DESMOPRESSIN ACETATE

1 INDICATIONS AND USAGE Desmopressin 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 nasal spray is not indicated for: Treatment of nephrogenic diabetes insipidus, Treatment of primary nocturnal enuresis [see Warnings and Precautions ( 5.1 )], 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) [see Warnings and Precautions ( 5.2 )]. 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 [see Dosage Forms and Strengths ( 3 )]. Desmopressin nasal spray is a vasopressin analog indicated as antidiuretic replacement therapy in the management of central diabetes insipidus for adults and pediatric patients 4 years of age and older ( 1 ) Limitations of Use: Desmopressin nasal spray is not indicated for: Treatment of nephrogenic diabetes insipidus ( 1 ) Treatment of primary nocturnal enuresis ( 1 , 5.1 ) Use in patients with conditions that compromise intranasal route of administration ( 1 , 5.2 ) Use in patients with an impaired level of consciousness ( 1 ) Use in patients requiring doses less than 10 mcg or doses that are not multiples of 10 mcg ( 1 , 3 )

2 DOSAGE AND ADMINISTRATION For intranasal use only ( 2.1 ) Instruct patients to prime pump prior to use ( 2.1 ) Adults : 10 mcg to 40 mcg daily (either as a single dose or divided into two or three daily doses) ( 2.2 ) Pediatrics: 10 mcg once daily into one nostril up to 30 mcg once daily (or 30 mcg divided as 20 mcg during the morning and 10 mcg at night) ( 2.2 ) See the Full Prescribing Information for recommendations for switching between desmopressin acetate formulations ( 2.3 ) 2.1 Important Administration Instructions Administer desmopressin nasal spray by intranasal use only. Instruct patients about appropriate fluid restriction during desmopressin nasal spray treatment [see Warnings and Precautions ( 5.1 )]. 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 nasal spray after 50 sprays since the amount delivered thereafter may be substantially less than the recommended dosage. 2.2 Recommended Dosage The use of desmopressin 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 [see Indications and Usage ( 1 )] . If other doses are required, use another desmopressin acetate product. Individualize the dosage of desmopressin 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 [see Warnings and Precautions ( 5.1 )] . Monitor continued response to desmopressin 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 nasal spray is not indicated. For pediatric patients 4 years of age and older, the recommended starting dosage of desmopressin 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 be associated with decreased responsiveness with prolonged use, consider increasing the dosage of desmopressin nasal spray if patients demonstrate decreased response over a long period of time. 2.3 Switching Between Desmopressin Acetate Formulations When switching from the desmopressin acetate injection to desmopressin 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 nasal spray individual dose titration is required because intranasal desmopressin is approximately 10 to 40 fold more potent than oral (tablet) desmopressin.

5 WARNINGS AND PRECAUTIONS Hyponatremia: Instruct patients about proper fluid restriction and monitor serum sodium as needed ( 2.1 , 5.1 ) Altered Absorption in Patients with Nasal Mucosa Abnormalities: May occur with chronic administration, and require use of other formulations instead ( 5.2 ) 5.1 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 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 [see Use in Specific Populations ( 8.4 , 8.5 )] . 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 [see Drug Interactions ( 7.1 )]. Desmopressin 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 [see Indications and Usage ( 1 )]. 5.2 Altered Absorption in Patients With Nasal Mucosa Abnormalities Chronic administration of desmopressin 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 nasal spray in such patients [see Indications and Usage ( 1 )] and consider use of other formulations of desmopressin acetate given by other routes of administration.

4 CONTRAINDICATIONS Desmopressin nasal spray is contraindicated in patients with: Known hypersensitivity to desmopressin acetate or to any of the components of desmopressin nasal spray. Severe allergic reactions and anaphylaxis have been reported [see Adverse Reactions ( 6 )] . Renal impairment defined as estimated creatinine clearance (CLcr) by Cockcroft-Gault equation less than 50 mL/min [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. Hyponatremia or a history of hyponatremia [see Warnings and Precautions ( 5.1 )]. Known hypersensitivity to desmopressin acetate or to any of the components of desmopressin nasal spray ( 4 , 6 ) Patients with renal impairment (creatinine clearance below 50 mL/min) ( 4 , 8.6 , 12.3 ) Hyponatremia or a history of hyponatremia ( 4 , 5.1 )

7 DRUG INTERACTIONS Drugs that Increase Risk of Hyponatremia: Requires more frequent monitoring of serum sodium ( 7.1 ) Other Vasoconstrictors: Concomitant use may elevate blood pressure and require a reduction in desmopressin nasal spray dosage ( 7.2 ) 7.1 Other Drugs that may Increase Risk of Hyponatremia The concomitant administration of desmopressin nasal spray with other drugs that may increase the risk of water intoxication with hyponatremia, (e.g., tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine, oxybutynin and carbamazepine) requires more frequent serum sodium monitoring [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6 )]. 7.2 Other Vasoconstrictors Desmopressin acetate can elevate blood pressure. Use of large doses of desmopressin nasal spray with other vasoconstrictors may require a reduction of the desmopressin dosage [see Adverse Reactions ( 6 )].

8.1 Pregnancy Risk summary Prolonged experience with desmopressin in pregnant women over several decades, based on the available published data and case reports, did not identify a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In addition, in vitro studies with human placenta demonstrate poor placental transfer of desmopressin. No adverse developmental outcomes were observed in animal reproduction studies with administration of desmopressin during organogenesis to pregnant rats and rabbits at doses approximately <1 and 38 times, respectively, the maximum recommended human dose based on body surface area (mg/m 2 ) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Desmopressin acetate at up to 50 ng/kg/day was given by subcutaneous injection to pregnant rats, from gestation day 1 to 20 during the period of early embryonic development and organogenesis without teratogenic effects. Desmopressin acetate at up to 10 mcg/kg/day was given to pregnant rabbits by subcutaneous injection from gestation day 6 to 18 during fetal organogenesis without teratogenic effects. These doses of desmopressin acetate represent approximately <1 times (rat) and 38 times (rabbit) the maximum recommended human dose based on body surface area (mg/m 2 ).

6 ADVERSE REACTIONS The following serious reactions are described below and elsewhere in the labeling: Hyponatremia [see Warnings and Precautions ( 5.1 )]. Altered Absorption in Patients with Changes in Nasal Mucosa [see Warnings and Precautions ( 5.2 )]. 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 [see Drug Interactions ( 7.1 )] . Severe allergic reactions and anaphylaxis [see Contraindications ( 4 )] Adverse reactions that have been identified in patients administered desmopressin nasal spray are headache, nasal congestion, rhinitis, nosebleed, sore throat, cough, upper respiratory infections, nausea, flushing, and mild abdominal cramps ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch