Nocdurna 25 mikrogram Frystorkad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

28-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

22-04-2018

Aktiva substanser:
desmopressinacetat
Tillgänglig från:
Ferring Läkemedel AB
ATC-kod:
H01BA02
INN (International namn):
desmopressin acetate
Dos:
25 mikrogram
Läkemedelsform:
Frystorkad tablett
Sammansättning:
desmopressinacetat 27,7 mikrog Aktiv substans; mannitol Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 30 x 1 tabletter (endos); Blister, 10 x 1 tabletter (endos); Blister, 90 x 1 tabletter (endos); Blister, 100 x 1 tabletter (endos)
Bemyndigande status:
Godkänd
Godkännandenummer:
52905
Tillstånd datum:
2016-06-16

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

10-01-2019

Produktens egenskaper Produktens egenskaper - engelska

21-04-2016

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

04-07-2016

Läs hela dokumentet

Package leaflet: Information for the user

Nocdurna 25 microgram oral lyophilisate

Nocdurna 50 microgram oral lyophilisate

desmopressin

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What Nocdurna is and what it is used for

What you need to know before you take Nocdurna

How to take Nocdurna

Possible side effects

How to store Nocdurna

Contents of the pack and other information

1.

What Nocdurna is and what it is used for

Nocdurna contains desmopressin , an antidiuretic, which reduces urine production.

Nocdurna is used for the treatment of nocturia (frequent need to get up to urinate at night) due to nocturnal

polyuria (overproduction of urine during night) in adults.

2.

What you need to know before you take Nocdurna

Do not take Nocdurna:

if you are allergic to desmopressin or any of the other ingredients of this medicine (listed in section 6)

if you suffer from polydipsia (excessive thirst and increased fluid intake) or psychogenic polydipsia

(psychologically caused increased thirst and increased fluid intake)

if you have known or suspected cardiac insufficiency (heart failure in which the heart is not able to

pump enough blood throughout the body)

if you have any disease requiring treatment with diuretics

if you have moderately or severely reduced kidney function

if you have or have had hyponatraemia (low sodium level in the blood)

if you have SIADH (hormone secretion disorder)

Warnings and precautions

Talk to your doctor or pharmacist before taking Nocdurna.

It is especially important that you talk to your doctor before taking Nocdurna if:

you have severe bladder dysfunction and problems urinating

you are 65 years or older since your doctor will have to monitor the level of sodium in your blood (see

the section 3 “How to take Nocdurna” below)

you have low levels of sodium in your blood

you have a medical condition(s) causing fluid and/or electrolyte imbalance

you have a medical condition(s) that could be made worse by fluid and/or electrolyte disturbance

you get an acute intercurrent illness (such as systemic infection, fever, and stomach flu) as it may be

necessary for the doctor to interrupt/reassess the treatment with Nocdurna

you have cystic fibrosis, coronary heart disease, high blood pressure, chronic kidney disease or pre-

eclampsia

You must limit fluid intake to a minimum from 1 hour before taking Nocdurna until 8 hours after taking

Nocdurna. Treatment without simultaneous reduction of fluid intake may lead to water retention and/or

mineral imbalances with or without accompanying warning signs and symptoms hereunder such as

headache, nausea/vomiting, weight gain and, in severe cases, convulsions.

Other medicines and Nocdurna

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

It is especially important you tell it to 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 tablets such as thiazides 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

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 around childbirth

lithium, which is used to treat e.g. bipolar disorder

Loperamide, which is a medicinal product used for the treatment of diarrhoea

Nocdurna with food and drink

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

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine.

Your doctor will decide if you can use this medicine during pregnancy or if you are breast-feeding.

Driving and using machines

Nocdurna has no or negligible influence on the ability to drive and use machines.

3.

How to take Nocdurna

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you

are not sure.

The recommended dose is

Women: 25 microgram daily, one hour before bedtime, administered under the tongue without water.

Men: 50 microgram daily, one hour before bedtime, administered under the tongue without water.

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

Instructions for use

1. Completely remove the end tab of a blister strip by tearing along the perforations, starting from the corner

with the hand symbol.

2. Now remove one blister from the strip by tearing along the perforations.

3. 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

4. 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.

5. 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. 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 the section

“Warnings and precautions” above). Your doctor can choose to restart treatment. When restarting treatment,

you must strictly restrict fluid intake. In addition, your doctor will closely monitor the sodium levels in your

blood.

