Consumer medicine information

Tolvaptan Lupin

Tolvaptan

BRAND INFORMATION

Brand name

Tolvaptan Lupin

Active ingredient

Tolvaptan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tolvaptan Lupin.

SUMMARY CMI

Tolvaptan Lupin

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.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using Tolvaptan Lupin?

Tolvaptan Lupin contains the active ingredient tolvaptan. Tolvaptan Lupin is used to treat a disease called Autosomal Dominant Polycystic Kidney Disease (ADPKD).

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

2. What should I know before I use Tolvaptan Lupin?

Do not use if you have ever had an allergic reaction to tolvaptan 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, are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Tolvaptan Lupin? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Tolvaptan Lupin 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 use Tolvaptan Lupin?

  • Tolvaptan Lupin is to be taken in two different doses every day. Your doctor will decide the best suitable dose based on your condition and response.
  • The dose combinations are 45 mg + 15 mg or 60 mg + 30 mg or 90 mg + 30 mg

More instructions can be found in Section 4. How do I use Tolvaptan Lupin? in the full CMI.

5. What should I know while using Tolvaptan Lupin?

Things you should do
  • Remind any doctor, dentist, or you visit that you are using tolvaptan.
  • Make sure you drink plenty of water – MAKE SURE YOU DRINK ENOUGH WATER
Things you should not do
  • Do not stop using Tolvaptan Lupin or change the dosage without first discussing it with your doctor.
  • Do not take this medicine to treat any other complaints unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you
Driving or using machines
  • Tolvaptan Lupin may cause side effects that can affect your ability to drive or use machines.
  • Tolvaptan Lupin may make you feel dizzy or sleepy, particularly at the beginning of treatment. If this happens to you, do not drive, or use any tools or machines.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep your medicine in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using Tolvaptan Lupin? in the full CMI.

6. Are there any side effects?

Common side effects include thirst; increased amount and frequency of urination; headache; constipation; diarrhoea; dry mouth; indigestion; decreased appetite; fatigue; weakness; dizziness; trouble sleeping; muscle spasms; rash; dry skin; itching; painful, swollen joints. Serious side effects include difficulty urinating; swelling of the face, lips or tongue; generalised rash; or severe wheezing or breathlessness; signs of electrolyte imbalances.

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.

WARNING: Tolvaptan Lupin can cause serious liver problems.

Stop taking Tolvaptan Lupin and call your healthcare provider right away if you get any of the following symptoms: feeling tired, fever, loss of appetite, rash, nausea, itching, right upper stomach (abdomen) pain or tenderness, yellowing of the skin and white part of the eye (jaundice), vomiting, dark urine.

To help reduce your risk of liver problems, your healthcare provider will ask you to do a blood test to check your liver before you start taking Tolvaptan Lupin – monthly for the first 18 months of treatment and then every 3 months.

It is important to stay under the care of your healthcare provider during treatment with Tolvaptan Lupin.



FULL CMI

Tolvaptan Lupin

Active ingredient: tolvaptan

Consumer Medicine Information (CMI)

This leaflet provides important information about using Tolvaptan Lupin. 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 Tolvaptan Lupin.

Where to find information in this leaflet:

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

1. Why am I using Tolvaptan Lupin?

Tolvaptan Lupin contains the active ingredient tolvaptan. Tolvaptan Lupin is vasopressin antagonist. This means that it prevents a hormone called vasopressin from binding to receptors in your kidneys. By blocking the effect of vasopressin, Tolvaptan Lupin slows the development of kidney cysts in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), reduces symptoms of the disease and increases urine production.

Tolvaptan Lupin is used to treat a disease called Autosomal Dominant Polycystic Kidney Disease (ADPKD). This disease causes growth of cysts in the kidneys which results in problems because of their size and the space they occupy.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Tolvaptan Lupin is not recommended for use in children and teenagers, or patients older than 55 years. The effects of Tolvaptan Lupin in people younger than 18 years had not been studied, and in patients older than 55 years has not been proven.

2. What should I know before I use Tolvaptan Lupin?

Warnings

Do not use Tolvaptan Lupin if:

  • you are allergic to tolvaptan, benzazepine derivative, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • you have been told that you have raised levels of liver enzymes in your blood.
  • you have high level of sodium in your blood (“hypernatraemia”).
  • you do not realise when you are thirsty.
  • your kidneys cannot produce urine.
  • you have low blood volume.
  • you are pregnant.
  • you are breastfeeding.
  • you are below the age of 18 years. Safety and effectiveness in children younger than 18 years have not been established.

Check with your doctor if you:

  • have, or have had, any other medical conditions, including if you:
    - suffer from liver disease;
    - suffer from too high or too low blood sodium;
    - suffer from high potassium levels in your blood;
    - have diabetes;
    - have high blood pressure and are taking medications to treat it;
    - have gout;
    - have lactose intolerance.
  • cannot drink enough water or if you are fluid restricted;
  • have difficulties in urination or have an enlarged prostate;
  • are dehydrated or suffer from excessive vomiting, diarrhoea or sweating;
  • 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.

Tolvaptan Lupin must not be taken if you are pregnant.

You must use a reliable method of contraception to avoid becoming pregnant while you are taking Tolvaptan Lupin. You should continue doing this for one month after stopping treatment.

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

Tolvaptan Lupin must not be taken if you are breastfeeding.

If you have not told your doctor about any of the above, tell them before you start taking Tolvaptan Lupin.

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 Tolvaptan Lupin and affect how it works.

In particular let your doctor know if you are taking:

  • treatments containing ketoconazole, fluconazole or itraconazole for fungal infections;
  • antibiotics, such as clarithromycin, erythromycin, and ciprofloxacin;
  • rifampicin, an antibiotic;
  • medicines for the treatment of HIV, such as saquinavir, ritonavir and atazanavir;
  • medicines for high blood pressure and chest pain, such as diltiazem and verapamil;
  • medicines which increase the level of sodium in your blood or which contain large amounts of salt, like tablets that dissolve in water and indigestion remedies;
  • digoxin, a medicine for the treatment of irregular heartbeat and heart failure;
  • cyclosporin, a medicine that reduces the immune response;
  • quinidine, a medicine used for malaria;
  • dabigatran, a medicine used to thin the blood;
  • rosuvastatin and pitavastatin, medicines used to lower cholesterol;
  • methotrexate, a medicine used to treat rheumatoid arthritis;
  • sulfasalazine, a medicine used to treat inflammatory bowel disease;
  • metformin, a medicine for diabetes;
  • medicines for the treatment of epilepsy, such as phenytoin and carbamazepine;
  • St John's Wort, a traditional herbal medicinal product for the relief of slightly low mood and mild anxiety;
  • fluid tablets and other medicines used for the treatment of high blood pressure;
  • desmopressin, a medicine used to control urine output or bedwetting.

It may still be alright for you to take these medicines and Tolvaptan Lupin together. Your doctor will be able to decide what is suitable for you.

Tolvaptan Lupin with food and drink

Do not drink grapefruit juice when taking Tolvaptan Lupin.

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

4. How do I use Tolvaptan Lupin?

How much to take

  • Tolvaptan Lupin is to be taken in two different doses every day. The dose combinations are 45 mg + 15 mg or 60 mg + 30 mg or 90 mg + 30 mg.
  • One tablet of the higher dose (45 mg, 60 mg or 90 mg) should be taken in the morning upon waking, at least 30 minutes before food, and one tablet with the lower dose (15 mg or 30 mg) should be taken 8 hours later. The afternoon dose can be taken with or without food.
  • Your doctor will start with a dose combination of 45 mg in the morning and 15 mg 8 hours later and may then increase it to a maximum of 90 mg in the morning and 30 mg after 8 hours.
  • To find the best dosage for you your doctor will regularly examine whether you tolerate a prescribed dose. You should always take the highest tolerable dose combination prescribed by your doctor.
  • If you take other medicines which can increase the effects of Tolvaptan Lupin you may receive lower Tolvaptan Lupin doses.
  • Your doctor may have prescribed a different dose.
  • Follow the instructions provided and use Tolvaptan Lupin until your doctor tells you to stop.

When to take Tolvaptan Lupin

  • Tolvaptan Lupin should be taken at about the same time each day.
  • Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
  • Your first dose should be taken in the morning and your second dose approximately 8 hours later.

How to take Tolvaptan Lupin

  • Swallow the tablets without chewing, with a glass of water.
  • The morning dose should be taken at least 30 minutes before the morning meal. The second daily dose can be taken with or without food.
  • Do not chew, crush or split the tablets. To ensure you get the entire dose, the tablets should be swallowed whole without chewing or crushing.

If you forget to use Tolvaptan Lupin

Tolvaptan Lupin should be taken regularly at the same time each day. If you miss your dose at the usual time you should take the dose as soon as you remember on the same day.

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.

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 use too much Tolvaptan Lupin

If you think that you have used too much Tolvaptan Lupin, 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.

5. What should I know while using Tolvaptan Lupin?

Things you should do

MAKE SURE YOU DRINK ENOUGH WATER

  • Tolvaptan causes water loss because it increases your urine production. You may experience urine loss of between 5-7 litres per day.
  • This water loss may result in side effects such as dry mouth and thirst or even more severe side effects like kidney problems (see additional information under Section 6. Are there any side effects?). It is therefore important that you have access to water and that you are able to drink sufficient amounts when you feel thirsty.
  • Unless your doctor tells you otherwise, drink plenty of water during the day and 1 or 2 glasses before going to bed, even if you do not feel thirsty. You must also drink water after you urinate at night.
  • Exposure to prolonged heat and humidity, exercise and intercurrent illness can further increase your risk of dehydration. In these circumstances, you should drink more water or fluid to reduce your risk of dehydration.
  • Special care must be taken if you have a disease that reduces appropriate fluid intake or if you are at an increased risk of water loss, eg. in case of vomiting or diarrhoea. If this occurs stop your tolvaptan treatment and seek medical advice immediately.
  • Due to the increased urine production, it is also important that you always have access to a toilet.

Call your doctor straight away if you:

  • become pregnant while taking Tolvaptan Lupin. Your doctor will advise you on whether you should stop treatment. Do not stop treatment without first discussing it with your doctor.

Remind any doctor, dentist, anaesthetist, or pharmacist you visit that you are using Tolvaptan Lupin.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking Tolvaptan Lupin. It may affect other medicines used during surgery.

If you are about to have any blood tests, tell your doctor that you are taking Tolvaptan Lupin. It may interfere with the results of some tests.

During treatment with Tolvaptan Lupin, your doctor will arrange regular (eg. monthly) blood tests to check for changes in your liver function.

Keep all of your doctor's appointments so that your progress can be checked.

Things you should not do

  • Do not take Tolvaptan Lupin to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.

Your doctor will carefully observe you when you start Tolvaptan Lupin, especially when your dose is being increased.

Driving or using machines

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

Tolvaptan Lupin may cause side effects that can affect your ability to drive or use machines.

Tolvaptan Lupin may cause dizziness and sleepiness in some people, particularly at the beginning of treatment. If this happens to you, do not drive or use any tools or machines.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Store in a cool dry place where the temperature stays below 25°C.
  • Keep your medicine in the original container. If you take it out of its original container it may not keep well.

Follow the instructions on 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.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

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.
  • Headache.
  • Fatigue, weakness, dizziness.
  • Trouble sleeping.
  • Muscle spasms.
Bladder related:
  • Increased amount of urine.
  • Increased frequency of urination during the day and at night.
Gastrointestinal related:
  • Constipation.
  • Diarrhoea.
  • Dry mouth.
  • Indigestion.
  • Decreased appetite.
Allergy related:
  • Rash.
  • Dry skin.
  • Itching.
Pain related:
  • Painful, swollen joints.
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
Bladder related:
  • Difficulty in urination.
Allergy related:
  • Symptoms of an allergic reaction such as swelling of the face, lips or tongue, itching, generalised rash, or severe wheezing or breathlessness.
General well-being related:
  • Signs of electrolytes imbalances such as dizziness, confusion, weakness, seizures, or palpitation.
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.

Tolvaptan Lupin may cause your liver to not work properly. Therefore, please inform your doctor immediately if you have any signs that could indicate potential liver problems, such as:

  • nausea;
  • vomiting;
  • fever;
  • tiredness;
  • loss of appetite;
  • pain in the abdomen;
  • dark urine;
  • jaundice (yellowing of the skin or eyes);
  • itching of your skin;
  • joint and muscle pain with fever;

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 Tolvaptan Lupin contains

Active ingredient
(main ingredient)		Tolvaptan
Other ingredients
(inactive ingredients)		Lactose monohydrate
Maize starch
Microcrystalline cellulose
Hyprolose
Magnesium stearate
Ferric oxide
Potential allergensLactose monohydrate

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

What Tolvaptan Lupin looks like

Tolvaptan Lupin 15 mg is a pink to light pink coloured, capsule-shaped, mottled tablet debossed with “FO5” on one side and “LU” on other side.

Tolvaptan Lupin 30 mg is a pink to light pink coloured, round, flat-faced, bevelled edged, mottled tablet debossed with “FO6” on one side and “LU” on other side.

Tolvaptan Lupin 45 mg is a pink to light pink coloured, octagonal-shaped, mottled tablet debossed with “FO7” on one side and “LU” on other side.

Tolvaptan Lupin 60 mg is a pink to light pink coloured, almond-shaped, flat-faced, bevelled edged, mottled tablet debossed with “FO8” on one side and “LU” on other side

Tolvaptan Lupin 90 mg is a pink to light pink coloured, capsule-shaped, biconvex, mottled tablet debossed with “FO9” on one side and “LU” on other side

Australian Registation Numbers

Tolvaptan Lupin 15 mg: AUST R 417522

Tolvaptan Lupin 30 mg: AUST R 417527

Tolvaptan Lupin 15 mg + 45 mg combination pack: AUST R 417526

Tolvaptan Lupin 30 mg + 60 mg combination pack: AUST R 417521

Tolvaptan Lupin 30 mg + 90 mg combination pack: AUST R 417524.

Who distributes Tolvaptan Lupin

Generic Health Pty Ltd
Suite 2, Level 2
19-23 Prospect Street
Box Hill, VIC, 3128
Australia

ii1422401  [email protected]

ii1422402  +61 3 9809 7900

ii1422403  www.generichealth.com.au

This leaflet was prepared in October 2024.

Published by MIMS May 2025

BRAND INFORMATION

Brand name

Tolvaptan Lupin

Active ingredient

Tolvaptan

Schedule

S4

 

Notes

Distributed by Generic Health Pty Ltd

1 Name of Medicine

Tolvaptan.

2 Qualitative and Quantitative Composition

Tolvaptan Lupin tablets are for oral use and contain 15 mg, 30 mg, 45 mg, 60 mg or 90 mg of tolvaptan as the active ingredient.

List of excipients with known effects.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tolvaptan Lupin 15 mg.

Pink to light pink coloured, capsule shape, mottled tablet debossed with "FO5" on one side and "LU" on other side.

Tolvaptan Lupin 30 mg.

Pink to light pink coloured, round shape, flat faced bevelled mottled tablet debossed with "FO6" on one side and "LU" on other side.

Tolvaptan Lupin 45 mg.

Pink to light pink coloured, octagonal shape, mottled tablet debossed with "FO7" on one side and "LU" on other side.

Tolvaptan Lupin 60 mg.

Pink to light pink coloured, almond shaped, flat faced bevelled mottled tablet debossed with "FO8" on one side and "LU" on other side.

Tolvaptan Lupin 90 mg.

Pink to light pink coloured, capsule shape, biconvex mottled tablet debossed with "FO9" on one side and "LU" on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Tolvaptan Lupin is indicated to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adults with chronic kidney disease (CKD) stage 1 to 3 at initiation of treatment with evidence of rapidly progressing disease (see Section 5.1 Pharmacodynamic Properties).

4.2 Dose and Method of Administration

Tolvaptan Lupin treatment must be initiated and monitored under the supervision of physicians with expertise in managing ADPKD and a full understanding of the risks of tolvaptan therapy including hepatic toxicity and monitoring requirements (see Section 4.4 Special Warnings and Precautions for Use).

Dosage.

Tolvaptan Lupin is to be administered twice daily in split dose regimens of 45 mg + 15 mg, 60 mg + 30 mg or 90 mg + 30 mg. The morning dose is to be taken at least 30 minutes before the morning meal. The second daily dose can be taken with or without food. According to these split dose regimens the total daily doses are 60 mg, 90 mg or 120 mg.

Dose titration.

The initial dose is 60 mg tolvaptan per day as a split-dose regimen of 45 mg + 15 mg (45 mg taken upon waking and prior the morning meal and 15 mg taken 8 hours later). The initial dose is to be titrated upward to a split-dose regimen of 90 mg tolvaptan (60 mg + 30 mg) per day and then to a target split-dose regimen of 120 mg tolvaptan (90 mg + 30 mg) per day, if tolerated, with at least weekly intervals between titrations. Dose titration has to be performed cautiously to ensure that high doses are not poorly tolerated through overly rapid up-titration. Patients may down-titrate to lower doses based on tolerability. Patients have to be maintained on the highest tolerable tolvaptan dose.
The aim of dose titration is to block activity of vasopressin at the renal V2 receptor as completely and constantly as possible, while maintaining acceptable fluid balance, in order to achieve optimal effects on TKV progression or diminution of renal function decline. Measurements of urine osmolality are recommended to monitor the adequacy of vasopressin inhibition and, if possible, an absolute urine osmolality of less than 300 mOsm/kg should be maintained at all times (see Section 5.1 Pharmacodynamic Properties).
Also, monitoring of plasma osmolality or serum sodium (to calculate plasma osmolality) and/or body weight should be considered to monitor the risk of dehydration secondary to the aquaretic effects of tolvaptan in case of patient's insufficient water intake.
The safety and efficacy of tolvaptan in CKD stage 5 have not been adequately explored and therefore tolvaptan treatment should be discontinued if renal insufficiency progresses to CKD stage 5.
Therapy must be interrupted if the ability to drink or the accessibility to water is limited (see Section 4.4 Special Warnings and Precautions for Use). Tolvaptan must not be taken with grapefruit juice (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients must be instructed to drink sufficient amounts of water or other aqueous fluids (see Section 4.4 Special Warnings and Precautions for Use).
At the onset of symptoms or signs consistent with hepatic injury or if clinically significant abnormal ALT or AST increases are detected during treatment, Tolvaptan Lupin administration must be immediately interrupted and repeat tests including ALT, AST, BT and alkaline phosphatase (AP) must be obtained as soon as possible (ideally within 48 to 72 hours). Testing must continue at increased time frequency until symptoms/signs/laboratory abnormalities stabilise or resolve, at which point Tolvaptan Lupin may be cautiously reinitiated.
If the abnormal liver tests results are determined to be definitively related to tolvaptan therapy, restarting therapy is not recommended. However, if bilirubin, ALT and AST levels remained below the permanent discontinuation threshold, and if it is determined that tolvaptan would still be beneficial for the patient, tolvaptan therapy may be cautiously reinitiated with more frequent monitoring at the same or a lower dose.
In patients with a stable, low baseline AST or ALT, an increase above 2 times baseline, even if less than 2 times upper limit of normal, may indicate early liver injury. Such elevations may warrant treatment suspension and prompt (48 to 72 hours) re-evaluation of liver test trends prior to reinitiating therapy with more frequent monitoring.
Recommended guidelines for permanent discontinuation include:
ALT or AST > 8-times ULN;
ALT or AST > 5-times ULN for more than 2 weeks;
ALT or AST > 3-times ULN and (BT > 2-times ULN or International Normalised Ratio [INR] > 1.5);
ALT or AST > 3-times ULN with persistent symptoms of hepatic injury noted above.

Dose adjustment for patients taking strong CYP3A inhibitors.

In patients taking strong CYP3A inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), tolvaptan doses have to be reduced as follows (see Table 1).

Dose adjustment for patients taking moderate CYP3A inhibitors.

In patients taking moderate CYP3A inhibitors, tolvaptan doses have to be reduced as follows (see Table 2).
Further reductions have to be considered if patients cannot tolerate the reduced tolvaptan doses.

Dosage adjustments for patients taking CYP3A inducers.

Concomitant use of tolvaptan with strong CYP3A inducers should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Elderly population.

Increasing age has no effect on tolvaptan plasma concentrations. However, the safety and effectiveness of tolvaptan in ADPKD patients aged over 55 years has not yet been established.

Renal impairment.

Dose adjustment is not required in patients with renal impairment. No clinical trials in subjects with a creatinine clearance < 10 mL/min or in patients undergoing dialysis have been conducted. The risk of hepatic damage in patients with severely reduced renal function (i.e. eGFR < 20) may be increased; these patients should be carefully monitored for hepatic toxicity (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Hepatic impairment.

In patients with severe hepatic impairment, the benefits and risks of treatment with Tolvaptan Lupin must be evaluated carefully. Patients must be managed carefully and liver enzymes must be monitored regularly (see Section 4.4 Special Warnings and Precautions for Use).
Tolvaptan is contraindicated in patients with elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
No dose adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B).

Paediatric population.

The safety and efficacy of tolvaptan in children and adolescents has not yet been established. No data are available. Tolvaptan is not recommended in the paediatric age group.

Method of administration.

For oral use.
Tablets must be swallowed without chewing and with a glass of water.

4.3 Contraindications

Hypersensitivity to the active substance, benzazepine derivatives or to any of the excipients listed, see Section 6.1 List of Excipients.
Elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan (see Section 4.4 Special Warnings and Precautions for Use).
Volume depletion.
Anuria.
Hypernatremia.
Patients who cannot perceive or respond to thirst.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

4.4 Special Warnings and Precautions for Use

Idiosyncratic hepatic toxicity.

