Auro-Desmopressin Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Auro-Desmopressin (desmopressin acetate tablets) is indicated for:

• treatment of Central Diabetes Insipidus
• treatment of Nocturnal Enuresis

Central Diabetes Insipidus

Auro-Desmopressin (0.1 and 0.2 mg desmopressin acetate) is indicated for the management of vasopressin sensitive central diabetes insipidus, and for the control of temporary polyuria and polydipsia following head trauma, hypophysectomy or surgery in the pituitary region.

Primary Nocturnal Enuresis

Auro-Desmopressin (0.1 and 0.2 mg desmopressin acetate) is indicated in the management of nocturnal enuresis in patients 5 years of age and older who have normal ability to concentrate urine. Auro-Desmopressin should be used in conjunction with non-medicinal therapy, such as motivational counselling and bladder exercises.

CONTRAINDICATIONS

• Hypersensitivity to desmopressin or any of the tablet constituents.
• Patients with type IIB or platelet-type (pseudo) Willerbrand disease, because of the risk of platelet aggregation and thrombocytopenia

• Any condition associated with impaired water excretion, such as:

  Hyponatremia

  Severe liver disease

  Nephrosis

  Cardiac insufficiency

  Chronic renal insufficiency Congestive heart failure

  Habitual or psychogenic polydypsia

• Any medical conditions which lead to sodium losing states such as:

  Vomiting

  Diarrhea

  Bulimia

  Anorexia nervosa

  Adrenocortical insufficiency

  Salt losing nephropathies,

• Lactose intolerance/allergies

WARNINGS AND PRECAUTIONS

General

In general, by adequate treatment with Auro-Desmopressin, thirst is automatically reduced. However, there is potential risk of water intoxication if, during treatment, excessive liquid is consumed. Fluid intake should be adjusted to reduce the possibility of water intoxication and hyponatremia especially in the very young and elderly patients (See DOSAGE AND ADMINISTRATION). Particular attention should be paid to the risk of extreme decrease in plasma osmolality and resulting seizures in young children.

Treatment with desmopressin should be interrupted during acute inter-current illnesses characterised by fluid and/or electrolyte imbalance (such as systemic infections, fever, and gastroenteritis).

In patients with Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) or with high intra-cranial pressure, it is necessary that extra care be exercised with liquid intake.

Desmopressin should not be administered to dehydrated patients until water balance has been adequately restored.

The product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp Lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Desmopressin is not effective in controlling polyuria caused by renal disease, nephrogenic diabetes insipidus, psychogenic diabetes insipidus, hypokalemia or hypercalcemia.

Cardiovascular

Desmopressin acetate can occasionally produce a slight elevation of blood pressure, which disappears with a reduction in dosage. The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease because of possible tachycardia and changes in blood pressure.

Genitourinary

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

Respiratory

Desmopressin should be used with caution in patients with cystic fibrosis because these patients are prone to hyponatremia.

Special Populations

Pregnant Women:

No controlled studies in pregnant women have been carried out. The physician should weigh possible therapeutic advantages against potential risks in each case.

Data on a limited number (n=53) of exposed pregnancies in women with diabetes insipidus indicate no adverse effects of desmopressin on pregnancy or on the health of the fetus or newborn child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.

Nursing Women:

There have been no controlled studies in nursing mothers. Results from analysis of milk from nursing mothers receiving high doses of desmopressin (300 mcg intranasal), indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis.

Pediatric:

Use of desmopressin in infants and children will require careful fluid intake restriction to prevent possible hyponatremia and water retention due to over ingestion of fluids.

Geriatric:

Geriatric patients should be closely observed for possible hyponatremia and water retention due to over ingestion of fluids.

Monitoring and Laboratory Tests

Central Diabetes Insipidus

Continued response to desmopressin acetate is monitored by urine volume and osmolality.

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Infrequently, high doses of desmopressin have produced transient headache and nausea. Nasal congestion, rhinitis, flushing, and mild abdominal cramps have been reported. These symptoms disappeared with reduction in dosage.

