Consumer medicine information

NOCDURNA

Desmopressin

BRAND INFORMATION

Brand name

Nocdurna

Active ingredient

Desmopressin

Schedule

What is in this leaflet

This leaflet answers some common questions about NOCDURNA. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking NOCDURNA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What NOCDURNA is used for

NOCDURNA contains the active ingredient desmopressin (as desmopressin acetate). Desmopressin is a synthetic version of vasopressin, a naturally occurring substance produced in the brain.

Like vasopressin, NOCDURNA works in the kidney as an antidiuretic, which reduces the amount of urine that is produced. NOCDURNA is used to treat adults who need to get up to urinate at night (nocturia) at least two or more times, regardless of lifestyle changes (e.g. before bedtime drink only enough to satisfy thirst; and avoid alcohol and caffeine-containing beverages).

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor's prescription.

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before you take NOCDURNA

When you must not take it

Do not take NOCDURNA if you have an allergy to:

any medicine containing desmopressin or any of the ingredients listed at the end of this leaflet.

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.

Do not take this medicine if you:

suffer from polydipsia (excessive thirst and increased fluid intake) or psychogenic polydipsia (psychologically caused increased thirst and increased fluid intake)
where you are in the habit of drinking large amounts of fluid
have cardiac insufficiency (heart failure in which the heart is not able to pump enough blood throughout the body resulting in shortness of breath, swelling of the feet or legs due to fluid build-up)
have any disease requiring treatment with diuretics (water or fluid tablets)
have moderately or severely reduced kidney function (kidney disease where little or no urine is passed)
have or have had hyponatraemia (low sodium level in the blood)
have cognitive impairment (e.g. diagnosed dementia)
have or have had or are at risk of having SIADH (hormone secretion disorder where there is an overproduction of a hormone causing fluid retention, resulting in weakness, tiredness or confusion)
have a condition which causes excessive release of vasopressin from the brain
have a condition which is associated with fluid or salt imbalance (abnormal electrolytes), such as nausea, eating disorders, chronic vomiting or diarrhoea, a condition of the adrenal glands (adrenal insufficiency).

Do not breast-feed if you are taking this medicine. The active ingredient in NOCDURNA passes into breast milk. Therefore this medicine is not recommended while you are breast-feeding.

Do not give this medicine to children. NOCDURNA is only for use in adults.

Do not take this medicine after the expiry date 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 this medicine, talk to your doctor.

Before you start to take it

Before NOCDURNA treatment is started, lifestyle changes which may contribute to the production of excess urine at night should be considered. Discuss with your doctor what lifestyle changes may be appropriate for you to make (e.g. before bedtime drink only enough to satisfy thirst; and avoid alcohol and caffeine-containing beverages).

NOCDURNA can cause low sodium levels (hyponatraemia) due to excessive fluid build-up in the body. It is important that your doctor checks your sodium levels before you start taking NOCDURNA.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you:

are over 65 years or you feel frail (see 'Things to be aware of').
have kidney disease
have diabetes mellitus (sugar diabetes)
have diabetes insipidus (a condition in which the pituitary does not produce antidiuretic hormone)
have a known allergy to vasopressin
have severe bladder dysfunction and problems urinating
have liver disease
have heart or blood vessel disease, high blood pressure (hypertension)
have high blood pressure during pregnancy (pre-eclampsia)
have systemic infections or fever
have cystic fibrosis.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

NOCDURNA should only be given to a pregnant woman if the benefits of treatment outweigh the risks.

Your doctor can discuss with you the risks and benefits involved.

It is recommended that you do not breast-feed while taking NOCDURNA.

If you have not told your doctor about any of the above, tell him/her before you start taking NOCDURNA.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop. Some medicines and NOCDURNA may interfere with each other.

It is especially important you tell your doctor if you are taking:

tricyclic antidepressants, which are medicines used to treat e.g. depression (such as clomipramine, imipramine, desipramine)
selective serotonine reuptake inhibitors (SSRIs), which are medicines used to treat e.g. depression or anxiety (such as citalopram, paroxetine, sertraline)
chlorpromazine, which is an anti-psychotic medicinal product used to treat e.g. schizophrenia
diuretics (water or fluid tablets such as thiazides or loop diuretics e.g. frusemide or other types of diuretics)
carbamazepine, which is used to treat e.g. bipolar disorder and epilepsy
antidiabetic medicinal products used for type II diabetes (medicines in the sulfonylurea group), particularly chlorpropamide
medicines used to treat high blood pressure and some other conditions (ACE inhibitors or angiotensin receptor blockers e.g. enalapril, perindopril, irbesartan etc.)
non-steroidal anti-inflammatory drugs (NSAIDs), which are medicinal products used for the treatment of pain and inflammation (e.g. aspirin and ibuprofen)
oxytocin, which is a medicinal product used in childbirth
lithium, which is used to treat e.g. bipolar disorder
loperamide, which is a medicinal product used for the treatment of diarrhoea.

