Consumer medicine information

Detrusitol

Tolterodine tartrate

BRAND INFORMATION

Brand name

Detrusitol

Active ingredient

Tolterodine tartrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Detrusitol.

SUMMARY CMI

DETRUSITOL®

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 taking DETRUSITOL?

DETRUSITOL contains the active ingredient tolterodine tartrate. DETRUSITOL is used to treat symptoms of an overactive bladder, for example urinary frequency, urgency or incontinence.

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

2. What should I know before I take DETRUSITOL?

Do not take if you have ever had an allergic reaction to DETRUSITOL 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 DETRUSITOL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DETRUSITOL 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 DETRUSITOL?

  • The usual dose is 1 mg or 2 mg twice daily. Your doctor will prescribe the dose that is right for you.
  • Take your medicine at about the same time each day.

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

5. What should I know while taking DETRUSITOL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking DETRUSITOL.
  • Tell your doctor if symptoms of your overactive bladder do not improve, or if they become worse.
Things you should not do
  • Do not stop taking your medicine or lower the dosage unless your doctor tells you to, even if you are feeling better.
  • Do not take DETRUSITOL to treat any other complaints unless your doctor tells you to.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how DETRUSITOL affects you. DETRUSITOL may cause dizziness and blurred vision in some people.
Drinking alcohol
  • Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, dizziness may be worse.
Looking after your medicine
  • Keep your tablets in the blister until it is time to take them.
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.
  • Keep it where young children cannot reach it.

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

6. Are there any side effects?

Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you: dry mouth; heartburn; headache; constipation, stomach pain or diarrhoea; dry eyes; nausea; tiredness; swollen ankles.

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: swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing; dizziness or confusion; fits; fast heartbeat or palpitations; shortness of breath and swelling of the feet or legs; blurred vision; difficulty or pain in urinating (passing water); hallucinations (seeing, hearing or feeling things that are not really there).

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.



FULL CMI

DETRUSITOL®

Active ingredient(s): tolterodine tartrate

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking DETRUSITOL?

DETRUSITOL contains the active ingredient tolterodine tartrate. DETRUSITOL belongs to a group of medicines called antispasmodics. It helps to control the release of urine by reducing spasm, and relaxing the smooth muscle of the bladder wall. It also increases the storage volume of the bladder, and can act on the brain to delay the desire to urinate.

DETRUSITOL is used to treat symptoms of an overactive bladder, for example urinary frequency, urgency or incontinence.

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

This medicine is not addictive.

Do not give DETRUSITOL to children.

Safety and effectiveness of DETRUSITOL in children have not been established.

2. What should I know before I take DETRUSITOL?

Warnings

Do not take DETRUSITOL if:

  • you are allergic to tolterodine, any of the ingredients listed at the end of this leaflet or any other similar medicines.
    Always check the ingredients to make sure you can take 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.
  • you are unable to pass urine
  • you have a blocked gastro-intestinal tract or other gastro-intestinal disorders (ulcerative colitis, toxic megacolon)
  • you have uncontrolled high pressure in the eye (narrow angle glaucoma)
  • you have a disease of the muscles causing drooping eyelids, double vision, difficulty in speaking and swallowing and sometimes muscle weakness in the arms or legs (myasthenia gravis)

Do not take DETRUSITOL after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking DETRUSITOL, talk to your doctor.

Check with your doctor if you:

  • you have allergies to any other medicines, foods, preservatives or dyes
  • you have or have had any of the following medical conditions:
    - kidney or liver problems
    - heart problems
    - problems with urine retention
    - intestinal blockage or other intestinal or stomach problems
    - autonomic neuropathy (a nerve problem which sometimes occurs with diabetes and can lead to diarrhoea, impotence or low blood pressure)
    - hiatus hernia (a part of the stomach protrudes through the diaphragm, causing belching and heart burn)
    - severe constipation
    - raised pressure in the eye(s)
  • take any medicines for any other condition.

If you have not told your doctor or pharmacist about any of the above, tell them before you start to take DETRUSITOL.

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.

Your doctor will discuss the risks and benefits of taking DETRUSITOL during pregnancy.

Do not take DETRUSITOL if you are breastfeeding.