Tolvaptan has been associated with idiosyncratic elevations of blood alanine and aspartate aminotransferases (ALT and AST) with infrequent cases of concomitant elevations in bilirubin-total (BT).
In post-marketing experience with tolvaptan in ADPKD, acute liver failure requiring liver transplantation has been reported.
In a double-blind, placebo-controlled trial in patients with ADPKD, elevation (> 3 x upper limit of normal [ULN]) of ALT was observed in 4.4% (42/958) of patients on tolvaptan and 1.0% (5/484) of patients on placebo, while elevation (> 3 x ULN) of AST was observed in 3.1% (30/958) of patients on tolvaptan and 0.8% (4/484) patients on placebo. Two (2/957, 0.2%) of these tolvaptan treated-patients, as well as a third patient from an extension open label trial, exhibited increases in hepatic enzymes (> 3 x ULN) with concomitant elevations in BT (> 2 x ULN). The period of onset of hepatocellular injury (by ALT elevations > 3 x ULN) was within 3 to 14 months after initiating treatment and these increases were reversible, with ALT returning to < 3 x ULN within 1 to 4 months. While these concomitant elevations were reversible with prompt discontinuation of tolvaptan, they represent a potential for significant liver injury. Similar changes with other medicinal products have been associated with the potential to cause irreversible and potentially life-threatening liver injury.
Prescribing physicians must comply fully with the safety measures required below.
To mitigate the risk of significant and/or irreversible liver injury, blood testing for hepatic transaminases and bilirubin is required prior to initiation of Tolvaptan Lupin, continuing monthly for 18 months and at regular 3-monthly intervals thereafter. Concurrent monitoring for symptoms that may indicate liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, dark urine or jaundice) is recommended.
If a patient shows abnormal ALT, AST or BT levels prior to initiation of treatment which fulfil the criteria for permanent discontinuation (see below) tolvaptan treatment should not be initiated (see Section 4.3 Contraindications). In case of abnormal baseline levels below the limits for permanent discontinuation, pre-existing liver disease is likely, and treatment can only be initiated if the potential benefits of treatment outweigh the potential risks and liver function testing must continue at increased time frequency. The advice of a hepatologist is recommended.
During the first 18 months of treatment, Tolvaptan Lupin can only be supplied to patients whose physician has determined that liver function supports continued therapy.
At the onset of symptoms or signs consistent with hepatic injury or if clinically significant abnormal ALT or AST increases are detected during treatment, Tolvaptan Lupin administration must be immediately interrupted and repeat tests including ALT, AST, BT and alkaline phosphatase (AP) must be obtained as soon as possible (ideally within 48 to 72 hours). Testing must continue at increased time frequency until symptoms/signs/laboratory abnormalities stabilise or resolve, at which point Tolvaptan Lupin may be cautiously reinitiated.
If the abnormal liver tests results are determined to be definitively related to tolvaptan therapy, restarting therapy is not recommended. However, if bilirubin, ALT and AST levels remained below the permanent discontinuation threshold, and if it is determined that tolvaptan would still be beneficial for the patient, tolvaptan therapy may be cautiously reinitiated with more frequent monitoring at the same or a lower dose.
In patients with a stable, low baseline AST or ALT, an increase above 2 times baseline, even if less than 2 times upper limit of normal, may indicate early liver injury. Such elevations may warrant treatment suspension and prompt (48 to 72 hours) re-evaluation of liver test trends prior to reinitiating therapy with more frequent monitoring.
Recommended guidelines for permanent discontinuation include:
ALT or AST > 8-times ULN;
ALT or AST > 5-times ULN for more than 2 weeks;
ALT or AST > 3-times ULN and (BT > 2-times ULN or International Normalized Ratio [INR] > 1.5);
ALT or AST > 3-times ULN with persistent symptoms of hepatic injury noted above.
Because of the risk of liver injury, prescriber education and certification on the risk of liver injury and the importance of regular liver function monitoring is mandatory. These are available through the Tolvaptan Portal on the sponsor website.
Further information is available at www.generichealth.com.au or by telephone at 03 9809 7900.

Access to water.

Tolvaptan may cause adverse reactions related to water loss such as thirst, polyuria, nocturia, and pollakiuria (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, patients must have access to water (or other aqueous fluids) and be able to drink sufficient amounts of these fluids (see Section 4.2 Dose and Method of Administration). Patients have to be instructed to drink water or other aqueous fluids at the first sign of thirst in order to avoid excessive thirst or dehydration.
Additionally, patients have to drink 1 to 2 glasses of fluid before bedtime regardless of perceived thirst and replenish fluids overnight with each episode of nocturia.

Dehydration.

Volume status must be monitored in patients taking tolvaptan because treatment with tolvaptan may result in severe dehydration which constitutes a risk factor for renal dysfunction. If dehydration becomes evident, take appropriate action which may include the need to interrupt or reduce the dose of tolvaptan and increase fluid intake. Special care must be taken in patients having diseases that impair appropriate fluid intake or who are at an increased risk of water loss e.g. in case of vomiting or diarrhoea. In such circumstances patients should be advised to cease tolvaptan treatment and seek urgent medical assistance.
Patients exposed to prolonged heat, humidity, exercise and intercurrent illness will be at greater risk of dehydration.

Urinary outflow obstruction.

Urinary output must be secured. Patients with partial obstruction of urinary outflow, for example patients with prostatic hypertrophy or impairment of micturition, have an increased risk of developing acute retention.

Fluid and electrolyte balance.

Fluid and electrolyte status must be monitored in all patients. Administration of tolvaptan induces copious aquaresis and may cause dehydration and increases in serum sodium (see Section 4.8 Adverse Effects (Undesirable Effects)) and is contraindicated in hypernatraemic patients (see Section 4.3 Contraindications). Therefore, serum creatinine, electrolytes and symptoms of electrolyte imbalances (e.g. dizziness, fainting, palpitations, confusion, weakness, gait instability, hyper-reflexia, seizures, coma) have to be assessed prior to and after starting tolvaptan to monitor for dehydration.
During long-term treatment electrolytes have to be monitored at least every three months.

Serum sodium abnormalities.

Pretreatment sodium abnormalities (hyponatraemia or hypernatraemia) must be corrected prior to initiation with tolvaptan therapy.

Hyperkalemia.

Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume which could results in increased serum potassium. Serum potassium levels should be monitored carefully after initiation of tolvaptan, especially in those who are receiving drugs known to increase serum potassium levels.

Anaphylaxis.

In post-marketing experience, anaphylaxis (including anaphylactic shock and rash generalised) has been reported very rarely following administration of tolvaptan. This type of reaction occurred after the first administration of tolvaptan. If an anaphylactic reaction or other serious allergic reactions occur, administration of tolvaptan must be discontinued immediately and appropriate therapy initiated. Since hypersensitivity is a contraindication (see Section 4.3 Contraindications) treatment must never be restarted after an anaphylactic reaction or other serious allergic reactions.

Lactose.

Tolvaptan Lupin 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.

Diabetes mellitus.

Diabetic patients with an elevated glucose concentration (e.g. in excess of 300 mg/dL) may present with pseudohyponatraemia. This condition must be excluded prior and during treatment with tolvaptan.
Tolvaptan may cause hyperglycaemia (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, diabetic patients treated with tolvaptan must be managed cautiously. In particular this applies to patients with inadequately controlled type II diabetes.