These medicines may be affected by NOCDURNA or may affect how well it works. They may also cause fluid build-up in the body and low sodium levels in the blood, which can make you unwell and is potentially serious.

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 to avoid while taking this medicine.

How to take NOCDURNA

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 pack, ask your doctor or pharmacist for help.

How to take it

When it is time for your dose:

Completely remove the end tab of a blister strip by tearing along the perforations, starting from the corner with the hand symbol.
Now remove one blister from the strip by tearing along the perforations.

Remove the foil on each blister, starting at the corner with the printed arrow, by peeling off the foil in the direction of the arrow. Do not push the tablet through the foil.
Carefully take a tablet out of its blister. Place the tablet under the tongue and allow it to dissolve. Do not chew or swallow the tablet.
If a tablet breaks into more than two pieces while you are taking it out of its blister, do not take the broken pieces. Take a tablet from another blister.

You must limit fluid intake to a minimum from 1 hour before taking NOCDURNA until 8 hours after taking NOCDURNA (see 'Things to be careful of'). If you experience any of the following symptoms the treatment should be stopped and your doctor contacted: headache, nausea/vomiting, weight gain and, in severe cases, convulsions (see "When you must not take it").

If you are restarting treatment with NOCDURNA, you must go back to following these fluid intake instructions. In addition, when you restart NOCDURNA, your doctor may again choose to closely monitor the sodium levels in your blood.

Please read the package insert that comes with NOCDURNA prior to use.

How much to take

Women: 25 micrograms daily, one hour before bedtime.

Men: 50 micrograms daily, one hour before bedtime

NOCDURNA is placed under the tongue where it dissolves without the need for water.

When to take it

Take NOCDURNA sublingual wafer 1 hour before bedtime.

NOCDURNA should not be taken with food, since the effect may be reduced.

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.

Treatment should only be interrupted or stopped on advice of your doctor.

If you forget to take it

Skip the missed dose. Do not take a double dose to make up for the forgotten dose. Continue taking the tablets as usual on the next day.

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 (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much NOCDURNA. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include confusion, drowsiness, continuing headache, nausea or vomiting, rapid weight gain due to a build-up of water in the body, or in severe cases, convulsions.

While you are using NOCDURNA

Things you must do

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

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

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

If you become pregnant while taking this medicine, tell your doctor immediately.

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

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests before and after you start treatment with NOCDURNA to make sure that it is safe for you.

Things you must not do

Do not take NOCDURNA to treat any other complaints unless your doctor tells you to do so.

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. If you stop taking it suddenly, your condition may worsen.

Things to be careful of

Restrict drinking fluids from one hour before taking NOCDURNA until at least eight hours after NOCDURNA administration.

If you need to drink fluids over this period, drink no more than a few sips of water or other fluids.

A high fluid intake over this period can increase the chance of fluid overload, which can make you feel unwell and is potentially serious.

Remember to drink normally during the day. This is very important in order to prevent dehydration during daytime.

Things to be aware of

Before your doctor prescribes NOCDURNA for you, you may need to complete a bladder diary, which will involve measuring how much you drink and how much urine you produce over 2 days. This will help to determine whether your nocturia is caused by an overproduction of urine at night (nocturnal polyuria) or not. You may also be required to complete other tests to rule out other causes.

Your doctor will also need to monitor the level of sodium in your blood before starting treatment, during the first week (4-8 days), one month after you start taking NOCDURNA, and then every 3-6 months or possibly when your other medications are changed or there is a change in your health.

If your sodium levels are found to be too low, your doctor may advise that you stop taking NOCDURNA.

Your doctor or pharmacist can give you more information concerning the above measures.

Side effects

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

This medicine helps most people with nocturia, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical attention if you get some of the side effects.

If you are over 65 years of age or you are female you may be at an increased risk of side effects.