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

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 DETRUSITOL and affect how it works. These include:

  • some medicines used to treat depression, such as: fluoxetine, amitriptyline
  • certain medicines used to treat irregular heart beats: flecainide, quinidine, procainamide, disopyramide, sotalol, amiodarone
  • some antifungals: fluconazole, ketoconazole, itraconazole, miconazole
  • some antibiotics: erythromycin, clarithromycin
  • cisapride, a medicine used to treat heartburn/reflux and related intestinal disorders
  • metoclopramide, a medicine used to treat nausea and gastric retention
  • tranquillisers, such as: haloperidol, chlorpromazine, thioridazine, pimozide
  • anti-proteases, medicines used to treat HIV infection, such as: ritonavir, indinavir
  • droperidol, a medicine used to prevent or reduce nausea and vomiting.

You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking DETRUSITOL.

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

4. How do I take DETRUSITOL?

How much to take

  • The usual dose is 1 mg or 2 mg twice daily.
  • Your doctor will prescribe the dose that is right for you.
  • Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.
  • If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

When to take DETRUSITOL

  • Take your medicine at about the same time each day.
    Taking DETRUSITOL at the same time each day will have the best effect. It will also help you remember when to take it.
  • It does not matter if you take DETRUSITOL before or after food.

How to take DETRUSITOL

  • Swallow the tablets whole with a full glass of water.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

Your doctor should re-assess your condition at regular intervals, for example after 6 months, to determine how long you need to keep taking DETRUSITOL for.

If you forget to take DETRUSITOL

DETRUSITOL should be taken regularly at the same time each day. If you miss your dose at the usual time and it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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 DETRUSITOL

If you think that you or anyone else have taken too much DETRUSITOL, urgent medical attention may be needed.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26 and New Zealand telephone 0800 POISON or 0800 764 766) for advice, 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.

The symptoms of taking too much DETRUSITOL may include shortness of breath, fits, fast heart beat, inability to pass urine, dilated pupils, feeling excited or hallucinations.

5.What should I know while taking DETRUSITOL?

Things you should do

  • If symptoms of your overactive bladder do not improve, or if they become worse, tell your doctor.
  • If you are about to start taking any new medicine, remind your doctor and pharmacist that you are taking DETRUSITOL.
  • If you become pregnant while taking DETRUSITOL, tell your doctor.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking DETRUSITOL. It may affect other medicines used during surgery.
  • Always discuss with your doctor any problems or difficulties during or after taking DETRUSITOL.

Remind any doctor, dentist or pharmacist you visit that you are taking DETRUSITOL.

Things you should not do

  • Do not take DETRUSITOL 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 or their symptoms seem similar to yours.
  • Do not stop taking your medicine or lower the dosage unless your doctor tells you to, even if you are feeling better.

Driving or using machines

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

DETRUSITOL may cause dizziness and blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol, dizziness may be worse.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Looking after your medicine

  • Keep your tablets in the blister until it is time to take them. If you take the tablets out of the blister they may not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.

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.

Heat and dampness can destroy some medicines.

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.

Getting rid of any unwanted medicine

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

Do not take this medicine after the expiry date.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking DETRUSITOL.

This medicine helps most people with an overactive bladder, but it may have unwanted side effects in a few people. 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.

Do not be alarmed by the following lists of possible side effects. You may not experience any of them.

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
  • Dry mouth
  • Heartburn
  • Headache
  • Constipation, stomach pain or diarrhoea
  • Dry eyes
  • Nausea
  • Tiredness
  • Swollen ankles
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • Dizziness or confusion
  • Fits
  • Fast heartbeat or palpitations
  • Shortness of breath and swelling of the feet or legs
  • Blurred vision
  • Difficulty or pain in urinating (passing water)
  • Hallucinations (seeing, hearing or feeling things that are not really there)
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.

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 or New Zealand at nzphvc.otago.ac.nz/reporting. 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 DETRUSITOL contains

Active ingredient
(main ingredient)		tolterodine tartrate 1 mg or 2 mg per tablet
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • calcium hydrogen phosphate dihydrate
  • sodium starch glycollate
  • magnesium stearate
  • silica colloidal anhydrous
  • hypromellose
  • stearic acid
  • titanium dioxide

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

What DETRUSITOL looks like

DETRUSITOL 1 mg tablet is a white, round, biconvex, film-coated tablet, engraved with arcs above and below the letters "TO" (AUST R 99393).

