Presinex

Desmopressin Acetate Nasal Spray is indicated as antidiuretic replacement therapy in the management of central diabetes insipidus in adults and pediatric patients 4 years of age and older.

Limitations Of Use

Desmopressin Acetate Nasal Spray is not indicated for:

• Treatment of nephrogenic diabetes insipidus,
• Treatment of primary nocturnal enuresis ,
• Use in patients with conditions that compromise the intranasal route of administration (e.g., severe nasal congestion and blockage, nasal mucosa atrophy, severe atrophic rhinitis, recent nasal surgery such as transsphenoidal hypophysectomy).
• Use in patients with an impaired level of consciousness,
• Use in patients requiring doses less than 10 mcg or doses that are not multiples of 10 mcg.

Presinex is indicated for:

i) The treatment of nocturia associated with multiple sclerosis where other treatments have failed.

ii) The diagnosis and treatment of vasopressin-sensitive cranial diabetes insipidus.

iii) Establishing renal concentration capacity.

Important Administration Instructions

Administer Desmopressin Acetate Nasal Spray by intranasal use only. Instruct patients about appropriate fluid restriction during Desmopressin Acetate Nasal Spray treatment.

Must prime the spray pump prior to the first use. Instruct patients to:

• Prime pump by pressing down on pump four times (if the spray pump is not used for one week, re-prime the pump by pressing down on the pump once).
• Discard Desmopressin Acetate Nasal Spray after 50 sprays since the amount delivered thereafter may be substantially less than the recommended dosage.

Recommended Dosage

The use of Desmopressin Acetate Nasal Spray is not indicated for patients who require less than 10 mcg doses or doses that are not multiples of 10 mcg because the spray pump can only deliver doses of 10 mcg. If other doses are required, use another desmopressin acetate product.

Individualize the dosage of Desmopressin Acetate Nasal Spray for each patient with particular attention in pediatric and elderly patients and adjust according to the diurnal pattern of response to limit nocturia and to ensure fluid intake with respect to urine output is not excessive. Monitor continued response to Desmopressin Acetate Nasal Spray by urine volume and osmolality to ensure adequate diuresis to limit the risk of hyponatremia, and include measurements of serum sodium and plasma osmolality as needed.

Adults

The recommended dosage in adults is 10 mcg once daily into one nostril up to 40 mcg once daily (or 40 mcg divided into two or three daily doses). If administered more than once a day, adjust for an adequate diurnal rhythm of urine output.

Pediatric Patients

• For pediatric patients requiring doses less than 10 mcg, Desmopressin Acetate Nasal Spray is not indicated.
• For pediatric patients 4 years of age and older, the recommended starting dosage of Desmopressin Acetate Nasal Spray is 10 mcg once daily into one nostril. The dose can be titrated up to 30 mcg once daily (or 30 mcg divided into two daily doses, typically with 20 mcg given in the morning and 10 mcg given at nighttime). If administered more than once a day, adjust for an adequate diurnal rhythm of urine output.

Because administration of desmopressin acetate can been associated with decreased responsiveness with prolonged use, consider increasing the dosage of Desmopressin Acetate Nasal Spray if patients demonstrate decreased response over a long period of time.

Switching Between Desmopressin Acetate Formulations

When switching from the desmopressin acetate injection to Desmopressin Acetate Nasal Spray, administer 10 times the amount of desmopressin acetate, rounding down to the nearest 10 mcg.

When switching from the desmopressin acetate tablets to Desmopressin Acetate Nasal Spray individual dose titration is required because intranasal desmopressin is approximately 10 to 40 fold more potent than oral (tablet) desmopressin.

Treatment of Nocturia:

When Presinex is used for the treatment of nocturia associated with multiple sclerosis, fluid intake must be limited to a minimum from 1 hour before using the spray at bedtime until the next morning and in any case for a minimum of 8 hours after administration.

For multiple sclerosis patients up to 65 years of age with normal renal function suffering from nocturia the dose is one or two sprays intranasally (10 to 20 micrograms) at bedtime. Not more than one dose should be used in any 24 hour period. If a dose of two sprays is required, this should be as one spray into each nostril.

Treatment of Diabetes Insipidus:

Dosage is individual but clinical experience has shown that the average maintenance dose in adults and children is one or two sprays (10 to 20 micrograms) once or twice daily. If a dose of two sprays is required, this should be as one spray into each nostril.

Diagnosis of Diabetes Insipidus:

The diagnostic dose in adults and children is two sprays (20 micrograms). Failure to elaborate a concentrated urine after water deprivation, followed by the ability to do so after the administration of Presinex confirms the diagnosis of cranial diabetes insipidus. Failure to concentrate after the administration suggests nephrogenic diabetes insipidus.

Renal Function Testing:

Recommended doses for the renal concentration capacity test:

Adults: Two sprays into each nostril (a total of 40 micrograms)

Children: (1-15 years): One spray into each nostril (a total of 20 micrograms).

Infants (to 1 year): One spray (10 micrograms).

Adults and children with normal renal function can be expected to achieve concentrations above 700mOsm/kg in the period of 5-9 hours following administration of Presinex. It is recommended that the bladder should be emptied at the time of administration.

In normal infants a urine concentration of 600mOsm/kg should be achieved in the 5 hour period following the administration of Presinex. The fluid intake at the two meals following the administration should be restricted to 50% of the ordinary intake in order to avoid water overload.

Desmopressin Acetate Nasal Spray is contraindicated in patients with:

• Known hypersensitivity to desmopressin acetate or to any of the components of Desmopressin Acetate Nasal Spray. Severe allergic reactions and anaphylaxis have been reported.
• Renal impairment defined as estimated creatinine clearance (CLcr) by Cockcroft-Gault equation less than 50 mL/min).
• Hyponatremia or a history of hyponatremia.

Presinex is contraindicated in cases of:

- syndrome of inappropriate ADH secretion (SIADH)

- known hyponatraemia

- a history of known or suspected cardiac insufficiency and other conditions requiring treatment with diuretics

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

- hypersensitivity to desmopressin or to any of the excipients of Presinex.

Before prescribing Presinex, the diagnoses of habitual or psychogenic polydipsia (resulting in a urine production exceeding 40mg/kg/24 hours) and alcohol abuse should be excluded.

When used to control nocturia in patients with multiple sclerosis, desmopressin should not be used in patients with hypertension or cardiovascular disease.

Desmopressin should not be prescribed to patients over the age of 65 for the treatment of nocturia associated with multiple sclerosis.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hyponatremia

Excessive fluid intake when urine output is limited by the antidiuretic effect of desmopressin may lead to water intoxication with hyponatremia. Cases of hyponatremia have been reported from postmarketing experience in patients treated with desmopressin acetate. Unless properly diagnosed and treated, hyponatremia can be fatal.

All patients receiving Desmopressin Acetate Nasal Spray should be observed for the following signs or symptoms associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium, weight gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss appetite, irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as hallucinations, decreased consciousness, and confusion. Severe symptoms due to an extreme decrease in serum sodium and plasma osmolality may include one or a combination of the following: seizure, coma, and/or respiratory arrest.

In order to decrease the risk of water intoxication with hyponatremia, fluid restriction is recommended. Careful fluid intake restriction is particularly important in pediatric and geriatric patients because these patients are at greater risk of developing hyponatremia. More frequent monitoring of serum sodium levels is recommended in the following patients: those with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure, renal disorders, habitual or psychogenic polydipsia or those taking concomitant drugs that may cause hyponatremia.

Desmopressin Acetate Nasal Spray is not an indicated formulation for the treatment of primary nocturnal enuresis due to a higher risk of hyponatremia and hyponatremic convulsions with the use of the nasal spray formulation compared to desmopressin tablets seen in postmarketing reports.

Altered Absorption In Patients With Nasal Mucosa Abnormalities

Chronic administration of Desmopressin Acetate Nasal Spray may result in changes to nasal mucosa. Nasal mucosa abnormalities (such as scarring and edema) due to chronic administration, or due to other causes (nasal blockage, nasal mucosal atrophy, severe atrophic rhinitis, recent nasal surgery such as transsphenoidal hypophysectomy) may cause erratic, unreliable absorption. Avoid use of Desmopressin Acetate Nasal Spray in such patients.

Geriatric Use

Clinical studies of Desmopressin Acetate Nasal Spray did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at a low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy

Because elderly patients are more likely to have renal impairment, care should be taken in dose selection, and monitoring renal function is recommended.

Use of Desmopressin Acetate Nasal Spray in geriatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia.

Renal Impairment

Desmopressin acetate is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment than patients with normal renal function. Desmopressin Acetate Nasal Spray is contraindicated in patients with estimated CLcr by Cockcroft-Gault equation less than 50 mL/min.

Presinex should only be used in patients where orally administered formulations are not suitable.

When Presinex is prescribed, it is recommended:

- to start at the lowest dose

- to ensure compliance with fluid restriction instructions

- to increase dosage progressively, with caution

- to ensure that in children, administration is under adult supervision in order to control the dose intake.