This risk is further increased if you are 75 years or older or if you feel frail.

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

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice the following and it worries you:

dry mouth.

This is the most common side effect of your medicine. It is usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

headache
dizziness
diarrhoea
generally feeling unwell
muscle cramps
stomach (abdominal) pain or discomfort
constipation.

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

nausea or vomiting
rapid weight gain (which may be due to a build-up of water in the body)
severe or prolonged headache
confusion
decreased consciousness
weakness (fatigue)
swelling of hands, ankles or feet (peripheral oedema)
convulsions.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using NOCDURNA

Storage

Keep NOCDURNA sublingual wafers in their original container in order to protect from moisture and light, until it is time to take them. If you store them out of the blister pack they may not keep well.

Keep NOCDURNA sublingual wafers in a cool dry place where the temperature stays below 25°C.

Do not store NOCDURNA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

NOCDURNA 25 microgram sublingual (under the tongue) wafers are white, round wafers marked with 25 on one side.

NOCDURNA 50 microgram sublingual (under the tongue) wafers are white, round wafers marked with 50 on one side.

NOCDURNA comes in boxes of 10 or 30 sublingual wafers. Each carton contains 1 or 3 aluminium blister trays with 10 sublingual wafers per blister tray.

Do not use this product if the packaging appears damaged in any way. Do not take the wafers if they appear different from the descriptions above or if they look different in any way.

Ingredients

NOCDURNA contains either 25 micrograms or 50 micrograms of desmopressin (desmopressin acetate) as the active ingredient, and the following inactive ingredients:

gelatin
mannitol
citric acid.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

NOCDURNA is supplied in Australia by:

Ferring Pharmaceuticals Pty Ltd
Suite 2, Level 1, Building 1
20 Bridge Street
Pymble NSW 2073
Australia.

AUST R 263596 -
NOCDURNA 25 microgram sublingual wafers

AUST R 264292 -
NOCDURNA 50 microgram sublingual wafers

This leaflet was prepared in November 2016.

#40805-v2H

NOCDURNA® is a registered trademark of Ferring B.V.

® = Registered trademark

Published by MIMS March 2017

BRAND INFORMATION

Brand name

Nocdurna

Active ingredient

Desmopressin

Schedule

1 Name of Medicine

Desmopressin (as acetate).

2 Qualitative and Quantitative Composition

Nocdurna contains 25 micrograms or 50 micrograms of desmopressin (as acetate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sublingual wafer.

Nocdurna 25.

White, round, sublingual wafer marked with '25' on one side.

Nocdurna 50.

White, round, sublingual wafer marked with '50' one one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Nocdurna is indicated for the treatment of nocturia due to idiopathic nocturnal polyuria in adults who awaken two or more times each night to void and have not responded to lifestyle measures.
Nocturnal polyuria should be confirmed on the basis of a 24 hour urine frequency-volume diary. It is defined as > 33% of urine passed overnight. Secondary causes of nocturia should be excluded (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

4.2 Dose and Method of Administration

Women.

25 micrograms daily, one hour before bedtime, administered sublingually without water.

Men.

50 micrograms daily, one hour before bedtime, administered sublingually without water.

Method of administration.

Nocdurna is placed under the tongue where it dissolves without the need for water.
Nocdurna should be discontinued if the serum sodium level falls below the lower limit of normal range (135 mmol/L) (see Section 4.4 Special Warnings and Precautions for Use).
In the event of signs or symptoms of water retention and/or hyponatraemia (e.g. headache, nausea/vomiting, weight gain, and, in severe cases, convulsions) treatment should be interrupted and reassessed (see Section 4.4 Special Warnings and Precautions for Use).
Food intake may reduce the intensity and duration of the antidiuretic effect at low doses of desmopressin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Nocdurna should be used under the guidance of physicians familiar with the diagnosis and management of nocturia and the use of desmopressin. Treatment should only be initiated after Contraindications, secondary causes of polyuria and bladder outlet obstruction has been considered. Monitoring of serum sodium is recommended (see Section 4.4 Special Warnings and Precautions for Use). If treatment with Nocdurna does not result in evidence of a therapeutic benefit after 1 month, treatment should be discontinued.

Special populations.

Use in the elderly.