Side effects reported from controlled clinical trials involving 638 subjects included headache (2%), and rhinitis (1%), nasal discomfort (1%), epistaxis (1%) and abdominal pain (1%). Other effects, reported at a frequency of less than 1% included dizziness, chills, wheezing, rash, edema of face and hands, nausea, constipation, anorexia, increased appetite, conjunctivitis and after taste in the mouth. These symptoms disappeared with reduction of dosage or withdrawal of drug. Adverse effects rarely necessitate discontinuance of the drug.

Serum SGOT levels were elevated in 4/16 patients 6 months after commencing oral desmopressin acetate therapy (200 to 600 µg/day). Two of these patients had exhibited baseline levels of SGOT that were above the normal range and all four patients had normal SGOT levels on repeat test at 9 months, even though desmopressin acetate administration continued. The possibility that desmopressin acetate has an adverse effect on serum enzymes is therefore remote.

DRUG INTERACTIONS

Drug-Drug Interactions

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.

Potential Drug-Drug Interaction

Drug-Food Interactions

Intake of a standardised meal with oral desmopressin resulted in significant decreased bioavailability compared to fasting. This is hypothesised to be due to reduced absorption from the gastrointestinal tract. However no effect on dynamics (urine production or osmolality) was observed.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Central Diabetes Insipidus

To institute desmopressin therapy, patients should be withdrawn from previous medication and allowed to establish a baseline polyuria and polydipsia. The stable polyuria is used as a baseline to determine the magnitude and duration of the response to medication.

Primary Nocturnal Enuresis

A restricted fluid intake is recommended a few hours before administration, especially one hour before bedtime. In the event that the child wakes up during the night, liquid intake should be restricted.

Recommended Dose and Dosage Adjustment

Central Diabetes Insipidus

A suitable starting dose for adults and children is 0.1 mg desmopressin acetate three times daily. This dosage regimen should then be adjusted in accordance with the patient's response in order to ensure an optimum dose.

For patients who have been controlled on intranasal desmopressin and who are to be switched to the oral form, the oral dose producing comparable antidiuresis is about 10-20 times greater than the established intranasal dose.

Geriatric patients may be more sensitive to the antidiuretic effect of desmopressin acetate.

In children, the evening dose is usually 2x higher than the morning and midday dose to ensure sufficient antidiuresis during sleep. This is generally not a requirement for adult patients, presumably because adults sleep for shorter periods of time.

The maximum recommended dosage for both adults and children is 1.2 mg per day (0.4 mg three times a day).

The lowest effective dosage should be given. Rarely, during long term use, patients may develop tolerance to the drug and require cautious increase in dosage to achieve adequate therapeutic response.

Primary Nocturnal Enuresis

The dosage of Auro-Desmopressin must be determined for each individual patient and adjusted according to response.

Patients previously on intranasal Auro-Desmopressin therapy can begin tablet therapy the night following (24 hours after) the last intranasal dose. The oral dose producing comparable antidiuresis is about 10-20 times greater than the established intranasal dose.

The recommended initial dose is 0.2 mg 1 hour before bedtime.

If the patient experiences a wet night after three days on an initial dose of 0.2 mg (1 x 0.2 mg tablet), increase the dose by 0.2 mg. The dose may be increased by 0.2 mg increments, in the manner described (every 3 days), to a maximal dose of 0.6 mg.

The physician should be consulted if enuresis persists at the maximal dose. A restricted fluid intake is recommended a few hours before administration, especially one hour before bedtime. In the event that the child wakes up during the night, liquid intake should be restricted.

The need for continued treatment should be reassessed every 3 months by means of a period of at least one week without Auro-Desmopressin. If the patient is still wetting the bed, then reintroduce Auro-Desmopressin at the same dosage prior to discontinuing treatment for another three months and reassess.

Missed Dose

Central Diabetes Insipidus

If the patient misses a dose, the patient should be advised to take the missed dose as soon as possible. However if it is almost time for the next dose, the patient should be advised to skip the missed dose, to return to the regular dosing schedule and to not double dose.