Use in elderly patients (65 years of age and older)

If you are 65 years or older your doctor will have to monitor the level of sodium in your blood before

starting the treatment, during the first week of treatment (4-8 days after initiation of the treatment) and again

in about one month after the initiation of the treatment.

Kidney impairment

If you have moderately or severely reduced kidney function, do not take Nocdurna

Talk to your doctor.

Liver impairment

If you have impaired liver function you should talk to your doctor before taking Nocdurna.

Use in children and adolescents

This medicine is for use in adults only

If you take more Nocdurna than you should

It is important that you do not take more than the prescribed dose in any 24 hour period. Special attention

should be given to signs of hyperhydration of the body (water intoxication), such as. weight gain, headache,

nausea and, in severe cases, convulsions.

Please consult your doctor if you have taken more Nocdurna than you should.

If you forget to take Nocdurna

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

day.

If you stop taking Nocdurna

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

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Drinking too much fluid may lead to a build up of water which dilutes the salt in the body in severe cases.

This can become a serious problem and may lead to convulsions.

Stop taking this medicine and tell your doctor immediately or go to your nearest casualty department if you

experience one or more of these symptoms,

an unusually bad or prolonged headache,

confusion,

unexplained weight gain,

nausea or vomiting.

Side Effects include:

Very common: may affect more than 1 in 10 people

Dry mouth

Common: may affect up to 1in 10 people

Nausea, feeling unwell, muscle weakness and confusion due to decreased level of sodium in the blood

(hyponatraemia)

Headache

Dizziness

Nausea

Diarrhoea

Uncommon: may affect up to 1 in 100 people

Constipation

Stomach discomfort

Weakness (fatigue)

Swelling of the tissue in the lower limbs (peripheral oedema)

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects

not listed in this leaflet.

You can also report side effects directly via the national reporting system listed in

Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Nocdurna

Keep this medicine out of the sight and reach of children.

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture and light.

Use immediately upon opening individual tablet blister.

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.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Nocdurna contains

The active substance is desmopressin added as desmopressin acetate.

Each oral lyophilisate contains 25 microgram desmopressin.

Each oral lyophilisate contains 50 microgram desmopressin.

The other ingredients are gelatin, mannitol (E 421) and citric acid, anhydrous

What Nocdurna looks like and contents of the pack

Nocdurna 25 microgram:

White, round, oral lyophilisate tablet of approximately 12 mm marked with 25 on one side.

Nocdurna 50 microgram:

White, round, oral lyophilisate tablet of approximately 12 mm marked with 50 on one side

.

Laminated aluminium blister sheets in an outer carton. Each perforated unit dose blister sheet contains 10

oral lyophilisates.

Pack size:

10x1, 30x1, 90x1 or 100x1 oral lyophilisates.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

<[To be completed nationally]>

<This medicinal product is authorised in the Member States of the EEA under the following names:>

<{Name of the Member State}> <{Name of the medicinal product}>

<{Name of the Member State}> <{Name of the medicinal product}>

This leaflet was last revised in 01/2019

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Nocdurna 25 microgram oral lyophilisate

Nocdurna 50 microgram oral lyophilisate

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each oral lyophilisate contains desmopressin acetate equivalent to 25 or 50 microgram desmopressin.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Oral lyophilisate.

Nocdurna 25 microgram:

White, round, oral lyophilisate of approximately 12 mm marked with 25 on one side.

Nocdurna 50 microgram:

White, round, oral lyophilisate of approximately 12 mm marked with 50 on one side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Nocdurna is indicated for symptomatic treatment of nocturia due to idiopathic nocturnal polyuria in adults

(see section 5.1).

4.2

Posology and method of administration

Posology

Women: 25 microgram daily, one hour before bedtime, administered sublingually without water.

Men: 50 microgram daily, one hour before bedtime, administered sublingually without water.

A dose increase with this product is not recommended in elderly patients ≥ 65 years.

If higher doses are considered for patients under the age of 65 years in case of an insufficient response to

Nocdurna, other desmopressin oral lyophilisate products should be used (see sections 4.4, 4.8 and 5.1)

In the event of signs or symptoms of water retention and/or hyponatremia (headache, nausea/vomiting,

weight gain, and, in severe cases, convulsions) treatment should be interrupted and reassessed. When

restarting treatment strict fluid restriction should be enforced and serum sodium levels monitored (see

section 4.4).