The risk of hyponatraemia increases with age; the risk/benefit balance of treatment beyond the age of 65 years should be carefully considered.
Elderly patients are at increased risk of developing hyponatraemia with desmopressin treatment and may also have impaired renal function. Caution should therefore be exercised in this age group and daily doses above 25 micrograms for females and 50 micrograms for males should not be used.

Renal impairment.

Nocdurna is contraindicated in patients with moderate and severe renal insufficiency (see Section 4.3 Contraindications).

Hepatic impairment.

No dose adjustment is needed for patients with hepatic impairment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Paediatric.

Nocdurna is only indicated in adults.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed, see Section 6.1 List of Excipients.
Habitual or psychogenic polydipsia (resulting in a urine production exceeding 40 mL/kg/24 hours).
A history of known or suspected cardiac insufficiency and other conditions requiring treatment with diuretics.
Moderate and severe renal insufficiency (creatinine clearance below 50 mL/min or an eGFR below 45 mL/min/1.73 m²).
Known history of hyponatraemia.
Patients with cognitive impairment who may not be expected to comply with the fluid intake restriction recommendations when taking Nocdurna (see Section 4.4 Special Warnings and Precautions for Use).
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and conditions that predispose the patient to SIADH.
Conditions associated with abnormal electrolyte such as nausea, eating disorders, chronic vomiting or diarrhoea, adrenal insufficiency, nephropathy.

4.4 Special Warnings and Precautions for Use

Nocdurna can cause hyponatraemia due to fluid overload.
Risk factors include age ≥ 65 years; underlying medical problems such as heart failure, renal impairment, peripheral oedema, SIADH; history of hyponatraemia; cognitive impairment; psychogenic or habitual polydipsia.
Nocdurna must only be used when contraindications, comorbidities and secondary causes of nocturnal polyuria have been excluded.
Monitoring of serum sodium is recommended (see Sodium monitoring below).
Nocdurna treatment should only be considered when nocturnal polyuria has been established as the primary cause of nocturia. Nocturnal polyuria should be diagnosed on the basis of a bladder diary and 24 hour urine output. Comprehensive assessment for causes and comorbidities prior to prescribing should also occur. Investigations may include blood examination (sodium, renal function, liver function, blood glucose, calcium, osmolality), cardiac examination, urine microscopy and culture.
Polyuria due to diabetes mellitus, diabetes insipidus, hypercalcaemia and renal disease should be excluded. Polyuria needs to be differentiated from urinary frequency with low volume urine output, such as due to bladder disorders, as Nocdurna will not be effective in these disorders. Severe bladder dysfunction and outlet obstruction should be considered before starting treatment.
Lifestyle modifications which may contribute to nocturia should be addressed before Nocdurna treatment and continued during treatment (e.g. before bedtime drink only enough to satisfy thirst; and avoid alcohol and caffeine containing beverages).
The risk of hyponatraemia increases with age and increasing dose of desmopressin. It is important that conditions such as cardiac failure, renal impairment and use of medications that may decrease serum sodium are screened for prior to commencing Nocdurna.
Fluid intake must be limited to a minimum from 1 hour before administration until the next morning (at least 8 hours) after administration. Treatment without a concomitant reduction of fluid intake may lead to prolonged fluid retention and/or hyponatraemia with or without accompanying warning signs and symptoms (headache, nausea/vomiting, weight gain, and, in severe cases, convulsions).

Sodium monitoring.

All patients should receive a single baseline sodium determination before starting Nocdurna and additional monitoring of sodium during the first week of treatment (4-8 days) and again at one month.
Sodium should be measured every 3 to 6 months and/or when medications are altered or the patient's clinical condition changes.
Treatment is not recommended if serum sodium is less than 135 mmol/L at baseline and should be discontinued if at any time the serum sodium level falls below this value. Treatment with Nocdurna should be interrupted and reassessed during acute intercurrent illnesses characterised by fluid and/or electrolyte imbalance (such as systemic infections, fever, and gastroenteritis) or during any hospitalisation.
Caution is required in cases of cystic fibrosis, coronary heart disease, hypertension, chronic renal disease and pre-eclampsia.
Extreme caution is required with concomitant use of the following medications: diuretics, ACE inhibitors, NSAID and lithium.

Use in the elderly.

The risk of hyponatraemia increases with age; the risk/benefit balance of treatment beyond the age of 65 years should be carefully considered. Particular care with selecting appropriate patients and sodium level monitoring should be exercised when considering Nocdurna for patients aged greater than 75 years. Treatment of frail elderly patients is not recommended.