DETRUSITOL 2 mg tablet is a white, round, biconvex, film-coated tablet, engraved with arcs above and below the letters "DT" (AUST R 99394).

DETRUSITOL tablets are available in blister packs of 56 tablets.

Who distributes DETRUSITOL

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

Distributed in New Zealand by:

Viatris Ltd
PO Box 11-183
Ellerslie
AUCKLAND
www.viatris.co.nz
Telephone 0800 168 169

This leaflet was prepared in July 2024.

DETRUSITOL® is a Viatris company trade mark

DETRUSITOL_cmi\Jul24/00

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Detrusitol

Active ingredient

Tolterodine tartrate

Schedule

S4

 

1 Name of Medicine

Tolterodine tartrate.

2 Qualitative and Quantitative Composition

Detrusitol tablets contain the active substance tolterodine tartrate, a competitive muscarinic receptor antagonist.
Detrusitol tablets 1 mg, contain 1 mg of tolterodine tartrate as the active ingredient.
Detrusitol tablets 2 mg, contain 2 mg of tolterodine tartrate as the active ingredient.

3 Pharmaceutical Form

Tablet, film coated.
The 1 mg tablet is white, round, biconvex, film-coated, engraved with arcs above and below the letters "TO".
The 2 mg tablet is white, round, biconvex film-coated, engraved with arcs above and below the letters "DT".

4 Clinical Particulars

4.1 Therapeutic Indications

Detrusitol is indicated for the treatment of patients with overactive bladder with symptoms of urinary frequency, urgency or incontinence or any combination of these symptoms.

4.2 Dose and Method of Administration

The recommended oral dose for tolterodine tablets is 2 mg twice daily. The dose may be lowered to 1 mg twice daily based on individual response and tolerability. For patients with significantly reduced hepatic function or severely impaired renal function (GFR ≤ 30 mL/min), the recommended dose is 1 mg twice daily (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant administration with potent CYP3A4 inhibitors is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Cytochrome P450 3A4 inhibitors).
After 6 months the need for further treatment should be considered.

4.3 Contraindications

Detrusitol is contraindicated in patients with urinary retention; gastric retention; uncontrolled narrow angle glaucoma; myasthenia gravis; severe ulcerative colitis; toxic megacolon. Detrusitol is also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

4.4 Special Warnings and Precautions for Use

Bladder outflow obstruction.

Detrusitol should be used with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

Gastrointestinal disorders.

Detrusitol should be used with caution in patients with gastrointestinal obstructive disorders, such as pyloric stenosis and in patients with autonomic neuropathy, hiatus hernia or decreased gastrointestinal motility.

Narrow angle glaucoma.

Detrusitol should be used with caution in patients being treated for narrow angle glaucoma.

Visual disturbance.

Patients should also be informed that antimuscarinic agents may produce blurred vision or dizziness.

Cardiac function.

As with other drugs in this class, caution should be used in patients with known risk factors for QT prolongation (i.e. congenital or documented acquired QT prolongation, hypokalaemia, hypomagnesaemia, hypocalcaemia, bradycardia, concurrent administration of drugs known to prolong the QT interval (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Drugs which prolong the QT/QTc interval) and relevant pre-existing cardiac diseases (i.e. myocardial ischaemia, arrhythmia, congestive heart failure, cardiomyopathy). (See Section 5.1 Pharmacodynamic Properties, Non-clinical QT interval data.)

Use in hepatic impairment.

Patients with significantly reduced hepatic function should not receive doses of Detrusitol greater than 1 mg twice daily. (See Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations.)

Use in renal impairment.

Patients with severe renal impairment should not receive doses of Detrusitol greater than 1 mg twice daily. The potential toxicological effects of metabolites should be taken into account when exposing patients with severe renal impairment (especially poor metabolisers) to repeated doses of tolterodine. (See Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations.)

Use in the elderly.

Of the 1,120 patients who were treated in the four phase III, 12 week clinical studies of Detrusitol, 474 (42%) were 65 to 91 years of age. No overall differences in safety were observed between the older and younger patients.

Paediatric use.