Nocdurna should be discontinued if the serum sodium level falls below the lower limit of normal range

(i.e.135 mmol/L)

Special Populations

Elderly patients (65 years of age and older)

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 microgram for females and 50 microgram for males should not be used. In elderly patients serum

sodium must be within the normal range, before initiating treatment, in the first week (4-8 days after

initiation) and again at one month. Nocdurna should be discontinued if the serum sodium level falls below

the lower limit of normal range (see section 4.4). Continued therapy must be carefully reconsidered in

elderly patients who show no evidence of therapeutic benefit beyond 3 months.

Renal impairment

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

Hepatic impairment

No dose adjustment is needed for patients with hepatic impairment (see section 5.2).

Paediatric population

There is no relevant use of Nocdurna in the paediatric population for the indication of symptomatic

treatment of nocturia due to idiopathic nocturnal polyuria.

Method of administration

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

Food intake may reduce the intensity and duration of the antidiuretic effect at low doses of desmopressin

(see section 5.2)

4.3

Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1

Habitual or psychogenic polydipsia (resulting in a urine production exceeding 40 ml/kg/24 hours)

Known or suspected cardiac insufficiency or other conditions associated with fluid overload, sufficient to

require treatment with diuretics, including a history of such conditions

Moderate and severe renal insufficiency (creatinine clearance below 50 ml/min)

Known history of hyponatremia

Syndrome of inappropriate ADH secretion (SIADH)

4.4

Special warnings and precautions for use

Patients, in particular the elderly, should undergo clinical examination and questioning before commencing

treatment with Nocdurna, given that nocturnal polyuria can be a symptom of cardiovascular or other medical

conditions associated with fluid overload. If there is any suspicion of such coexistent conditions, treatment

with desmopressin is not recommended (see also section 4.3).

Fluid intake must be limited to a minimum from 1 hour before until 8 hours after administration. Treatment

without concomitant reduction of fluid intake may lead to prolonged fluid retention and/or hyponatremia

with or without accompanying warning signs and symptoms (headache, nausea/vomiting, weight gain, and,

in severe cases, convulsions).

Elderly patients with serum sodium levels in the lower range of normal may have an increased risk of

hyponatremia. Patients 65 years and older should have their serum sodium monitored before initiating the

treatment, in the first week of treatment (4-8 days) and again at one month after treatment initiation (see

section 4.2).

At a 50 microgram dose level females may have an increased risk of hyponatraemia compared with males

(see Section 5.1). It is therefore important that the gender-specific recommendations for dose are adhered to.

Nocdurna should be discontinued if the serum sodium level falls below the lower limit of normal range.

Desmopressin should be used with caution in patients with conditions characterized by fluid and/or

electrolyte imbalance.

Treatment with desmopressin should be interrupted and reassessed during acute intercurrent illnesses

characterised by fluid and/or electrolyte imbalance (such as systemic infections, fever, and gastroenteritis).

Precautions to avoid hyponatremia including careful attention to fluid restriction and more frequent

monitoring of serum sodium must be taken in case of concomitant treatment with drugs, which are known to

induce SIADH, e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine,

diuretics and carbamazepine, and some antidiabetics of the sulfonylurea group, particularly chlorpropamide,

and in case of concomitant treatment with non-steroidal anti-inflammatory drugs (NSAIDs).

Special caution should be exercised in patients taking thiazide or loop diuretics for hypertension or other

medical conditions not associated with fluid overload. Sodium monitoring in these patients is warranted.

Severe bladder dysfunction and outlet obstruction should be considered before starting treatment.

Caution is required in cases of cystic fibrosis, coronary heart disease, hypertensions, chronic renal disease

and pre-eclampsia.

A diagnosis of nephrogenic diabetes insipidus should be considered if there is no reduction in night-time

urine output after commencement of desmopressin.

Special caution should be exercised in patients taking lithium in case of masking of early-stage lithium-

induced nephrogenic diabetes insipidus by administration of desmopressin for a nocturia indication.

Desmopressin is not recommended in patients suspected of having lithium-induced nephrogenic diabetes

insipidus.

4.5

Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Substances, which are known to induce SIADH, may cause an increased risk of water

retention/hyponatremia (e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors,

chlorpromazine, diuretics and carbamazepine as well as some antidiabetics of the sulfonylurea group

particularly chlorpropamide) (see section 4.4).

NSAIDs and oxytocin may potentiate the antidiuretic effect of desmopressin and may induce water

retention/ hyponatremia (see section 4.4).

