3 x upper limit of normal) in serum alanine aminotransferase (ALT), along with clinically significant increases (greater than 2 x upper limit of normal) in serum total bilirubin were observed in 3 patients treated with Samsca. In addition, an increased incidence of ALT greater than three times the upper limit of normal was observed in patients treated with Samsca [42/958 or 4.4%] compared to those receiving placebo [5/484 or 1.0%]. Cases of serious liver injury were generally observed starting 3 months after initiation of tolvaptan although elevations of ALT occurred prior to 3 months. These findings may suggest that Samsca can cause irreversible and potentially fatal liver injury.
In postmarketing experience with tolvaptan in ADPKD, acute liver failure requiring liver transplantation has been reported.
Liver function tests should be promptly performed in patients taking Samsca who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. If liver injury is suspected, Samsca should be promptly discontinued, appropriate treatment should be instituted, and investigations should be performed to determine the probable cause. Samsca should not be reinitiated in patients unless the cause for the observed liver injury is definitively established to be unrelated to treatment with Samsca.
Limit duration of therapy with Samsca to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover from liver injury may be impaired.

Too rapid increases in serum sodium.

Patients should be monitored frequently during initiation and after each titration for serum sodium and volume status to avoid any adverse neurologic outcomes that may result from rapid increases (e.g. > 12 mmol/L/24 hr) in serum sodium. Too rapid correction of hyponatraemia can cause osmotic demyelination which may result in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.
Coadministration of Samsca with other treatments for hyponatraemia, such as hypertonic saline or other therapies that may increase serum sodium levels, is not recommended, particularly during initiation or in patients with fluctuating serum sodium. Correction of hyponatraemia should be slower particularly in patients suffering from severe malnutrition, alcoholism, SIADH, hypoxia or advanced liver disease.
In patients receiving tolvaptan who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with tolvaptan and consider administration or ingestion of hypotonic fluids as appropriate.

Hypernatremia.

Potent aquaresis (free water clearance), may induce hypernatremia which can lead to adverse neurologic events. If serum sodium increases above normal range, tolvaptan dose should be adjusted, serum sodium should be carefully monitored and appropriate measures should be taken if necessary.

Dehydration and hypovolaemia.

Patients receiving Samsca should have access to water and should continue ingestion of fluid in response to thirst.
Samsca therapy induces copious aquaresis, which is normally partially offset by fluid intake. Dehydration and hypovolaemia can occur, especially in potentially volume depleted patients receiving diuretics or those who are fluid restricted.
In patients treated with Samsca who develop medically significant signs or symptoms of hypovolaemia, treatment with Samsca should be discontinued or interrupted. In such patients the fluid balance, electrolyte levels and vital signs should be carefully managed. Fluid restriction during therapy with Samsca may increase the risk of dehydration and hypovolaemia.

Hyperkalaemia or drugs that increase serum potassium.

Treatment with Samsca 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 Samsca treatment in patients with a serum potassium > 5 mmol/L as well as those who are receiving drugs known to increase serum potassium levels.

Urinary outflow obstruction.

Urinary output must be secured. Patients with partial obstruction of urinary outflow have an increased risk of developing acute retention. Patients with urinary outflow obstructions must be monitored to ensure urinary output is achieved.

Lactose and galactose intolerance.

Samsca contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in hepatic impairment.

Moderate and severe hepatic impairment do not affect exposure to Samsca to a clinically relevant extent. Avoid use of tolvaptan in patients with underlying liver disease.

Use in renal impairment.

Exposure and response to Samsca 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 Samsca in patients with a creatinine clearance < 10 mL/min or in patients on chronic dialysis have not been studied. Samsca is contraindicated in anuric patients. No benefit can be expected in patients who are anuric.

Use in the elderly.

Of the total number of hyponatraemic 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 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.

Paediatric use.

Safety and effectiveness of Samsca in pediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Ketoconazole and other strong CYP3A inhibitors.

Use of ketoconazole and other strong CYP34A inhibitors with Samsca is contraindicated (see Section 4.3 Contraindications). Samsca is metabolized primarily by CYP3A. Ketoconazole is a strong inhibitor of CYP3A and also an inhibitor of P-glycoprotein. Coadministration of Samsca and ketoconazole 200 mg daily results in a 5-fold increase in exposure to Samsca. Coadministration of Samsca with 400 mg ketoconazole daily or with other strong CYP3A 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 Samsca exposure. Thus, Samsca and strong CYP3A inhibitors should not be coadministered.

Moderate CYP3A inhibitors.