Care should be taken with patients who have reduced renal function and/or cardiovascular disease or cystic fibrosis.

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

When Presinex is used for the treatment of nocturia associated with multiple sclerosis, periodic assessments should be made of blood pressure and weight to monitor the possibility of fluid overload. Treatment with desmopressin should be interrupted during acute intercurrent illness characterised by fluid and/or electrolyte imbalance (such as vomiting, diarrhoea, systemic infections, fever, gastroenteritis).

In the event of signs or symptoms of water retention and/or hyponatraemia (headache, nausea/vomiting, weight gain and in severe cases, convulsions) treatment should be interrupted until the patient has fully recovered. When restarting treatment, strict fluid restriction should be enforced.

Elderly patients and patients with low serum sodium levels may have an increased risk of hyponatraemia.

Precautions to avoid hyponatraemia, 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, carbamazepine and NSAIDs.

When used for diagnostic purposes, fluid intake must be limited and not exceed 0.5 litres from 1 hour before until 8 hours after administration.

Following diagnostic testing for diabetes insipidus or renal concentration capacity, care should be taken to prevent fluid overload. Fluid should not be forced, orally or parenterally, and patients should only take as much fluid as they require to satisfy thirst.

There is some evidence from post-marketing data for the occurrence of severe hyponatraemia in association with the nasal spray formulation of desmopressin, when it is used in the treatment of cranial diabetes insipidus.

Precautions to prevent fluid overload must be taken in:

- conditions characterised by fluid and/or electrolyte imbalance

- patients at risk for increased intracranial pressure

Renal concentration capacity testing in children below the age of 1 year should only be performed under carefully supervised conditions in hospital.

The following serious reactions are described below and elsewhere in the labeling:

• Hyponatremia.
• Altered Absorption in Patients with Changes in Nasal Mucosa.

The following adverse reactions have been identified during post-approval use of desmopressin acetate. 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:

Increase in blood pressure, headache, nasal congestion, rhinitis, nosebleed, sore throat, cough, upper respiratory infections, nausea, flushing, and abdominal cramps.

Water intoxication with hyponatremia

Hyponatremic convulsions associated with concomitant use of the following medications: oxybutinin and imipramine.

Severe allergic reactions and anaphylaxis

Side-effects include headache, stomach pain, nausea, nasal congestion, rhinitis and epistaxis. Isolated cases of allergic skin reactions and more severe general allergic reactions have been reported. Very rare cases of emotional disorders including aggression in children have been reported. Treatment without concomitant reduction of fluid intake may lead to water retention/hyponatraemia with or without accompanying warning signs and symptoms (headache, nausea/vomiting, weight gain, decreased serum sodium and in severe cases, convulsions).

Signs of desmopressin acetate overdosage may include confusion, drowsiness, continuing headache, problems with passing urine, and rapid weight gain due to fluid retention. In case of overdosage, reduce the dosage, decrease the frequency of administration, or discontinue Desmopressin Acetate Nasal Spray. There is no known specific antidote for desmopressin acetate.

An overdose of Presinex leads to a prolonged duration of action with an increased risk of water retention and/or hyponatraemia.

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.

The use of Desmopressin Acetate Nasal Spray in patients with central diabetes insipidus reduces urinary output, increases urine osmolality, and decreases plasma osmolality.

Desmopressin is a structural analogue of vasopressin, with two chemical changes, namely desamination of the N-terminal and replacement of the 8-L-Arginine by D-8-Arginine. These changes have increased the antidiuretic activity and prolonged the duration of action. The pressor activity is reduced to less than 0.01% of the natural peptide as a result of which side-effects are rarely seen.

Absorption

Desmopressin acetate is absorbed through the nasal mucosa.

Elimination

Desmopressin acetate exhibits a biphasic elimination profile, with half-lives of 7.8 and 75.5 minutes for the initial and terminal phases, respectively.

Following intranasal administration, the bioavailability of desmopressin is of the order of 10%.

Pharmacokinetic parameters following intravenous administration have been reported as follows:

Total clearance: 2.6ml/ min/kg body wt.

T_½: 55mins

Plasma kinetics of DDAVP in man

H. Vilhardt, S. Lundin, J. Falch

Acta Pharmacol et Toxicol, 1986, 58, 379-381

In vitro, in human liver microsome preparations, it has been shown that no significant amount of desmopressin is metabolised in the liver and thus human liver metabolism in vivo is not likely to occur.

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. However, formal in vivo interaction studies have not been performed.