Paediatric use.

Nocdurna is only indicated in adults.

Effects on laboratory tests.

Prior to treatment with Nocdurna, all patients should have serum sodium within the normal range.

4.5 Interactions with Other Medicines and Other Forms of Interactions

See Table 1.

Pharmacokinetic interactions.

Concomitant treatment with loperamide may result in a 3-fold increase of desmopressin plasma concentrations, which may lead to an increased risk of water retention/hyponatraemia. Although not investigated, other drugs slowing intestinal transport might have the same effect. Should concomitant treatment with loperamide be initiated, sodium monitoring should be undertaken at baseline, 4-8 days, 1 month, every 3 to 6 months, depending on clinical need and if dose of loperamide is adjusted.
It is unlikely that desmopressin will interact with drugs affecting hepatic metabolism, since desmopressin has been shown not to undergo significant metabolism following incubation with human liver microsomes and not to inhibit CYP450 isozymes in in vitro studies. However, formal in vivo interaction studies with coadministered drugs that interact with CYP450 enzymes have not been performed with Nocdurna.
In a double blind randomised clinical study, the efficacy and safety of combination therapy with Nocdurna and tolterodine extended release capsules was investigated for the treatment of overactive bladder with nocturia in women, for a period of 3 months. Forty-nine (49) subjects were exposed to a combination of Nocdurna 25 micrograms and tolterodine 4 mg. No serious adverse events were observed in this study and the safety profile of the combination treatment was similar to the safety profile of Nocdurna 25 micrograms. The efficacy in terms of reduction from baseline in mean number of nocturnal voids during 3 months treatment was numerically greater in the combination therapy group versus tolterodine monotherapy group (treatment contrast, -0.34 voids) in full analysis set, and the difference reached statistical significance (p = 0.049) with a treatment contrast of -0.41 voids in the per protocol analysis set.
A standardised 27% fat meal significantly decreased absorption (rate and extent) of desmopressin tablets. No significant effect was observed with respect to pharmacodynamics (urine production or osmolality). Food intake may reduce the intensity and duration of the antidiuretic effect at low oral doses of desmopressin tablet.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A study with desmopressin in rats showed no impairment of fertility in male or female animals at subcutaneous doses up to 200 micrograms/kg/day. In vitro analysis of human cotyledon models have shown that there is no transplacental transport of desmopressin when administered at therapeutic concentrations corresponding to the recommended dose.
(Category B1)
Caution should be exercised when prescribing to pregnant women.
Data on a limited number (n = 53) of exposed pregnancies in women with diabetes insipidus as well as data on a limited number of exposed pregnancies in women with bleeding complications (n = 216) indicate no adverse effects of desmopressin on pregnancy or on the health of the fetus/newborn child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development.
Embryofetal development studies performed with desmopressin in rats and rabbits given subcutaneous doses up to 50 nanogram/kg/day and 200 micrograms/kg/day, respectively, and in rats given intravenous doses up to 241 micrograms/kg/day, revealed no evidence for a harmful effect on the fetus.
Results from analyses of milk from nursing mothers receiving high dose desmopressin acetate (300 micrograms intranasal) indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, adverse effects of Nocdurna include dizziness which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The incidences of treatment emergent adverse events (≥ 2%) recorded in each arm of the phase III Nocdurna clinical trials are reported in Table 2.

Description of selected adverse reactions.

The most serious adverse reaction that could result from the antidiuretic effects of desmopressin is hyponatraemia. The clinical manifestations of hyponatraemia include headache, nausea, vomiting, weight increase, malaise, abdominal pain, muscle cramps, dizziness, confusion, decreased consciousness and in severe cases convulsions and coma. The hyponatraemia is an antidiuretic effect, arising from increased water reabsorption by the renal tubules and osmotic dilution of plasma. In studies of adult subjects with nocturia treated with desmopressin, those who developed low serum sodium did so usually within the first month of commencing treatment. Special attention should be paid to the precautions raised, see Section 4.4 Special Warnings and Precautions for Use.
Females have a higher risk of hyponatraemia which may be due to increased sensitivity of the kidney tubules to vasopressin and its analogues in women compared with men. The risk of this is minimised by recommendation of a lower dose in women. The risk of hyponatraemia in the over 65 years age group is further reduced by monitoring of serum sodium in this age group (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Tabulated list of adverse reactions.