The impact of moderate CYP3A inhibitors (e.g. erythromycin, fluconazole, aprepitant, diltiazem and verapamil) on the exposure to coadministered Samsca has not been assessed. A substantial increase in the exposure to Samsca would be expected when Samsca is coadministered with moderate CYP3A inhibitors. Coadministration of Samsca with moderate CYP3A inhibitors should therefore generally be avoided.

Grapefruit juice.

Samsca should not be taken with grapefruit juice.

Rifampin and other CYP3A inducers.

Rifampin is an inducer of CYP3A and P-glycoprotein. Coadministration 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.

P-glycoprotein (P-gp) inhibitors.

Tolvaptan is a substrate for P-glycoprotein. Reduction in the dose of Samsca may be required in patients concomitantly treated with P-gp inhibitors, such as, e.g. ciclosporin, based on clinical response.

Lovastatin, warfarin, amiodarone, frusemide, and hydrochlorothiazide.

Coadministration of Samsca does not appear to alter the pharmacokinetics of lovastatin, warfarin, frusemide, hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone) to a clinically significant degree.

Digoxin.

Steady-state digoxin concentrations have been increased (1.3-fold increase in maximum observed plasma concentration [Cmax] and 1.2-fold increase in area under the plasma concentration time curve over the dosing interval [AUCT]) when coadministered with multiple once daily 60 mg doses of Samsca. Patients receiving digoxin should therefore be evaluated for excessive digoxin effects when treated with Samsca.

Coadministration with hypertonic saline.

There is no experience with concomitant use of Samsca and hypertonic saline. Concomitant use with hypertonic saline is not recommended.

Coadministration with vasopressin analogs.

In addition to its renal aquaretic effect, Samsca is capable of blocking vascular vasopressin V2-receptors involved in the release of coagulation factors (e.g. von Willebrand's factor) from endothelial cells. Therefore, the effect of vasopressin analogs such as desmopressin (DDAVP) may be attenuated in patients using such analogs to prevent or control bleeding when coadministered with Samsca.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility was unaffected in male and female rats given tolvaptan at oral doses up to 1000 mg/kg/day (yielding 1.3 times in males and 3.4 times in females the AUC in patients at the maximum recommended human dose [MRHD] of 60 mg per day). However, oestrus cycles were altered in rats at oral doses ≥ 300 mg/kg/day (2.5 times the clinical AUC at the MRHD).
(Category D)
There are no adequate and well controlled studies of Samsca use in pregnant women. Samsca should not be used during pregnancy unless the potential benefit clearly justifies the potential risk to the fetus.
Tolvaptan and/or its metabolites were shown to cross the placenta in rats and rabbits. In rats treated with tolvaptan during organogenesis, reduced fetal weights and delayed fetal ossification occurred at an oral dose of 1000 mg/kg/day (yielding 12 times the clinical AUC at the MHRD. In rabbits, there were abortions at oral doses ≥ 300 mg/kg/day (≥ 0.8 times the clinical AUC at the MRHD). At 1000 mg/kg/day (about 5 times the clinical AUC at the MRHD), there were increased rates of embryofetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations. These adverse effects on embryofetal development were observed in conjunction with maternal toxicity (reduced maternal bodyweight gain and food consumption) although a direct effect of the drug cannot be excluded.
The effect of Samsca on labour and delivery in humans is unknown.
 It is not known whether tolvaptan is excreted into human milk. Studies in rats have shown excretion of tolvaptan and/or its metabolites in breast milk at high levels. Breastfeeding should be discontinued when receiving tolvaptan.

4.7 Effects on Ability to Drive and Use Machines

When driving vehicles or using machines it should be taken into account that occasionally dizziness, asthenia or syncope may occur.

4.8 Adverse Effects (Undesirable Effects)

In multiple dose, placebo controlled trials, 607 hyponatraemic patients (serum sodium < 135 mmol/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) Samsca treated patients had a serum sodium < 130 mmol/L, and 52 patients had a serum sodium < 125 mmol/L. Hyponatraemia 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 4000 patients have been treated with oral doses of Samsca in open label or placebo controlled clinical trials. Approximately 650 of these patients had hyponatraemia; approximately 219 of these hyponatraemic patients were treated with Samsca for 6 months or more.
The most common adverse reactions (incidence ≥ 5% more than placebo) seen in two 30 day, double blind, placebo controlled hyponatraemia trials in which Samsca 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 Samsca 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 Samsca treated patients with hyponatraemia (serum sodium < 135 mmol/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 Samsca treated patients and 6% in placebo treated patients.
In a subgroup of patients with hyponatraemia (N = 475, serum sodium < 135 mmol/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).
The following adverse reactions occurred in < 2% of hyponatraemic 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 hyponatraemia (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.