The safety and effectiveness of Detrusitol in paediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concomitant medication with other drugs that possess anticholinergic properties may result in more pronounced therapeutic effect and side effects. Conversely, the therapeutic effect of tolterodine may be reduced by concomitant administration of muscarinic cholinergic receptor agonists. The effect of prokinetics like metoclopramide and cisapride may be decreased by tolterodine.
Clinical drug interaction studies have shown that:

Fluoxetine.

Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor of cytochrome P450 2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics of tolterodine and its metabolites, it was observed that fluoxetine significantly inhibited the metabolism of tolterodine in extensive metabolisers, resulting in a 4.8-fold increase in tolterodine AUC. However, DD01 showed a 52% decrease in Cmax and a 20% decrease in AUC. Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be EMs of tolterodine to resemble the pharmacokinetic profile in poor metabolisers. The sums of unbound serum concentrations of tolterodine and DD01 are 25% higher during the interaction. However, no dose adjustment is required when Detrusitol and fluoxetine are coadministered.

Other drugs metabolised by P450 2D6.

Detrusitol is not expected to influence the pharmacokinetics of drugs that are metabolised by P450 2D6, such as flecainide and tricyclic antidepressants; however, the potential effect of tolterodine on the pharmacokinetics of these drugs has not been formally evaluated.

Warfarin.

In healthy volunteers, coadministration of Detrusitol 2 mg twice daily for 7 days and a single dose of warfarin 25 mg on day 4 had no effect on prothrombin time, Factor VII suppression or on the pharmacokinetics of warfarin.

Oral contraceptives.

Detrusitol 2 mg twice daily has no effect on the pharmacokinetics of an oral contraceptive (ethinyloestradiol 30 mg; levonorgestrel 150 mg) as evidenced by the monitoring of ethinyloestradiol and levonorgestrel over a 2 month cycle in healthy female volunteers.

Diuretics.

Coadministration of tolterodine up to 4 mg twice daily for up to 12 weeks with diuretic agents, such as indapamide, hydrochlorothiazide, triamterene, bendrofluazide, chlorothiazide, methyclothiazide or frusemide, did not cause any adverse electrocardiographic (ECG) effects in patients with overactive bladder.

Cytochrome P450 3A4 inhibitors.

In both poor metabolisers (PM) and extensive metabolisers (EM), cytochrome P450 3A4 is involved as the primary metabolising enzyme (PM) or secondary metabolising enzyme (EM). In the presence of ketoconazole, the mean Cmax and AUC of tolterodine increased 1.9 and 2.2-fold, respectively, in poor metabolisers and the half-life of tolterodine increased by 50%. Based on these findings, other potent CYP3A4 inhibitors may also increase serum concentrations of tolterodine.
Therefore, concomitant administration with potent CYP3A4 inhibitors, such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole, itraconazole and miconazole) and antiproteases (ritonavir and indinavir), is not recommended.

Drugs which prolong the QT/QTc interval.

There is no satisfactory information on the concurrent use of tolterodine with drugs known to prolong the QT/QTc interval. In the absence of such information on these combinations the potential risk of pathological QT/QTc prolongation resulting in arrhythmias cannot be ruled out. Drugs known to prolong the QT/QTc interval include erythromycin, quinidine, procainamide, disopyramide, sotalol, amiodarone, cisapride, fluconazole, amitriptyline, haloperidol, chlorpromazine, thioridazine, pimozide, droperidol. (Also see Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical QT interval data.)

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In female mice treated for 2 weeks before mating and during gestation with 20 mg/kg/day (corresponding to AUC value of about 500 microgram.hour/L), neither effect on reproductive performance or fertility nor any anomalies or malformations were seen. Based on AUC values, the systemic exposure was about 15-fold higher in animals than in humans. In male mice, a dose of 30 mg/kg/day did not induce any adverse effects on fertility.
(Category B3)
In mice, tolterodine has been shown to cause embryolethality, reduce foetal weight and increase the incidence of foetal abnormalities (cleft palate, digital abnormalities, intra-abdominal haemorrhage and various skeletal abnormalities, primarily reduced ossification) when given at doses of greater than 20 mg/kg/day. At this dose, the AUC value was about 15-fold higher than in humans. Rabbits treated subcutaneously with the maximum possible dose (0.8 mg/kg/day) achieved an AUC of 100 microgram.hour/L, which is about three-fold higher than that resulting from the human dose. This dose did not result in any embryotoxicity or teratogenicity.
There are no studies of tolterodine in pregnant women. Therefore, Detrusitol should be used during pregnancy only if the potential benefit for the mother justifies the potential risk for the foetus.
 It is not known whether tolterodine is excreted in human milk. Administration of Detrusitol should, therefore, be discontinued during nursing.