Primary Nocturnal Enuresis

If the patient misses a dose, the patient should be advised not to take the missed dose.

OVERDOSAGE

Overdosage will increase the risk of fluid retention and symptoms which include headaches, abdominal cramps, nausea, and facial flushing. Dosage and frequency of administration should be reduced, or the drug withdrawn, according to severity of the condition.

If hyponatremia occurs following medication or excessive fluid intake, treatment should be discontinued and fluid intake restricted until serum sodium is normalized. In most cases this is sufficient. In cases with severe symptoms, (e.g., those associated with the central nervous system (CNS) such as unconsciousness), admission to hospital and a slow normalization of serum sodium is required to avoid additional complications.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Desmopressin acetate is a synthetic structural analogue of the antidiuretic hormone, arginine vasopressin, which alters the permeability of the renal tubule to increase resorption of water. The increase in the permeability of both the distal tubules and collecting ducts appears to be mediated by a stimulation of the adenylcyclase activity in the renal tubules.

The synthetic analogue exhibits a greater antidiuretic potency, as well as a longer half-life and duration of action, as compared to vasopressin.

Pharmacodynamics

Clinical studies have demonstrated that peroral administration of desmopressin acetate is active in eliciting an antidiuretic effects in humans, be they normal subjects, or adults and children suffering from central diabetes insipidus (CDI) of various etiologies, or from nocturnal enuresis.

The only recognized pharmacodynamic actions detected after orally administered desmopressin are reduction in urine flow and increase in urine osmolality. A number of studies have examined dose, and concentration-effect relationships of desmopressin with respect to its antidiuretic effects. Some studies show clear dose- and concentration-effect relationships, while others do not.

Pharmacokinetics

Absorption:

Dose-response relationships and pharmacokinetic profiles of orally administered desmopressin acetate were similar in normal subjects and in adults and children with CDI. In all studies, both the magnitude of the plasma peak concentration and the AUC were dose dependent. Time to peak plasma concentration and the plasma half-life were not affected by the size of the dose.

Plasma desmopressin levels increased in a dose-dependent fashion and its disappearance from plasma followed an exponential time course, with half-life of 86 to 142 minutes.

Pharmacokinetics of Oral Desmopressin in Normal Subjects and CDI Patients. Numbers in brackets indicate the number of subject/patients from which the parameter was derived.

Pharmacokinetics of Typical Therapeutic Doses of Oral Desmopressin in Pediatric CDI Patients

Distribution:

The distribution of desmopressin has not been fully characterized. It is not known if desmopressin crosses the placenta, but small quantities have been shown to be distributed into milk.

Metabolism:

The in-vitro 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.

In healthy subjects the fraction excreted unchanged was 52% (44% - 60%).

Excretion:

Urinary clearance in 6 hydrated volunteers was calculated to be 0.514 mL/min/kg body weight and the amount of peptide excreted in the urine during the 6-hour observation period constituted 16.4% of the amount absorbed from the intestine over the same period of time. Urinary clearance for desmopressin is thus smaller than that reported for vasopressin.

STORAGE AND STABILITY

Store between 15°C to 25°C and protect from moisture and light. Avoid exposure to excessive heat and light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

* 0.1 mg and 0.2 mg of Desmopressin acetate.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Desmopressin acetate

Chemical names: Vasopressin, 1-(3-mercaptopropanoic acid)-8-D-arginine-, monoacetate (salt) trihydrate;

or

1-(3-Mercaptopropionic acid)-8-D-arginine-vasopressin monoacetate (salt) trihydrate.

Molecular formula and molecular mass: C₄₈H₆₈N₁₄O₁₄S₂.3H₂O and 1183.31 g/mol

Structural formula:

Physicochemical properties: White or almost white fluffy powder. Soluble in water and in ethanol (96 percent) and in glacial acetic acid. pH 3.5 to 6.0

CLINICAL TRIALS

Comparative Bioavailability Studies

A randomized, single-dose (3 x 0.2 mg), two-treatment, four period, two-sequence, replicated crossover comparative bioavailability study of Auro-Desmopressin tablets 0.2 mg (Auro Pharma Inc.) with ^PrDDAVP^® Tablets 0.2 mg (Ferring Inc., Canada) was conducted in healthy, adult male subjects under fasting conditions.