Ischaemic colitis.

Metabolism and nutrition disorders.

Diabetic ketoacidosis.

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis.

Nervous system.

Cerebrovascular accident.

Renal and urinary disorders.

Urethral haemorrhage.

Reproductive system and breast disorders (female).

Vaginal haemorrhage.

Respiratory, thoracic, and mediastinal disorders.

Pulmonary embolism, respiratory failure.

Vascular disorder.

Deep vein thrombosis.
Hyperkalaemia also occurred commonly (≥ 2% and < 10%). See Section 4.4 Special Warnings and Precautions for Use, Hyperkalaemia or drugs that increase serum potassium.

Gastrointestinal bleeding in patients with cirrhosis.

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

Postmarketing experience.

The following adverse reaction has been reported spontaneously during the postmarketing period. The exact incidence of the spontaneously reported adverse reactions is unknown.
Osmotic demyelination syndrome (central pontine myelinolysis); hypernatremia; anaphylaxis.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Contact the Poisons Information Centre on telephone 13 11 26 for advice on management of overdose.
Single oral doses up to 480 mg and multiple doses up to 300 mg of Samsca, taken once daily for 5 days have been well tolerated in studies in healthy subjects.
There is no specific antidote for Samsca overdose. 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/ hypovolaemia.
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 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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Tolvaptan is a Vasopressin antagonist: ATC code C03XA01.

Mechanism of action.

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor greater than that of native arginine vasopressin. When taken orally, 15 to 60 mg doses of Samsca tablets cause an increase in urine excretion resulting in increased aquaresis, decreased urine osmolality and increased serum sodium concentrations. Urine excretion of sodium and potassium are not significantly affected.
Tolvaptan metabolites do not appear to have relevant pharmacological activity at clinical concentrations in humans.
Oral administration of 15 to 120 mg doses of Samsca produced a significant increase in urine excretion rate within 2 hours of dosing. The increase in 24 hour urine volume was dose dependent. Following single oral doses of 15 to 60 mg, urine excretion rates returned to baseline levels after 24 hours. A mean of about 7 litres was excreted during 0 to 12 hours, independent of dose. Markedly higher doses of tolvaptan produce more sustained responses without affecting the magnitude of excretion, as active concentrations of tolvaptan are present for longer periods of time.

Clinical trials.

In two double blind, placebo controlled, multicenter studies (SALT-1 and SALT-2), a total of 424 patients with euvolaemic or hypervolaemic hyponatraemia (serum sodium < 135 mmol/L) resulting from a variety of underlying causes (heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone [SIADH] and others) were treated for 30 days with tolvaptan or placebo, and were followed for an additional 7 days after withdrawal. Symptomatic patients, patients likely to require saline therapy during the course of therapy, patients with acute and transient hyponatraemia associated with head trauma or postoperative state and patients with hyponatraemia due to primary polydipsia, uncontrolled adrenal insufficiency or uncontrolled hypothyroidism were excluded. Patients were randomized to receive either placebo (N = 220) or tolvaptan (N = 223) at an initial oral dose of 15 mg once daily.
The mean serum sodium concentration at study entry was 129 mmol/L. Fluid restriction was to be avoided if possible during the first 24 hours of therapy to avoid overly rapid correction of serum sodium. During the first 24 hours of therapy 87% of patients had no fluid restriction. Thereafter, patients could resume or initiate fluid restriction (defined as fluid intake of ≤ 1.0 liter/day) as clinically indicated.
The dose of tolvaptan could be increased at 24 hour intervals to 30 mg once daily, then to 60 mg once daily, until either the maximum dose of 60 mg or normonatraemia (serum sodium > 135 mmol/L) was reached. Serum sodium concentrations were determined at 8 hours after study drug initiation and daily up to 72 hours, within which time titration was typically completed. Treatment was maintained for 30 days with additional serum sodium assessments on days 11, 18, 25 and 30. On the day of study discontinuation, all patients resumed previous therapies for hyponatraemia and were re-evaluated 7 days later.
The primary endpoint for the studies was the average daily AUC for change in serum sodium from baseline to day 4 and baseline to day 30 in patients with a serum sodium less than 135 mmol/L. Compared to placebo, tolvaptan caused a statistically significant greater increase in serum sodium (p < 0.0001) during both periods in both studies (see Table 2). In addition, for patients with a serum sodium of < 130 mmol/L or < 125 mmol/L, the effects at day 4 and day 30 was also significant (see Table 2). This effect was also seen across all disease etiology subsets (e.g. CHF, cirrhosis, SIADH/ other).
In patients with hyponatraemia (defined as < 135 mmol/L), serum sodium concentration increased to a significantly greater degree in tolvaptan treated patients compared to placebo treated patients as early as 8 hours after the first dose, and the change was maintained for 30 days. The percentage of patients requiring fluid restriction (defined as ≤ 1 L/day at any time during the treatment period) was also significantly less (p < 0.01) in the tolvaptan treated group (30/215, 14%) as compared with the placebo treated group (51/206, 25%).
Figure 1 shows the change from baseline in serum sodium by visit in patients with serum sodium < 135 mmol/L. Within 7 days of tolvaptan discontinuation, serum sodium concentrations in tolvaptan treated patients declined to levels similar to those of placebo treated patients.
See Figure 2.
In the open label study SALTWATER, 111 patients, 94 of them hyponatraemic (serum sodium < 135 mmol/L), previously on tolvaptan or placebo therapy were given Samsca as a titrated regimen (15 to 60 mg once daily) after having returned to standard care for at least 7 days. By this time, their baseline mean serum sodium concentration had fallen to between their original baseline and postplacebo therapy level. Upon initiation of therapy, average serum sodium concentrations increased to approximately the same levels as observed for those previously treated with tolvaptan, and were sustained for at least a year. Figure 3 shows results from 111 patients enrolled in the SALTWATER study.