Lithium may diminish the antidiuretic effect.

Pharmacokinetic interactions

Concomitant treatment with loperamide may result in a 3-fold increase of desmopressin plasma

concentrations following oral administration, which may lead to an increased risk of water

retention/hyponatremia. Although not investigated, other drugs slowing intestinal transport might have the

same effect.

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

Pregnancy

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 foetus/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/foetal development, parturition or postnatal development.

Animal reproduction studies have shown no clinically relevant effects on parents and offspring. In-vitro

analysis of human cotyledon models have shown that there is no transplacental transport of desmopressin

when administered at therapeutic concentration corresponding to recommended dose.

Breastfeeding

Results from analyses of milk from nursing mothers receiving high dose desmopressin acetate (300

microgram intranasal); indicate that the amounts of desmopressin that may be transferred to the child are

considerably less than the amounts required to influence diuresis. Therefore it is not considered necessary to

stop breastfeeding.

Fertility

Studies with desmopressin in animals have shown no impairment of fertility in male and female rats.

4.7

Effects on ability to drive and use machines

Nocdurna has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

Based on the frequency of adverse drug reactions reported in clinical studies with Nocdurna for nocturia

indication conducted in male subjects (50 mcg; N=222) and in female subjects (25 mcg; N=219) the most

commonly reported adverse reaction during treatment was dry mouth (13%), headache (3%), hyponatraemia

(3%), and dizziness (2%).

Description of selected adverse reactions:

The most serious adverse reaction with desmopressin is hyponatraemia, which is associated with headache,

nausea, vomiting, decreased serum sodium, 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 re-absorption by the renal tubules and

osmotic dilution of plasma. In studies with adult subjects treated for nocturia, the majority of the subjects

developed low serum sodium within the first days of treatment or in relation to dose increase. Special

attention should be paid to the precautions addressed in section 4.4.

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 and 4.4).

Tabulated list of adverse reactions

The below table 1 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 (≥1/1,000 to <1/100).

Table 1:

Frequency of adverse drug reactions reported (Phase III studies and Post-marketing reports)

MedDRA System

Organ Class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Metabolism and

nutrition disorders

Hyponatraemia

Nervous system

disorders

Headache

Dizziness

Gastrointestinal

disorders

Dry mouth*

Nausea

Diarrhoea

Constipation

Abdominal discomfort

General disorders and

administration site

conditions

Fatigue

Oedema peripheral

*It is to be noted that subjects were specifically queried about dry mouth in some of the clinical studies

.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

4.9

Overdose

Symptoms:

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

hyponatremia.

Treatment:

Although the treatment of hyponatraemia should be individualised, the following general recommendations

can be given. Hyponatraemia is treated by discontinuing the desmopressin treatment, fluid restriction and

symptomatic treatment if needed.

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 anti-diuretic hormone arginine

vasopressin (AVP). Desmopressin mimics vasopressin’s anti-diuretic 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 microgram

for females and 50 microgram for males), and the limited duration of action ofNocdurna, 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 hyponatremia is dose

dependent. Females are at higher risk of developing hyponatraemia than males. The incidences of

hyponatremia rises with increasing age (see section 4.2 and 4.4).

Clinical efficacy

The efficacy of Nocdurna has been demonstrated in two randomised double blinded placebo controlled

studies in respectively 268 women (study CS40, desmopressin Melt 25 microgram versus placebo) and 395

men (study CS41, desmopressin Melt 50 microgram and 75 microgram versus placebo ) with nocturia

defined as an average of ≥2 nocturnal voids per night and polyuria in 90% of women and 87% of men.

Both studies met the 2 co-primary endpoints with statistically significant differences favouring

desmopressin Melt over the 3-month period. There was a statistically significant decrease in the adjusted

mean number of nocturnal voids from the baseline on desmopressin Melt 25 microgram (-1.46) compared to

placebo (-1.24) in the female study (p=0.028) (Fig. 1) and on desmopressin Melt 50 microgram (-1.25)

compared to placebo (-0.88) in the male study (p=0.0003) (Fig. 2). The proportion of subjects with >33%

decrease in the mean number of nocturnal voids (responders) was significantly increased, nearly doubled.

The odds ratio for >33% decrease of desmopressin Melt 25 microgram compared to placebo was 1.85

(p=0.006) in the female study and the odds ratio for >33% decrease of desmopressin Melt 50 microgram

compared to placebo was 1.98 (p=0.0009) in the male study.

For secondary endpoints, there was an increase from baseline to 3 months in the first undisturbed sleep

period (FUSP)/time to first void with a treatment contrast of 49 minutes in the female study and 39 minutes

in the male study. There was a statistically significant improvement in quality of life for desmopressin Melt

25 microgram (N-QoL total score 27.24) compared to placebo (21.90) (p=0.0226) in female and an

improvement for desmopressin Melt 50 microgram (N-QoL total score 18.37) compared to placebo (13.88)

(p=0.0385) in male. There was a strong association (p<0.0001) in the both studies between treatment

response (reduction in number of nocturnal voids and increase in FUSP) and improvements in patients’

quality of life.

Figure 1. Co-Primary Endpoint: Adjusted mean change from baseline

in nocturnal voids during 3

months of treatment – (Females, CS40 Full Analysis Set)

Figure 2. Co-Primary Endpoint: Adjusted mean change from baseline

in nocturnal voids during 3

months of treatment – (Males, CS41 Full Analysis Set)

In a double-blind randomised clinical study, the efficacy and safety of a combination therapy with

desmopressin Melt 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 subjects were exposed to a

combination of Nocdurna (desmopressin Melt) 25 microgram and tolterodine 4 milligram. No serious

adverse events were observed in this study and safety profile of the combination treatment was similar to the

safety profile of Nocdurna 25 microgram. 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.

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 microgram: In females, there was no further gain in pharmacodynamic effect above

the dose of 25 microgram, indicating that the dose response plateau was reached at 25 microgram in

females. In males, reduction in urine volume was greater at 50 microgram, but not substantially higher at

100 microgram. Increasing doses to 50 microgram 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 from earlier dose-

ranging studies of doses of 200, 400 and 800 mcg is 0.25%, with a 95% confidence interval 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

in the range of 60 to 240 mcg.

However, the bioavailability of doses below 60 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.

Biotransformation

The in-vivo metabolism of desmopressin has not been studied. In vitro human liver microsome metabolism

studies of desmopressin have shown that no significant amount is metabolized in the liver by the cytochrome

P450 system. Thus human liver metabolism in vivo by the cytochrome P450 system is unlikely to occur. The

effect of desmopressin on the PK of other drugs is likely to be minimal due to its lack of inhibition of the

cytochrome P450 drug metabolizing system.

Elimination

The total clearance of desmopressin has been calculated to 7.6 L/hr. The terminal half-live of desmopressin

is estimated to 2.8 hours. In healthy subjects the fraction excreted unchanged was 52 % (44 % - 60 %).

Linearity/non-linearity

There are no indications of non-linearities in any of the pharmacokinetic parameters of desmopressin.

Characteristics in specific groups of patients

Renal impairment

:

Depending on the degree of renal impairment the AUC and half-live increased with the severity of the renal

impairment. Desmopressin is contraindicated in patients with moderate and severe renal impairment

(creatinine clearance below 50 ml/min).

Table 2: Pharmacokinetic parameters for different degrees of renal impairment. Data from CS001.

Creatinine

Clearance

Renal Function

AUC (Hrs*pg/mL)

(Hrs)

Healthy

>80 mL/min

Normal

Mild

50-80 mL/min

Mildly impaired

Moderate

30-49 mL/min

Moderately impaired

Severe

5-29 mL/min

Severely impaired

Hepatic impairment:

No studies have been performed in this population.

It is unlikely that desmopressin will interact with drugs affecting hepatic metabolism, since desmopressin

has been shown not to undergo significant liver metabolism in in vitro studies with human microsomes.

5.3

Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction.

Carcinogenicity studies have not been performed with desmopressin, because it is closely related to the

naturally-occurring peptide hormone.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Gelatin

Mannitol (E 421)

Citric acid, anhydrous

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

4 years

6.4

Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture and light.

Use immediately upon opening individual tablet blister

6.5

Nature and contents of container

Perforated unit dose blisters packed in a carton. The blister bottom foil and the blister lid foil are multilayer

laminates consisting of PVC/OPA/Alu/OPA/PVC and heat seal laquer/Alu/PET/paper, respectively.

Pack size:

10x1, 30x1, 90x1 or 100x1 oral lyophilisates

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste material should be disposed in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

8.

MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<Date of first authorisation: {DD month YYYY}>

<Date of latest renewal: {DD month YYYY}>

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

2016-04-21

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