4.7 Effects on Ability to Drive and Use Machines

Since this drug may cause accommodation disturbances and influence reaction time, the ability to drive and use machines may be negatively affected. Patients should be advised to exercise caution.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The clinical program for Detrusitol comprised 2,398 patients who were treated with either Detrusitol (n = 1,619), oxybutynin (n = 349) or placebo (n = 430). No differences in the safety profile of tolterodine were identified based on age, gender, race or metabolism. A total of 1,120 patients were treated in four phase III, 12 week, controlled clinical studies with either Detrusitol 2 mg twice daily (n = 474), Detrusitol 1 mg twice daily (n = 121), oxybutynin 5 mg three times daily (n = 349), or placebo (n = 176). These four studies form the basis for the main evaluation of safety and are discussed below.
The percentage of patients reporting any adverse event in the 12 week studies was similar for Detrusitol 2 mg twice daily (75.5%), Detrusitol 1 mg twice daily (74.4%) and placebo (77.8%). The incidence of serious adverse events was similar among treatment groups (Detrusitol 1 and 2 mg twice daily, 3.7%; placebo, 3.4%). Dry mouth was the most frequently reported adverse event across all treatment groups. The only other adverse events reported that are considered to be dose related or treatment related (present in 1% of patients in either Detrusitol treatment group and that occurred at an incidence of at least twice the rate observed for placebo) were dyspepsia, headache, constipation and xerophthalmia. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention and xerophthalmia are all expected side effects of antimuscarinic agents. The incidence of confusion among patients treated with Detrusitol twice daily was 0.6%.
Discontinuation of treatment due to adverse events in the 12 week studies was reported for 8.0% of patients treated with Detrusitol 2 mg twice daily, 5.7% of the patients treated with placebo and 1.7% of the patients treated with Detrusitol 1 mg twice daily. The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment for all treatment groups.
Table 1 lists the adverse events reported in ≥ 1% of the patients treated with Detrusitol 1 mg or 2 mg twice daily in the 12 week studies. The relationship to study medication for most of these events is uncertain; many are thought to represent spontaneous events reported by patients with bladder dysfunction (and other concomitant diseases) and are not necessarily causally related to Detrusitol.

Postmarketing experience.

The following adverse events have been reported in association with tolterodine use.

Body as a whole.

Anaphylactoid reactions, including angioedema (very rare).

Central and peripheral nervous systems.

Dizziness (common), convulsions (rare), memory impairment (uncommon).

Cardiovascular.

Tachycardia, palpitations (rare), cardiac failure (very rare). There has been no substantive evidence of torsades de pointes attributable to tolterodine in postmarketing experience following administration to approximately 8 million patients.

Gastrointestinal tract.

Diarrhoea (common), gastroesophageal reflux (uncommon).

Skin.

Flushed skin (uncommon).

General.

Mild to moderate oedema (uncommon).

Psychiatric.

Disorientation (not known), confusion (not known), hallucinations (rare).
Common: ≥ 1 and < 10%; uncommon: ≥ 0.1 and < 1%; rare: ≥ 0.01 and < 0.1%; very rare: < 0.01%.

Other events.

In view of the pharmacological activity of this product, the following events may develop: paralytic ileus, ileus and gastrointestinal obstruction.
Cases of aggravation of symptoms of dementia (e.g. confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia.

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

The highest dose of tolterodine given to human volunteers was 12.8 mg as single dose. The most severe adverse events observed were accommodation disturbances and micturition difficulties. Overdosage with tolterodine can potentially result in severe central antimuscarinic effects. These effects may be delayed and cyclical.
A 27 month old child who ingested five to seven Detrusitol 2 mg tablets was treated with a suspension of activated charcoal and was hospitalised overnight with symptoms of dry mouth. The child fully recovered.
Treatment of overdosage with Detrusitol should consist of activated charcoal. Activated charcoal is usually most effective when administered within 1 hour of ingestion, however this may be successful even if delayed as anticholinergics slow GI motility. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. Ipecac induced emesis is not recommended, and dialysis is not likely to be of benefit as tolterodine is highly protein bound.
Treatments for symptoms of overdosage are recommended as follows. For severe central anticholinergic effects (hallucinations, severe excitation), an anticholinesterase agent, such as physostigmine, may be used. If excitation and convulsions occur, administer an anticonvulsant, such as diazepam. Patients with respiratory insufficiency should be given artificial respiration. Patients with tachycardia may be treated with a beta-blocker. Those with urinary retention may be catheterised. Patients with troublesome mydriasis may be placed in a dark room and/or treated with pilocarpine eye drops. Overdosage with Detrusitol may prolong the QTc interval, therefore, in the event of overdosage, ECG monitoring is recommended and standard supportive measures for managing QT prolongation should be adopted.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors.
After oral administration, tolterodine is metabolised in the liver, resulting in the formation of the 5-hydroxymethyl derivative (DD01), a major pharmacologically active metabolite. The DD01 metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and DD01 exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels.
The main effects of tolterodine on urodynamic parameters at 1 and 5 hours after administration, as determined in healthy volunteers, were an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with an antimuscarinic action on the lower urinary tract.

Non-clinical QT interval data.

Tolterodine, its 5-hydroxymethyl metabolite (DD01), and its N-dealkylated metabolite have been shown to prolong action potential duration (90% repolarisation) in canine Purkinje fibres (14 to 75 times therapeutic Cmaxunbound) and block the K+ current in cloned human ether-a-go-go-related gene (hERG) channels (0.5 to 10 times therapeutic Cmaxunbound). In dogs, prolongation of the QT interval has been observed after application of tolterodine and its human metabolites at 3 to 42 times therapeutic Cmaxunbound. The clinical relevance of these findings is unknown. (See Section 4.4 Special Warnings and Precautions for Use.)

Clinical trials.

Detrusitol tablets were evaluated for the treatment of patients with an overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence, or any combination of these symptoms in four 12-week controlled studies (study numbers 008, 009, 010 and 015). Two studies (008 and 010) compared Detrusitol 2 mg twice daily (N=227) with oxybutynin 5 mg three times daily (N=230) and placebo (N=113). A third study (009) compared Detrusitol 1 mg (N=123) and 2 mg (N=129) twice daily and placebo (N=64). The fourth study (015) compared Detrusitol 2 mg twice daily (N=120) and oxybutynin 5 mg three times daily (N=120). The primary efficacy end point in these studies was the mean number of micturitions per 24 hours; secondary end points were the mean number of incontinence episodes per 24 hours, and the mean volume of urine voided per micturition. After 12 weeks of treatment, Detrusitol was shown to be significantly more effective than placebo in two of the three placebo-controlled studies in reducing the mean number of micturitions per 24 hours, and in all three placebo-controlled studies in increasing the mean volume voided per micturition (see Table 2).
None of the individual placebo-controlled studies demonstrated a statistically significant reduction in the number of incontinence episodes per 24 hours, when comparing Detrusitol with placebo. However, when pooled analyses for these studies were conducted, Detrusitol was significantly more effective than placebo. None of the placebo-controlled studies showed significant subjective improvement in bladder function from patient questionnaires.
In the three active comparator studies, Detrusitol and oxybutynin were equivalent in the reduction of mean number of micturitions per 24 hours and mean number of incontinence episodes per 24 hours. Significant improvement was seen after 2 weeks of treatment with Detrusitol, with further improvement up to 8 weeks of treatment; this therapeutic effect was sustained for up to 12 months of treatment.

Clinical QT interval data.

A post-hoc pooled analysis of ECG data from 13 phase I-III clinical studies was conducted to assess the effect of tolterodine on QT interval. There were 102/468 (21.8%) patients in the tolterodine group who developed an increase in corrected QT interval of ≥ 30 ms compared with 18/141 (12.8%) in the placebo group. No subject experienced a QTc interval exceeding the potentially clinically relevant threshold of 500 ms. No case of torsades de pointes was reported in this analysis, or in any of the tolterodine clinical studies. (Also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Drugs which prolong the QT/QTc interval; Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience.)

5.2 Pharmacokinetic Properties

Absorption.

Tolterodine is rapidly absorbed and reaches its maximum serum concentrations 1-2 hours after dose administration. The average peak serum concentration increases proportionally in the dose interval 1 to 4 mg. Food intake increases the bioavailability of tolterodine (average increase 53%) but does not affect the levels of DD01 in EM. This change is not expected to be a safety concern and adjustment of dose is not needed.

Distribution.

Tolterodine is highly bound to plasma proteins, primarily α1-acid glycoprotein. Unbound concentrations of tolterodine average 3.7% over the concentration range achieved in clinical studies. DD01 is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4%. The blood to serum ratio of tolterodine and DD01 averages 0.6 and 0.8 respectively, indicating that these compounds do not distribute extensively into erythrocytes. The volume of distribution of tolterodine following administration of a 1.28 mg intravenous dose is 113 ± 26.7 L.

Metabolism.

Tolterodine is extensively metabolised by the liver following oral dosing. The primary metabolic route involves the oxidation of the 5-methyl group and is mediated by the isoenzyme cytochrome P450 2D6 leading to the formation of the pharmacologically active metabolite DD01. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for 51% ± 14% and 29% ± 6.3%, respectively, of the metabolites recovered in the urine.
A subset (about 7%) of the population is devoid of the drug-metabolising isoenzyme cytochrome P450 2D6, responsible for the formation of the 5-hydroxymethyl metabolite DD01 of tolterodine. The identified pathway of metabolism for these individuals, referred to as 'poor metabolisers' (PM), is dealkylation via cytochrome P450 3A4 to N-dealkylated tolterodine. The remainder of the population is referred to as 'extensive metabolisers'.
Pharmacokinetic studies revealed that tolterodine is metabolised at a slower rate in poor metabolisers than in extensive metabolisers. This results in significantly higher serum concentrations of tolterodine and in negligible concentrations of DD01. Because of differences in the protein-binding characteristics of tolterodine and DD01, the sum of unbound serum concentrations of tolterodine and DD01 is similar in extensive and poor metabolisers at steady state. Since tolterodine and DD01 have similar antimuscarinic effects, the net activity of Detrusitol tablets is expected to be similar in extensive and poor metabolisers. (Also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Cytochrome P450 3A4 inhibitors.)

Excretion.

The primary route of elimination for tolterodine is by hepatic metabolism.
Following administration of a 5 mg oral dose of [14C]-tolterodine to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in faeces. Less than 1% (< 2.5% in poor metabolisers) of the dose was recovered as intact tolterodine and 5% to 14% (< 1% in poor metabolisers) was recovered as the active DD01 metabolite. Most of the radioactivity was recovered in the first 24 hours, which is consistent with the apparent half-life of tolterodine: 1.9 to 3.7 hours in pharmacokinetic studies.
A summary of mean (± standard deviation) pharmacokinetic parameters of tolterodine and DD01 in EMs and PMs is provided in Table 3. These data were obtained following single and multiple doses of tolterodine 4 mg administered daily to 16 healthy male subjects (8 EM, 8 PM).

Pharmacokinetics in special populations.

Age.

In phase I multiple-dose studies in which tolterodine 2 mg was administered twice daily, serum concentrations of tolterodine and of DD01 were similar in healthy elderly volunteers (aged 64 through 80 years) and healthy young volunteers (aged less than 40 years). In another phase I study, elderly volunteers (aged 71 through 81 years) were given tolterodine 1 or 2 mg twice daily. Mean serum concentrations of tolterodine and DD01 in these elderly volunteers were approximately 20% and 50% higher, respectively, than reported in young healthy volunteers. However, no overall differences were observed in safety between older and younger patients in phase III, 12-week, controlled clinical studies; and therefore, no dosage adjustment is recommended (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Paediatric.

The pharmacokinetics of tolterodine have not been established in paediatric patients.

Gender.