Uric acid increases.

Decreased uric acid clearance by the kidney is a known effect of tolvaptan. In a double-blind, placebo-controlled trial of patients with ADPKD, potentially clinically significant increased uric acid (greater than 10 mg/dL) was reported at a higher rate in tolvaptan-patients (6.2%) compared to placebo-treated patients (1.7%). Adverse reactions of gout were reported more frequently in tolvaptan-treated patients (28/961, 2.9%) than in patients receiving placebo (7/483, 1.4%). In addition, increased use of allopurinol and other medicinal products used to manage gout were observed in the double-blind, placebo-controlled trial. Effects on serum uric acid are attributable to the reversible renal hemodynamic changes that occur in response to tolvaptan effects on urine osmolality and may be clinically relevant. However, events of increased uric acid and/or gout were not serious and did not cause discontinuation of therapy in the double-blind, placebo-controlled trial. Uric acid concentrations are to be evaluated prior to initiation of Tolvaptan Lupin therapy, and as indicated during treatment based on symptoms.

Effect of tolvaptan on glomerular filtration rate (GFR).

A reversible reduction in GFR has been observed in ADPKD trials at the initiation of tolvaptan treatment.

Use in the elderly.

Increasing age has no effect on tolvaptan plasma concentrations. However, the safety and effectiveness of tolvaptan in ADPKD patients aged over 55 years has not yet been established.

Paediatric use.

No data are available. Tolvaptan is not recommended in the paediatric age group.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other medicinal products on the pharmacokinetics of tolvaptan.

CYP3A inhibitors.

Concomitant use of medicinal products that are moderate (e.g. amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) or strong (e.g. itraconazole, ketoconazole, ritonavir, clarithromycin, saquinavir) CYP3A inhibitors increase tolvaptan exposure. Co-administration of tolvaptan and ketoconazole resulted in a 440% increase in area under time-concentration curve (AUC) and 248% increase in maximum observed plasma concentration (Cmax) for tolvaptan.
Co-administration of tolvaptan with 240 mL grapefruit juice, a moderate to strong CYP3A inhibitor, produced a doubling of peak tolvaptan concentrations (Cmax).
Dose reduction of tolvaptan is recommended for patients while taking moderate or strong CYP3A inhibitors (see Section 4.2 Dose and Method of Administration). Patients taking moderate or strong CYP3A inhibitors must be managed cautiously, in particular if the inhibitors are taken more frequently than once a day.

CYP3A inducers.

Concomitant use of medicinal products that are potent CYP3A inducers (e.g. rifampicin) will decrease tolvaptan exposure and efficacy. Co-administration of tolvaptan with rifampicin reduces Cmax and AUC for tolvaptan by about 85%. Therefore, concomitant administration of tolvaptan with potent CYP3A inducers (e.g. rifampicin, rifabutin, rifapentin, phenytoin, carbamazepine, and St. John's wort) is to be avoided.

P-gp inhibitors.

Reduction in the dose of tolvaptan may be required in patients concomitantly treated with P-glycoprotein (P-gp) inhibitors, such as cyclosporine and quinidine, based on clinical response (see Section 4.2 Dose and Method of Administration). If P-gp inhibitors also act as strong CYP3A inhibitors (e.g. ketoconazole, clarithromycin, ritonavir, saquinavir), substantial dose reduction of tolvaptan is required (see Section 4.2 Dose and Method of Administration).

Co-administration with medicinal products that increase serum sodium concentration.

There is no experience from controlled clinical trials with concomitant use of tolvaptan and hypertonic saline, oral sodium formulations, and medicinal products that increase serum sodium concentration. Medicinal products with high sodium content such as effervescent analgesic preparations and certain sodium containing treatments for dyspepsia may also increase serum sodium concentration. Concomitant use of tolvaptan with medicinal products that increase serum sodium concentration may result in a higher risk for developing hypernatraemia (see Section 4.4 Special Warnings and Precautions for Use) and is therefore not recommended.

Diuretics.

Tolvaptan has not been extensively studied in ADPKD in combination with diuretics. While there does not appear to be a synergistic or additive effect of concomitant use of tolvaptan with loop and thiazide diuretics, each class of agent has the potential to lead to severe dehydration, which constitutes a risk factor for renal dysfunction. If dehydration or renal dysfunction becomes evident, appropriate action must be taken which may include the need to interrupt or reduce doses of tolvaptan and/or diuretics and increased fluid intake. Other potential causes of renal dysfunction or dehydration must be evaluated and addressed.

Effect of tolvaptan on the pharmacokinetics of other products.

CYP3A substrates.

In healthy subjects, tolvaptan, a CYP3A substrate, had no effect on the plasma concentrations of some other CYP3A substrates (e.g. warfarin or amiodarone). Tolvaptan increased plasma levels of lovastatin by 1.3 to 1.5-fold. Even though this increase has no clinical relevance, it indicates tolvaptan can potentially increase exposure to CYP3A4 substrates.

Transporter substrates.

In vitro studies indicate that tolvaptan is a substrate and competitive inhibitor of P-gp. In vitro studies indicate that tolvaptan or its oxobutyric metabolite may have the potential to inhibit OATP1B1, OATP1B3, OAT3, BCRP and OCT1 transporters.
Steady state digoxin concentrations were increased (1.3-fold in maximum observed plasma concentration [Cmax] and 1.2-fold in area under the plasma concentration-time curve over the dosing interval [AUCτ]) when co-administered with multiple once daily 60 mg doses of tolvaptan. Patients receiving digoxin or other narrow therapeutic P-gp substrates (e.g. dabigatran) must therefore be managed cautiously and evaluated for excessive effects when treated with tolvaptan.
Statins commonly used in the tolvaptan phase 3 pivotal trial (e.g. rosuvastatin and pitavastatin) are OATP1B1 or OATP1B3 substrates, however no difference in AE profile was observed during the phase 3 pivotal trial for tolvaptan in ADPKD.
If OATP1B1 and OATP1B3 substrates (e.g. statins such as rosuvastatin and pitavastatin), OAT3 substrates (e.g. methotrexate, ciprofloxacin), BCRP substrates (e.g. sulfasalazine) or OCT1 substrates (e.g. metformin) are co-administered with tolvaptan, patients must be managed cautiously and evaluated for excessive effects of these medications.

Diuretics or non-diuretic anti-hypertensive drug(s).

Standing blood pressure was not routinely measured in ADPKD trials, therefore a risk of orthostatic/postural hypotension due to a pharmacodynamic interaction with tolvaptan cannot be excluded.

Co-administration with vasopressin analogues.

In addition to its renal aquaretic effect, tolvaptan is capable of blocking vascular vasopressin V2 receptors involved in the release of coagulation factors (e.g. von Willebrand factor) from endothelial cells. Therefore, the effect of vasopressin analogues such as desmopressin may be attenuated in patients using such analogues to prevent or control bleeding when co-administered with tolvaptan. It is not recommended to administer Tolvaptan Lupin with vasopressin analogues.

Smoking and alcohol.

Data related to smoking or alcohol history in ADPKD trials are too limited to determine possible interactions of smoking or alcohol with efficacy and safety of ADPKD treatment with tolvaptan.

