NOQDIRNA

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.

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. 4). 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.

4). Continued therapy must be carefully reconsidered in elderly patients who show no evidence of therapeutic benefit beyond 3 months. 3). 2). Paediatric population There is no relevant use of Noqdirna in the paediatric population for the indication of symptomatic treatment of nocturia due to idiopathic nocturnal polyuria.

Method of administration Noqdirna is placed under the tongue where it dissolves without the need for water. 2)

Summary of the safety profile Based on the frequency of adverse drug reactions reported in clinical studies with Noqdirna 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.

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.

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.

Patients, in particular the elderly, should undergo clinical examination and questioning before commencing treatment with Noqdirna, given that nocturnal polyuria can be a symptom of cardiovascular or other medical conditions associated with fluid overload.

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. 2). 1). It is therefore important that the gender-specific recommendations for dose are adhered to. Noqdirna 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).

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.

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)