Table 3 shows the frequencies of adverse reactions reported. The frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 to < 1/100).

Postmarketing experience.

The following adverse reactions have been identified during postapproval use of desmopressin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Desmopressin has been marketed worldwide since 1972 in several formulations, including intranasal, intravenous, and oral formulations for the treatment of diabetes insipidus and primary nocturnal enuresis. These oral formulations are available at much higher doses than Nocdurna.
The most frequently reported adverse reactions for oral formulations of desmopressin are as follows.

Electrolytes.

Hyponatraemia.

Gastrointestinal disorders.

Abdominal pain, vomiting, nausea.

Nervous system.

Headache, convulsions.

Skin.

Rash/urticaria.

Sensitivity/resistance.

Lack of effect.

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

4.9 Overdose

Overdose of Nocdurna leads to a prolonged duration of action with an increased risk of water retention and hyponatraemia.

Treatment.

Treatment of hyponatraemia should be individualised. Treatment should include discontinuing desmopressin and instigating fluid restriction and symptomatic treatment, if needed.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: vasopressin and analogues.
ATC code: H01B A02.

Mechanism of action.

Nocdurna contains desmopressin, a synthetic analogue of naturally occurring antidiuretic hormone arginine vasopressin (AVP). Desmopressin mimics vasopressin's antidiuretic effect, binding to the V₂ receptors in the renal collecting tubules of the kidneys, causing reabsorption of water into the body. This reabsorption in turn decreases night-time urine production. Due to the proposed low gender specific doses (25 micrograms for females and 50 micrograms for males), and the limited duration of action of Nocdurna, the antidiuretic activity is limited to the night-time sleep period.

Pharmacodynamic effects.

In study CS29, the weight corrected Nocdurna dose that induced 50% maximum achievable drug effect on nocturnal urine volume differed significantly between females and males. The estimated exposure value for males was 2.7-fold (95% CI: 1.3-8.1) higher than the value for females to obtain an identical dynamic effect, corresponding to higher desmopressin sensitivity among females. The development of hyponatraemia is dose dependent. Females are at higher risk of developing hyponatraemia than males. The incidence of hyponatraemia rises with increasing dose and with increasing age (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Clinical trials.

The studies CS40 (conducted in females) and CS41 (conducted in males) had similar overall designs using the same coprimary and secondary clinical endpoints, investigating change from baseline over 3 months of treatment.
The studies included patients ≥ 18 years of age with at least 2 nocturnal voids every night in a consecutive 3 day period during the screening period. Patients with evidence of severe daytime voiding dysfunction were excluded, as were those with interstitial cystitis, chronic prostatitis/chronic pelvic pain syndrome, suspicion of bladder outlet obstruction (BOO) or urine flow < 5 mL/sec, surgical treatment, including transurethral resection, for BOO or benign prostatic hyperplasia within the past 6 months, urinary retention or a postvoid residual volume in excess of 250 mL, habitual or psychogenic polydipsia, central or nephrogenic diabetes insipidus, syndrome of inappropriate antidiuretic hormone, current or a history of urologic malignancies, genitourinary tract pathology, detrusor overactivity, suspicion or evidence of cardiac failure, uncontrolled hypertension, uncontrolled diabetes mellitus, hyponatraemia, renal insufficiency, hepatic and/or biliary diseases, a history of obstructive sleep apnoea, previously treated with desmopressin for nocturia, and on concomitant treatment with any prohibited medication (e.g. loop diuretics).
Randomisations for studies CS40 and CS41 were stratified by equal split according to patients under 65 years of age and patients 65 years of age and over; the median ages were 63 and 64 years, respectively. The adjusted mean changes in nocturnal voids from baseline during 3 months of treatment in CS40 and CS41 are presented in Figure 1 and Figure 2, respectively.

CS40 study (females).