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 1.9-times in males and 5.1-times in females the AUC in patients at the maximum recommended human dose [MRHD] of 120 mg per day). However, oestrus cycles were altered in rats at oral doses ≥ 300 mg/kg/day (3.8-times the clinical AUC at the MRHD).
(Category D)
Tolvaptan and/or its metabolites were shown to cross the placenta in rats and rabbits.
In rats treated with tolvaptan during organogenesis, reduced foetal weights and delayed foetal ossification occurred at an oral dose of 1000 mg/kg/day (yielding 17-times the clinical AUC at the MRHD).
Teratogenicity was noted in rabbits given 1000 mg/kg/day (7.5 times the exposure from the 120 mg/day human dose on an AUC basis). The effects were increased rates of embryo-foetal death, foetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations. These adverse effects on embryo-foetal development were observed in conjunction with maternal toxicity (reduced maternal body weight gain and food consumption) although a direct effect of the drug cannot be excluded.
No teratogenic effects were seen in rabbits at 300 mg/kg/day (about 1.25 to 2.65 times the exposure in humans at the 120 mg/day dose, based on AUC). However, increasing the dose from 300 mg/kg/day to 1000 mg/kg/day increased abortions from 1/17 to 5/18 animals.
There are no adequate data from the use of tolvaptan in pregnant women. The potential risk for humans is unknown.
Women of childbearing potential must use adequate contraceptive measures during Tolvaptan Lupin use. Tolvaptan Lupin must not be used during pregnancy (see Section 4.3 Contraindications).
 It is unknown whether tolvaptan is excreted in human breast milk. Studies in rats have shown excretion of tolvaptan in milk.
The potential risk for humans is unknown. Tolvaptan Lupin is contraindicated during breastfeeding (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Tolvaptan Lupin has minor influence on the ability to drive or use machines. However, when driving vehicles or using machines it has to be taken into account that occasionally dizziness, asthenia or fatigue may occur.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The pharmacodynamically predictable and most commonly reported adverse reactions are thirst, polyuria, nocturia and pollakiuria occurring in approximately 55%, 38%, 29% and 23% of patients, respectively. Furthermore, tolvaptan has been associated with idiosyncratic elevations of blood alanine and aspartate aminotransferases (ALT and AST) with infrequent cases of concomitant elevations in bilirubin-total (BT).

Tabulated list of adverse reactions.

The adverse reaction profile of tolvaptan in the ADPKD indication is based on the results of two clinical trials: 156-04-251 of 1,444 treated patients (961 patients treated with tolvaptan, 483 treated with placebo) and 156-13-210 of 1,366 patients (681 patients treated with tolvaptan, 685 treated with placebo), and is consistent with the pharmacology of the active substance.
Adverse reactions associated with tolvaptan obtained from ADPKD clinical studies are tabulated in Table 3 and Table 4.

Description of selected adverse reactions.

To mitigate the risk of significant or irreversible liver injury, blood testing for hepatic transaminases is required prior to initiation of Tolvaptan Lupin treatment, continuing monthly for 18 months and at regular 3-monthly intervals thereafter (see Section 4.4 Special Warnings and Precautions for Use).
The most frequent adverse reactions are related to water loss. It is therefore of greatest importance that patients have access to water and are able to drink sufficient amounts of fluids.
The volume status of patients taking tolvaptan must be monitored to prevent dehydration (see Section 4.4 Special Warnings and Precautions for Use).

Post-marketing reports.

The following adverse reactions have been reported during post-marketing surveillance of tolvaptan. The exact incidence of spontaneously reported adverse reactions is unknown: anaphylaxis; generalised rash.

Reporting suspected adverse effects.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Single oral doses up to 480 mg (4 times the maximum recommended daily dose) and multiple doses up to 300 mg once daily for 5 days have been well tolerated in trials in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst and dehydration/hypovolemia.
No mortality was observed in rats or dogs following single oral doses of 2000 mg/kg (maximum feasible dose). A single oral dose of 2000 mg/kg was lethal in mice and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia.
In patients with suspected tolvaptan overdose, assessment of vital signs, electrolyte concentrations, ECG and fluid status is recommended. Appropriate replacement of water and/or electrolytes must continue until aquaresis abates. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (> 98%).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Tolvaptan is a vasopressin antagonist: ATC code C03XA01.

Mechanism of action.

Tolvaptan is a vasopressin antagonist that specifically blocks the binding of arginine vasopressin (AVP) at the V2 receptors of the distal portions of the nephron. Tolvaptan affinity for the human V2 receptor is 1.8 times that of native AVP.

Pharmacodynamic effects.

The pharmacodynamic effects of tolvaptan have been determined in healthy subjects and subjects with autosomal dominant polycystic kidney disease (ADPKD) across chronic kidney disease (CKD) stages 1 to 4. Effects on free water clearance and urine volume are evident across all CKD stages with smaller absolute effects observed at later stages, consistent with the declining number of fully functioning nephrons. Acute reductions in mean total kidney volume were also observed following 3 weeks of therapy in all CKD stages, ranging from -4.6% for CKD stage 1 to -1.9% for CKD stage 4.
With the recommended split-dose regimens in patients with autosomal dominant polycystic kidney disease (ADPKD), tolvaptan inhibits vasopressin from binding to the V2 receptor in the kidney for the entire day, as indicated by increased urine output and decreased urine osmolality to below 300 mOsm/kg. Higher doses, e.g. 90 + 30 mg/day, reduced urine osmolality to below 300 mOsm/kg in a greater proportion of patients than the lower doses.
In healthy subjects or patients with CKD stage 1 to 4 receiving a single dose of tolvaptan, the onset of the aquaretic effects occurs within 1 to 2 hours post-dose and peaks between 4 and 8 hours post-dose. Higher doses of tolvaptan do not increase the peak effect in urine excretion rate but sustain the effect for a longer period of time. The offset of tolvaptan action is rapid with urine excretion rate returning to baseline within 24 hours following a 90 mg dose.
Increases in daily urine output in response to tolvaptan treatment are positively correlated with baseline renal function. Following a 90 + 30 mg split-dose regimen in patients with CKD stage 1 or 2, the change in mean daily urine volume was about 4 L for a mean total daily volume of about 7 L. In stage 4 patients, the mean change in daily urine volume was about 2 L for a total daily urine volume of about 5 L.

Clinical trials.