5.2 Pharmacokinetic Properties

Absorption and distribution.

After oral administration, tolvaptan is rapidly absorbed with peak plasma concentrations occurring about 2 hours after dosing. The absolute bioavailability of tolvaptan is about 56%. Coadministration with food has no effect on plasma concentrations. Following single oral doses of ≥ 300 mg, peak plasma concentrations appear to plateau, possibly due to saturation of absorption. Tolvaptan binds reversibly (98%) to plasma proteins and is distributed into an apparent volume of distribution of about 3 L/kg.

Metabolism.

Tolvaptan is extensively metabolised by the liver. Less than 1% of intact active substance is excreted unchanged in the urine. Radiolabelled tolvaptan experiments showed that 40% of the radioactivity was recovered in the urine and 59% was recovered in the faeces where unchanged tolvaptan accounted for 32% of radioactivity. Tolvaptan is only a minor component in plasma (3%). The terminal elimination half-life is about 8 hours and steady-state concentrations of tolvaptan are obtained after the first dose. After oral dosing, clearance is about 4 mL/min/kg.

Linearity.

Tolvaptan has linear pharmacokinetics for doses of 15 to 60 mg.

5.3 Preclinical Safety Data

Genotoxicity.

Tolvaptan tested negative for genotoxicity in in vitro (bacterial reverse mutation assay, mammalian forward mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and in vivo (rat micronucleus assay) test systems.

Carcinogenicity.

Up to two years of oral administration of tolvaptan to male and female rats at doses up to 1000 mg/kg/day (yielding 1.3 and 3.4 times respectively, the AUC for tolvaptan in patients at the maximum recommended human dose [MRHD]), to male mice at doses up to 60 mg/kg/day (relative exposure, 0.3) and to female mice at doses up to 100 mg/kg/day (relative exposure, 0.4) did not increase the incidence of tumours. The predictive value of these studies is limited by the inability to obtain high multiples of the clinical exposure to tolvaptan. However, negative findings in genotoxicity assays and the absence of preneoplastic lesions observed in these and other studies lend support to tolvaptan being unlikely to pose a particular carcinogenic risk in patients.

6 Pharmaceutical Particulars

6.1 List of Excipients

Maize starch, hyprolose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and indigo carmine aluminium lake.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
Protect from light and moisture.

6.5 Nature and Contents of Container

Samsca is supplied as 15 mg and 30 mg tolvaptan tablets in PVC/aluminium perforated unit dose blister packs of 10 or 30 tablets each.
Not all presentations and pack sizes may be available in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Tolvaptan is (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-o-tolu-m-toluidide. The empirical formula is C26H25ClN2O3. Molecular weight is 448.94.

Chemical structure.


Tolvaptan is practically insoluble in water and the aqueous solubility of the drug substance is poor (~ 0.1 mg/250 mL) across all pH ranges. It is slightly soluble in ethyl acetate, sparingly soluble in ethanol, soluble in methanol and freely soluble in benzyl alcohol. The octanol:water partition coefficient was reported to be greater than 5000 at 25°C.

CAS number.

The CAS Registry Number for tolvaptan is 150683-30-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4: Prescription Only Medicine (S4).

Summary Table of Changes