Pharmacokinetic data from three Phase I clinical studies (Studies 022, 024, and 028) in which a tolterodine dose of 2 mg was administered in the fasting state were analysed with respect to gender. The pharmacokinetics of tolterodine and DD01 are not influenced by gender. Mean Cmax of tolterodine (1.6 microgram/L in males versus 2.2 microgram/L in females) and DD01 (2.2 microgram/L in males versus 2.5 microgram/L in females) are similar in males and females who were administered tolterodine 2 mg. Mean AUC values of tolterodine (6.7 microgram.hour/L in males versus 7.8 microgram.hour/L in females) and DD01 (10 microgram.hour/L in males versus 11 microgram.hour/L in females) are also similar. The elimination half-life of tolterodine for both males and females is 2.4 hours, and the half-life of DD01 is 3.3 hours in males and 3.0 hours in females.

Race.

Differences among races regarding metabolic capacity can be assumed to be of a quantitative nature and are probably less than the thoroughly documented difference between extensive and poor metabolisers. The few non-Caucasians included do not show a different pharmacokinetic profile of tolterodine or DD01.

Renal insufficiency.

The mean exposure of unbound tolterodine and its 5-hydroxymethyl metabolite is doubled in patients with severe renal impairment (inulin clearance GFR ≤ 30 mL/min). The plasma levels of other metabolites were markedly increased in these patients and individual levels 9 to 30-fold higher than placebo were observed. A 60-fold higher level of one metabolite was observed in one patient with poor metabolism. The clinical relevance of the increased exposure of these metabolites is unknown. There is no data in mild to moderate renal impairment. Patients with severe renal impairment should not receive doses of greater than 1 mg twice daily (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic insufficiency.

As might be predicted from a drug in which hepatic metabolism is the primary route of elimination, liver impairment can significantly alter the disposition of tolterodine. In a study of cirrhotic patients, elimination half-life of tolterodine was longer in cirrhotic patients (mean, 8.7 hours) than in healthy, young and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered tolterodine was substantially lower in cirrhotic patients (1.1 ± 1.7 L/h.kg) than in the healthy volunteers (5.7 ± 3.8 L/h.kg). Patients with significantly reduced hepatic function should not receive doses of greater than 1 mg twice daily (see Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Carcinogenicity studies with tolterodine were conducted in mice and rats. At the maximum tolerated dose in mice (30 mg/kg/day), female rats (20 mg/kg/day), and male rats (30 mg/kg/day), AUC values obtained for tolterodine were 355, 291, and 462 microgram.hour/L, respectively. In comparison, the human AUC value for a 2 mg dose administered twice daily is estimated at 34 microgram.hour/L in extensive metabolisers and 209 microgram.hour/L in poor metabolisers. Thus, tolterodine exposure in the carcinogenicity studies was 9 to 14 fold higher than expected in humans with extensive metabolism and 1.4 to 2.2 fold higher in poor metabolisers. No increase in tumours was found in either mice or rats.

Carcinogenicity.

No mutagenic effects of tolterodine were detected in a battery of in vitro tests, including bacterial mutation assays (Ames test) in four strains of Salmonella typhimurium and in two strains of Escherichia coli, a gene mutation assay in L5178Y mouse lymphoma cells, and chromosomal aberration tests in human lymphocytes. Tolterodine was also negative in vivo on the bone marrow micronucleus test in the mouse.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet also contains the following ingredients: microcrystalline cellulose, calcium hydrogen phosphate dihydrate, sodium starch glycollate, magnesium stearate, colloidal anhydrous silica, hypromellose, stearic acid, and titanium dioxide.

6.2 Incompatibilities

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 degrees Celsius.

6.5 Nature and Contents of Container

Detrusitol tablets 1 mg and 2 mg are supplied in the following forms:
Blister pack containing: 14, 28, 56 and 140 tablets.

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

Tolterodine tartrate is a white, odourless, crystalline powder. It is sparingly soluble in water, soluble in methanol, slightly soluble in ethanol and practically insoluble in toluene. The solubility in water has a minimum at pH 3 to 3.5, where the solubility is 4.7 mg/mL.

Chemical structure.

Non-proprietary name: tolterodine tartrate.
Chemical name: (R)-N,N-diisopropyl-3- (2-hydroxy- 5-methylphenyl)-3- phenylpropanamine L-hydrogen tartrate.
Tolterodine has one chiral centre, and it is obtained as a pure (+)-isomer by fractional crystallisation as the L-tartaric acid salt with a molecular formula C26H37NO7 and a molecular weight of 475.58. The structural formula of tolterodine tartrate is:

CAS number.

124937-52-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription medicine.

Summary Table of Changes