The primary focus of the clinical program for development of tolvaptan tablets for the treatment of ADPKD is a single pivotal, multinational, phase 3, randomised, placebo-controlled trial in which the long-term safety and efficacy of oral split dose tolvaptan regimens (titrated between 60 mg/day and 120 mg/day) were compared with placebo in 1,445 adult subjects with ADPKD. In total, 14 clinical trials involving tolvaptan have been completed worldwide in support of the ADPKD indication, including 8 trials in the US, 1 in the Netherlands, 3 in Japan, 1 in Korea, and the multinational phase 3 pivotal trial.
In the pivotal double-blind, 36-month, placebo-controlled, multi-centre trial (TEMPO 3:4), a total of 1,445 adult patients (age 18 to 50 years) with early, rapidly-progressing ADPKD (meeting modified Ravine criteria, total kidney volume (TKV) ≥ 750 cc, estimated creatinine clearance ≥ 60 mL/min) were randomised 2:1 to treatment with tolvaptan or placebo, respectively. A total of 1,445 patients were treated for up to 3 years, then followed for 14 to 42 days after treatment withdrawal. Randomisation was stratified based on several predictors of more rapid progression, namely baseline hypertension status, kidney volume and renal function. Other known predictors of risk of rapid progression, not used in the stratification, include a family history of ADPKD with early end-stage renal disease (ESRD) or high bilateral cyst number. All patients remained on standard concomitant medications. Concomitant use of potent cytochrome P450 CYP3A4 inhibitors was avoided. Investigational drug was up-titrated from a daily, oral split dose of 45 mg on waking plus 15 mg 9 hours later (45 mg/15 mg) weekly, as tolerated to 60 mg/30 mg then 90 mg/30 mg. Patients were to maintain the highest tolerated dose for 3 years, but could interrupt, decrease and/or increase as clinical circumstances warranted within the range of titrated doses. All patients were encouraged to drink adequate water to avoid thirst or dehydration and at night before retiring. Patients were evaluated at screening, baseline, during weekly titration steps and at intervals of at least 4 months for outcome, laboratory and safety assessments. At baseline and yearly visits, MRI-TKV and pharmacokinetic assessments were also performed. Patients who completed the study terminated treatment at 3 years, and were followed for a further period of 2 to 6 weeks to assess off-drug effects.
Tolvaptan (N=961) and placebo (N=484) groups were well matched and representative of regional populations with an average age of 39 years, with 52% being male, 84% Caucasian, 13% Asian and 3% other races. At baseline 79% had hypertension, average estimated glomerular filtration rate (eGFR) was 82 mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology formula (CKD-EPI)) and mean TKV was 1692 cc (height adjusted 972 cc/m). Using CKD-EPI eGFR, tolvaptan and placebo patients were distributed across Kidney Disease Outcomes Quality Initiative chronic kidney disease (KDOQI-CKD) stages 1 (34% and 36%), 2 (49% and 46%) and 3 (17% and 17%), respectively. Within the study population receiving placebo, stratification factors successfully predicted more rapid progression in those who had larger kidneys, lower eGFR, or hypertension at baseline. No anti-hypertensive medications were being taken by 23% of patients; in the remaining 77% of patients, 71% were taking agents acting on the renin-angiotensin system, 20% calcium channel blockers and, 18% beta blockers. Analgesics were used in 10% of patients for unspecified indications while an additional 5% of patients used these for kidney pain. Dietary restrictions for sodium, protein or caffeine were prescribed in 31%, 17% and 34% of patients, respectively.
The primary endpoint (TKV slope) was the intergroup difference for rate of change of TKV normalised as a percentage. TKV increased in the tolvaptan group at a rate of 2.80% per year (95% confidence interval [CI], 2.5% to 3.1%) compared with 5.51% per year (95% CI, 5.1% to 6.0%) for placebo representing a 49.2% reduction in growth rate averaged over 3 years (p < 0.0001).
Pre-specified secondary end-points were tested sequentially. The key secondary composite endpoint (ADPKD progression) was time to multiple clinical progression events of: 1) worsening kidney function (defined as a persistent [reproduced over at least 2 weeks] 25% reduction in reciprocal serum creatinine during treatment (from end of titration to last on-drug visit); 2) medically significant kidney pain (defined as requiring prescribed leave, last-resort analgesics, narcotic and anti-nociceptive, radiologic or surgical interventions); 3) worsening hypertension (defined as a persistent increase in blood pressure category or an increased anti-hypertensive prescription); 4) worsening albuminuria (defined as a persistent [reproduced at 2 of 3 successive assessments] increase in albumin/creatinine ratio category).
The relative rate of ADPKD-related events was decreased by 13.5% in tolvaptan-treated patients, (44 vs. 50 events; hazard ratio, 0.87; 95% CI, 0.78 to 0.97; p=0.0095).
The result of the key secondary composite endpoint is primarily attributed to effects on worsening kidney function and medically significant kidney pain. The renal function events were 61.4% less likely for tolvaptan compared with placebo (2 events per 100 person-years of follow-up in the tolvaptan group vs. 5 in the placebo group; hazard ratio, 0.39; 95% CI, 0.26 to 0.57; nominal p < 0.0001, see Figure 1), while renal pain events were 35.8% less likely in tolvaptan-treated patients (5 events per 100 person-years of follow-up in the tolvaptan group vs. 7 in the placebo group; hazard ratio, 0.64; 95% CI, 0.47 to 0.89; nominal p = 0.007, see Figure 1). In contrast, there was no effect of tolvaptan on either progression of hypertension or albuminuria.
The next sequentially ordered secondary endpoint of slope of kidney function decline was assessed as change in estimated glomerular filtration rate (eGFR-CKD EPI) during treatment (from end of titration to last on-drug visit). The tolvaptan-treated patients had a 26.4% reduction in the rate of renal function decline compared with placebo (-2.7 mL/min/1.73 m2 versus -3.7 mL/min/1.73 m2, p < 0.0001, Figure 2). Figure 2 represents slope of renal function for tolvaptan (solid) and placebo (dashed) change from end of titration baseline (i.e. end of week 3). Box plots derived from mixed effect model repeat measurement (MMRM) analyses to each indicated 12-month visit with 5th, 25th, mean, 75th and 95th percentiles of change from end of titration for tolvaptan (grey) and placebo (white) groups.
Subgroup analysis of all endpoints above (change in TKV, key composite [including time to worsening of kidney function and time to medically significant kidney pain] and change in slope of decline in renal function) demonstrated consistent efficacy (directional) in all pre-specified subgroups, including those stratified by age, gender, race, geographical location, baseline hypertension, baseline eGFR and baseline TKV.
Patients were not genotyped to separate into ADPKD type 1 and 2 and it is not known whether tolvaptan has comparable efficacy in these subgroups.
The Phase 3, multi-centre, international, randomised-withdrawal, placebo-controlled, double-blind trial 156-13-210 (REPRISE) compared the efficacy and safety of tolvaptan (45 to 120 mg/day) to placebo in later stage ADPKD (CKD stage 2 to 4). A total of 1,370 patients (age 18 to 65) were randomised to either tolvaptan (n = 683) or placebo (n = 687) and were treated for a period of 12 months. Approximately 5%, 75% and 20% had an eGFR 60 mL/min/1.73 m2 or greater (CKD stage 2), or less than 60 mL/min/1.73 m2 and greater than 30 mL/min/1.73 m2 (CKD stage 3) or less than 30 mL/min/1.73 m2 but greater than 15 mL/min/1.73 m2 (CKD stage 4), respectively.
The primary endpoint of the trial was the change in estimated glomerular filtration rate (eGFR) from pre-treatment baseline levels to post-treatment assessment. In patients treated with tolvaptan the reduction in eGFR was significantly less than in patients treated with placebo (p < 0.0001).
The treatment difference in eGFR change observed in this trial is 1.27 mL/min/1.73 m2, representing a 35% reduction in the loss of kidney function compared to placebo over the course of one year (see Table 5).
The key secondary endpoint was a comparison of the efficacy of tolvaptan treatment versus placebo in reducing the decline of annualised eGFR slope across all measured time points in the trial. These data also showed statistically significant benefit from tolvaptan vs. placebo (p < 0.0001) (see Table 6).
Pre-specified subgroup analyses of the primary endpoint showed a beneficial effect of tolvaptan across subgroups that were defined according to sex, baseline estimated GFR, stage of chronic kidney disease (except for stage 2) and geographic region, as well as in the subgroups of patients who were 55 years of age or younger and patients who were white.
The pre-specified subgroup analysis was inconclusive in the smaller sample size subgroups of patients who were non-white, or who were older than 55 years of age, a subgroup which also had a notably slower rate of eGFR decline. The prespecified analysis was not significant for patients who had chronic kidney disease of stage 2 due to the limited sample size in REPRISE trial.
Safety results were consistent with the known safety profile based on previous tolvaptan clinical trials.
In a long-term, open-label, multi-centre dose ranging phase 2 trial (TEMPO 2:4) in 46 adult patients (age 18 to 50 years) with ADPKD (meeting modified Ravine criteria and an estimated GFR ≥ 30 mL/min) patients were titrated in weekly intervals for the first 4 weeks among split doses of 30 mg/15 mg (down-titration to 15 mg/15 mg allowed for tolerability) to 90 mg/30 mg, then maintained at their maximal tolerated dose (MTD) through Month 2 (Titration Period). Following a determination of final long-term dosing regimens based on objective criteria (trough spot urine osmolality < 300 mOsm/kg, median tolerability) using data from the Titration Period, patients were randomly allocated to a fixed high dose regimen (60 mg/30 mg) and fixed low dose regimen (45 mg/15 mg) for up to Month 36 (Fixed-dose Period). All patients discontinued treatment at the end of this phase of the trial and after a period of 4 to 6 months had an option to enter an Extension Period of treatment for an additional 12 months.
All 46 of the patients who entered the Titration Period were treated in the Fixed-dose Period, including 22 patients in the tolvaptan 45 mg/15 mg group and 24 patients in the tolvaptan 60 mg/30 mg group. Over the course of 36 to 48 months of open-label tolvaptan treatment, 39/46 patients (84.8%) completed the 36-month portion of the trial and 35/35 patients (100%) completed the 12-month Extension. At Month 36, TKV increased from baseline in both groups, with a higher mean (SD) percent increase seen in the tolvaptan 45 mg/15 mg group (9.86% [11.81%]) compared with the tolvaptan 60 mg/30 mg group 5.06% [9.77%]; nominal p = 0.0553). The mean (SD) annual rate of change from pre-dose baseline in creatinine clearance estimate by Cockcroft-Gault equation (eCrCLCG) was -2.17 (14.45) mL/min/year in the tolvaptan 45 mg/15 mg group and -0.450 (4.86) mL/min/year in the tolvaptan 60 mg/30 mg group. Upon withdrawal from treatment, TKV increased at higher rates than while on treatment. Upon resumption of treatment, in the extension phase rates of TKV growth again slowed (see Figure 3). These results support that patients treated with higher doses of tolvaptan have a greater treatment effect and that continued treatment is required to maintain benefits and provided support for the dosing recommendations in the pivotal trial discussed above.
Data are not currently available to show whether long-term therapy with tolvaptan continues to slow the rate of renal function decline and affect clinical outcomes of ADPKD, including delay in the onset of end-stage renal disease.