A 3 month, randomised, double blind study comparing Nocdurna 25 micrograms versus placebo in women with nocturia, defined as an average of ≥ 2 nocturnal voids per night.
Two hundred and sixty-eight (268) subjects were randomised, with the majority having 2-3 voids/night and 90% of the subjects had nocturnal polyuria.
The study met the coprimary endpoints with statistically significant differences favouring Nocdurna compared with placebo over the 3month period: there was a statistically significant (p = 0.028) decrease in the adjusted mean number of nocturnal voids from baseline on Nocdurna 25 micrograms (-1.46) compared to placebo (-1.24), with a treatment contrast of 0.22 voids/night (Figure 1);
the proportion of subjects with > 33% decrease in the mean number of nocturnal voids was significantly increased (p = 0.006). The risk ratio of Nocdurna 25 micrograms compared to placebo was 1.20 (95% CI: 1.04-1.36).
There was consistent differentiation between Nocdurna 25 micrograms and placebo for the secondary endpoints, including an increase from baseline to 3 months in the first undisturbed sleep period (FUSP)/time to first void (TTFV) of 155 minutes for Nocdurna compared to 106 minutes for placebo, with a treatment contrast of 49 minutes.
There was a strong association (p < 0.0001) between treatment response, measured by reduction in number of nocturnal voids and increase in FUSP, and improvements in patients' quality of life.
There was a statistically significant (p = 0.0226) improvement in quality of life for Nocdurna 25 micrograms (N-QoL total score 27.24) compared to placebo (21.90).

CS41 study (males).

A 3 month, randomised, double blind study comparing Nocdurna 50 micrograms and 75 micrograms versus placebo in men with nocturia, defined as an average of ≥ 2 nocturnal voids per night.
Three hundred and ninety-five (395) subjects were randomised, with the majority having 2-3 voids/night and 87% of the subjects had nocturnal polyuria.
The study met the coprimary endpoints with statistically significant differences favouring Nocdurna compared with placebo over the 3 month period: there was a statistically significant (p = 0.0003) decrease in the adjusted mean number of nocturnal voids on Nocdurna 50 micrograms (-1.25) compared to placebo (-0.88), with a treatment contrast of 0.37 voids/night (Figure 2);
the proportion of subjects with > 33% decrease in the mean number of nocturnal voids was significantly increased (p = 0.0009). The risk ratio of Nocdurna 50 micrograms compared to placebo was 1.32 (95% CI:1.11-1.54).
There was consistent differentiation between Nocdurna 50 micrograms and placebo for the secondary endpoints, including an increase from baseline to 3 months on the FUSP/TTFV of 112 minutes for Nocdurna compared to 73 minutes for placebo, with a treatment contrast of 39 minutes.
There was a strong association (p < 0.0001) between treatment response, measured by reduction in number of nocturnal voids and increase in FUSP, and improvements in patients' quality of life.
There was a statistically significant (p = 0.0385) improvement in quality of life for Nocdurna 50 micrograms (N-QoL total score 18.37) compared to placebo (13.88).

Gender differences in clinical safety and efficacy.

Clinical study [FE992026 CS029] analysed the dose response to Nocdurna in females and males at doses ranging from 10 to 100 micrograms. In females, there was no further gain in pharmacodynamic effect above the dose of 25 micrograms, indicating that the dose response plateau was reached at 25 micrograms in females. In males, reduction in urine volume was greater at 50 micrograms, but not substantially higher at 100 micrograms. Increasing doses to the 50 micrograms dose level in females did not yield further efficacy, but was associated with a 5-fold increase in the risk of hyponatraemia compared with males in the age group above 50 years (p = 0.015).

5.2 Pharmacokinetic Properties

Absorption.

The overall mean absolute bioavailability of desmopressin administered sublingually in doses of 200, 400 and 800 micrograms is 0.25%, with a 95% confidence interval (95% CI) of 0.21-0.31%.
Desmopressin exhibits a moderate to high variability in bioavailability, both within and between subjects.
Desmopressin shows dose linearity regarding AUC and C_max in the range of 60 to 240 micrograms. Bioavailability at doses below 60 micrograms has not been evaluated.

Distribution.

The distribution of desmopressin is best described by a two compartment distribution model with a volume of distribution during the elimination phase of 0.3-0.5 L/kg.

Metabolism.

The in vivo metabolism of desmopressin has not been studied. The presence of the D-amino acid isomer in position eight of the molecule is thought to protect desmopressin from degradation by the enzyme that inactivates natural arginine vasopressin. In vitro human liver microsome metabolism studies of desmopressin have shown that no significant amount is metabolised in the liver by the cytochrome P450 system. Thus, human liver metabolism in vivo by the cytochrome P450 system is unlikely to occur.

Excretion.

The total clearance of desmopressin has been calculated to 7.6 L/hr. The terminal half-life of desmopressin is estimated to 2.8 hours. In healthy subjects the fraction excreted unchanged was 52% (44%-60%).