Comparative bioavailability data from 35 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ Auro-Desmopressin (desmopressin acetate) tablets, 0.2 mg (Auro Pharma Inc.)

^{2 Pr}DDAVP^® Tablets (desmopressin acetate), 0.2 mg (Ferring Inc., Canada)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV%) only

Central Diabetes Insipidus

Six patients aged 23 to 65 years took part in an open dose-ranging study of desmopressin acetate tablets followed by a four week open study on an out-patient basis. All patients completed the dose range study in hospital and were discharged on a dosage regimen ranging from 25 to

200 mcg t.i.d.

A dose-dependent effect was seen at doses of 12.5, 25, 50, 100 and 200 mcg desmopressin acetate both for duration and magnitude of antidiuretic activity. All doses elicited an antidiuretic response although doses of 100 to 200 mcg induced a more optimum duration of antidiuretic activity. Although there were large interindividual differences, most patients were stabilized on a mean daily dose of 345 mcg desmopressin acetate (range 75 to 900 mcg). One patient dropped out of the study due to inadequate response to oral therapy, despite being treated with 400 mcg t.i.d.

This patient had been previously well controlled with a dosage of 10 mcg t.i.d., intranasally. The individual response varied greatly between patients in both magnitude and duration but was found to be of the same order of magnitude as for intranasal desmopressin acetate which had previously been administered in daily doses of 15 to 75 mcg in these patients.

No significant deviations from normal laboratory values for hematology, blood chemistry including liver function, serum electrolytes or urinalysis were noted, and there were no clinically important changes in body weight or blood pressure. Two patients who received cortisone had lower baseline diuresis than other patients and required a lower desmopressin acetate dose to control adequate water turnover. However, neither cortisone nor thyroxine interfered with desmopressin acetate efficacy.

Six patients aged 21 to 59 years completed 18 months of oral desmopressin acetate therapy and 4 patients had completed 6 to 12 months of therapy. These patients were well controlled with satisfactory water turnover at doses within the range of 100-200 mcg t.i.d., with no development of tolerance to desmopressin acetate.

None of the minor changes noted in serum total protein, electrolytes (Na, K, C1) or glucose or in the plasma osmolality were considered to be of any clinical significance. There were no clinically significant changes in blood pressure or body weight.

Primary Nocturnal Enuresis

Two trials investigated the long-term efficacy and safety of desmopressin acetate tablets for primary nocturnal enuresis. The first study continued for six months. One hundred and twenty-five (of the 232 enrolled) completed the trial; 92 were male, 33 were female. Patients were 6-17 years of age with a mean age of 9.34. All patients were assigned to a dose of 200 mcg for two weeks. The dose was increased in increments of 200 mcg every two weeks until the patient was completely dry (over a 14-day period) or had reached a maximum dose of 600 mcg. The data obtained in this trial indicate that desmopressin 200 mcg reduces the mean number of wet nights within two weeks and sustains this effect over a six-month treatment period. The safety profile was unremarkable. The number of patients who reported one or more adverse events was: 200 mcg dose - 57 (25%); 400 mcg dose - 54 (24%), and 600 mcg dose - 44 (47%). Headache, pharyngitis, rhinitis and infection were the most commonly reported adverse events.

The second (Canadian) trial investigated the long-term safety of oral desmopressin treatment for up to one year, in children with nocturnal enuresis. Two hundred and fifty-six patients were treated with desmopressin; 80% of these patients were male with a mean age of 9.6 years (range 6-18 years). Of the 80 children completing the trial, 27 became dry (at most one wet night) for at least 28 days. Of the 24 adverse events evaluated as possibly/probably related to treatment, 16 were evaluated as mild, seven were moderate [nausea (1), headache (3), mood swings (2), bacterial infection (1)], and one was severe (vomiting).

In summary, a total of 117/236 children who completed the titration period (49.6%; 95% confidence interval 40–57%) responded (>50% reduction over baseline). Throughout the study their response rate remained constant at ~74%. Continuous treatment reduced the median number of wet nights during the observation period from 5.75 to 1.00 per week. A total of 12.4% of children received the 0.2 mg dose and 87.6% the 0.4 mg dose. The proportion of full responses increased over the course of the study from 5.8% to 37.5%. Desmopressin acetate was well tolerated: the majority of reported adverse events were mild, although two adverse events leading to withdrawal were reported. ^{40, 41}

TOXICOLOGY

1. (i) Acute Toxicity

The IV acute toxicity of desmopressin acetate is very low. Mice tolerate IV doses of 2 mg/kg (Table 3). At doses of 30 mcg/kg in rats and 50 mcg/kg in rabbits, only transient changes in clinical behaviour were observed. Intravenous doses up to 24 mcg/kg in dogs did not produce any cardiovascular changes.

Acute Toxicity of Desmopressin Acetate

1. (ii) Subacute Toxicity

Results from 14-day studies show that the drug given intravenously to rats at 18 mcg/kg/day and to rabbits at 6 mcg/kg/day caused no biologically significant changes in hematological and clinical chemistry parameters. Post-mortem examinations did not reveal any abnormalities.

Rats which received 5 mg/kg/day SC for 3 weeks did not show any significant changes in weight, blood count, or organ changes.

(iii) Chronic Toxicity

Subcutaneous Administration

Rat Studies

Rats (20 per group) which received doses of 5, 50 and 500 ng/kg/day, for six months did not show any significant changes in weight, blood values, or levels of transaminases. The weight of heart, lungs and kidneys decreased in female animals in the lower dose groups but not in the higher ones. In the male animals a decrease in non-esterified fatty acids was noted.

Dog Studies

Dogs (3 per group) which received SC doses of 10 and 100 ng/kg/day for 6 months did not show any significant changes in comparison with control groups in blood sugar or transaminases and did not show histological or morphological organ changes.

Oral Administration

Rat Studies

Oral administration of desmopressin to rats (20 male and 20 females per group dosed at 25, 75 and 200 mcg/kg/day) did not reveal any clinical findings related to desmopressin. Treated male and female rats were comparable to controls with respect to food consumption, body weight gain and water consumption. There were no drug-induced ocular abnormalities.

A dosage-related reduction was seen in levels of total circulating white blood cells, attributable to reduced neutrophil and lymphocyte counts in treated females, when compared with controls, at the week 13 and 26 investigations. Treated males were not affected.

Reduced plasma Factor VIII levels were seen in treated females at week 14 and treated males at week 25 in comparison with controls.

The terminal studies revealed no morphological or histological changes related to treatment with desmopressin.

Dog Studies

When desmopressin was given orally to dogs (4 males and 4 females per group, at 0, 25, 75 and 200 mcg/kg/day) all animals survived the 26-week period and no clinical signs were observed that were related to treatment. There were no adverse effects on body weight, food and water consumption and no ocular abnormalities. Hematological investigations revealed no treatment- related findings.

During weeks 6, 13 and 26 serum total protein concentrations of treated animals were increased due to an increase in the globulin fraction. However, there were no changes from the pre-dose values in males at 200 mcg/kg/day after 13 and 26 weeks treatment and males at 75 mcg/kg/day after 26 weeks treatment.

No organ morphological or histological changes were seen on autopsy which could be related to treatment with desmopressin.

(iv) Reproduction Studies

Subcutaneous Administration

Rat Studies

In a teratogenicity study in Wistar rats, neither teratologic nor embryotoxic effects were observed in 369 fetuses from 40 females dosed with up to 50 ng/kg/day desmopressin acetate SC during day 1 to day 20 of gestation.

Rabbit Studies

In a study of 78 Dutch belted rabbits which received SC doses of desmopressin acetate up to 10 mcg/kg/day during the sixth and eighteenth day of pregnancy, neither teratogenic nor embryotoxic effects were observed in 296 fetuses. Weaning was unaffected.

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