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%.
Co-administration of tolvaptan with a high-fat meal increased peak concentrations of tolvaptan up to 2-fold but left AUC unchanged. Even though the clinical relevance of this finding is not known, to minimise the unnecessary risk of increasing the maximal exposure the morning dose should be taken under fasted conditions (see Section 4.2 Dose and Method of Administration).
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.

Metabolism.

Tolvaptan is extensively metabolised in the liver almost exclusively by CYP3A. Tolvaptan is a weak CYP3A4 substrate and does not appear to have any inhibitory activity.
In vitro studies indicated that tolvaptan has no inhibitory activity for CYP3A. Fourteen metabolites have been identified in plasma, urine and faeces; all but one were also metabolised by CYP3A. Only the oxobutyric acid metabolite is present at greater than 10% of total plasma radioactivity; all others are present at lower concentrations than tolvaptan.
Tolvaptan metabolites have little to no contribution to the pharmacological effect of tolvaptan; all metabolites have no or weak antagonist activity for human V2 receptors when compared with tolvaptan.

Excretion.

The terminal elimination half-life is about 8 hours and steady-state concentrations of tolvaptan are obtained after the first dose.
Less than 1% of intact active substance is excreted unchanged in the urine. Radio labelled 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%).

Linearity.

Following single oral doses, Cmax values show less than dose proportional increases from 30 mg to 240 mg and then a plateau at doses from 240 mg to 480 mg, AUC increases linearly.
Following multiple once daily dosing of 300 mg, tolvaptan exposure was only increased 6.4-fold when compared to a 30 mg dose. Based on calculations from 4 different studies in split-dose regimens of 30 mg, 60 mg and 120 mg/day in ADPKD patients, tolvaptan exposure (AUC) increases approximately linearly.

Pharmacokinetics in special populations.

Elderly.

Clearance of tolvaptan is not significantly affected by age.

Hepatic dysfunction.

The effect of mildly or moderately impaired hepatic function (Child-Pugh classes A and B) on the pharmacokinetics of tolvaptan was investigated in 87 patients with liver disease of various origins. For single doses of 10 mg to 60 mg, Cmax and AUC∞ increase linearly with dose. Although mean Cmax values for 30 mg and 60 mg doses do not appear to be much higher compared to healthy subjects, 1.07 to 1.65-fold, AUC values are 1.56 to 2.75-fold higher. Following multiple dosing (QD, 13 days) tolvaptan concentrations also appear to accumulate 1.7 to 1.6-fold. Clearance following a single dose is about half that of healthy subjects and following multiple dosing is about a third that of healthy subjects. Very limited information is available in patients with severe hepatic impairment (Child-Pugh class C).
In a population pharmacokinetic analysis in patients with hepatic oedema, AUC of tolvaptan in severely (Child-Pugh class C) and mildly or moderately (Child-Pugh classes A and B) hepatic impaired patients were 3.1 and 2.3 times higher than that in healthy subjects.

Renal dysfunction.

In a population pharmacokinetic analysis for patients with ADPKD, tolvaptan concentrations were increased, compared to healthy subjects, as renal function decreased below eGFR of 60 mL/min/1.73 m2. An eGFRCKD-EPI decrease from 72.2 mL/min/1.73 m2 to 9.79 mL/min/1.73 m2 was associated with a 32% reduction in total body clearance.

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 (rats 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 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 clinical exposure to tolvaptan. However, negative findings in genotoxicity assays and the absence of pre-neoplastic 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

Inactive ingredients include maize starch, hyprolose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and ferric oxide as colorant.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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. Store in original container.
Protect from light and moisture.

6.5 Nature and Contents of Container

The following pack sizes and configurations are available:
Tolvaptan Lupin 15 mg tablets are available in a PVC/Aluminium blister in packs of 7 or 28 tablets.
Tolvaptan Lupin 30 mg tablets are available in a PVC/Aluminium blister in packs of 7 or 28 tablets.
Tolvaptan Lupin combination pack of 15 mg + 45 mg tablets are available in a PVC/Aluminium foil blister in packs of 56 tablets.
Tolvaptan Lupin combination pack of 30 mg + 60 mg tablets are available in a PVC/Aluminium foil blister in packs of 56 tablets.
Tolvaptan Lupin combination pack of 30 mg + 90 mg tablets are available in a PVC/Aluminium foil blister in packs of 56 tablets.
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 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.

Chemical structure.


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

CAS number.

150683-30-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes