Desmopressin Acetate

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 acetate nasal solution (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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Desmopressin acetate nasal solution (nasal spray) is contraindicated in patients with: Known hypersensitivity to desmopressin acetate or to any of the components of desmopressin acetate nasal solution (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 acetate nasal solution (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 )

11 DESCRIPTION Desmopressin acetate is a synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation. It is chemically defined as follows: Molecular weight: 1183.34 Molecular formula: C 46 H 64 N 14 O 12 S 2 •C 2 H 4 O 2 •3H 2 O 1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate. Desmopressin acetate nasal solution (nasal spray) is provided as an aqueous solution for intranasal use. Each mL contains: Desmopressin acetate, USP 0.1 mg Sodium Chloride 7.5 mg Citric acid monohydrate 1.7 mg Disodium phosphate dihydrate 3.0 mg Benzalkonium chloride solution (50%) 0.2 mg Purified water to 1 mL The desmopressin acetate nasal solution (nasal spray) compression pump delivers 0.1 mL (10 mcg) of desmopressin acetate per spray. Image

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 acetate nasal solution (nasal spray) by intranasal use only. Instruct patients about appropriate fluid restriction during desmopressin acetate nasal solution (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 acetate nasal solution (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 acetate nasal solution (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 acetate nasal solution (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 acetate nasal solution (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 solution (nasal spray) is not indicated. For pediatric patients 4 years of age and older, the recommended starting dosage of desmopressin acetate nasal solution (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 solution (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 acetate nasal solution (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 solution (nasal spray) individual dose titration is required because intranasal desmopressin is approximately 10 to 40 fold more potent than oral (tablet) desmopressin.

1 INDICATIONS AND USAGE Desmopressin acetate nasal solution (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 solution (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 acetate nasal solution (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 acetate nasal solution (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 )

10 OVERDOSAGE Signs of desmopressin acetate overdosage may include confusion, drowsiness, continuing headache, problems with passing urine, and rapid weight gain due to fluid retention [see Warnings and Precautions ( 5.1 )]. In case of overdosage, reduce the dosage, decrease the frequency of administration, or discontinue desmopressin acetate nasal solution (nasal spray). There is no known specific antidote for desmopressin acetate.

7 DRUG INTERACTIONS Drugs that Increase Risk of Hyponatremia: Requires more frequent monitoring of serum sodium ( 7.1 ) Other Vasocontrictors: Concomitant use may elevate blood pressure and require a reduction in desmopressin acetate nasal solution (nasal spray) 7.1 Other Drugs that may Increase Risk of Hyponatremia The concomitant administration of desmopressin acetate nasal solution (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 acetate nasal solution (nasal spray) with other vasocontrictors may require a reduction of the desmopressin acetate nasal solution (nasal spray) dosage [ see Adverse Reactions ( 6 ) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The antidiuretic effects of desmopressin are mediated by stimulation of vasopressin 2 (V2) receptors, thereby increasing water re-absorption in the kidney, and hence reducing urine production. Desmopressin is a replacement hormone for antidiuretic hormone in the treatment of central diabetes insipidus. The change in structure of arginine vasopressin to desmopressin acetate resulted in a decreased vasopressor action and decreased actions on visceral smooth muscle relative to the enhanced antidiuretic activity, so that clinically effective antidiuretic doses were usually below threshold levels for effects on vascular or visceral smooth muscle. 12.2 Pharmacodynamics The use of desmopressin acetate nasal solution (nasal spray) in patients with central diabetes insipidus reduces urinary output, increases urine osmolality, and decreases plasma osmolality. 12.3 Pharmacokinetics 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. Specific Populations Renal Impairment Desmopressin acetate is mainly excreted in the urine. A pharmacokinetic study was conducted in subjects with normal renal function and patients with mild, moderate, and severe renal impairment (n=24, 6 subjects each group) with a single 2 mcg dose of desmopressin acetate injection (this results in approximately 20 times the exposure of 10 mcg of desmopressin acetate nasal solution (nasal spray)). The terminal half-life was 2.8 hours in subjects with normal renal function, 4.0 hours in mild renal impairment, 6.6 hours in moderate renal impairment and 8.7 hours in severe renal impairment. In patients with mild, moderate and severe renal impairment, mean desmopressin exposure was 1.5 fold, 2.4 fold and 3.6 fold higher, respectively compared to that of subjects with normal renal function [see Contraindications ( 4 ), Use in Specific Populations ( 8.6 )].

12.1 Mechanism of Action The antidiuretic effects of desmopressin are mediated by stimulation of vasopressin 2 (V2) receptors, thereby increasing water re-absorption in the kidney, and hence reducing urine production. Desmopressin is a replacement hormone for antidiuretic hormone in the treatment of central diabetes insipidus. The change in structure of arginine vasopressin to desmopressin acetate resulted in a decreased vasopressor action and decreased actions on visceral smooth muscle relative to the enhanced antidiuretic activity, so that clinically effective antidiuretic doses were usually below threshold levels for effects on vascular or visceral smooth muscle.

12.2 Pharmacodynamics The use of desmopressin acetate nasal solution (nasal spray) in patients with central diabetes insipidus reduces urinary output, increases urine osmolality, and decreases plasma osmolality.

12.3 Pharmacokinetics 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. Specific Populations Renal Impairment Desmopressin acetate is mainly excreted in the urine. A pharmacokinetic study was conducted in subjects with normal renal function and patients with mild, moderate, and severe renal impairment (n=24, 6 subjects each group) with a single 2 mcg dose of desmopressin acetate injection (this results in approximately 20 times the exposure of 10 mcg of desmopressin acetate nasal solution (nasal spray)). The terminal half-life was 2.8 hours in subjects with normal renal function, 4.0 hours in mild renal impairment, 6.6 hours in moderate renal impairment and 8.7 hours in severe renal impairment. In patients with mild, moderate and severe renal impairment, mean desmopressin exposure was 1.5 fold, 2.4 fold and 3.6 fold higher, respectively compared to that of subjects with normal renal function [see Contraindications ( 4 ), Use in Specific Populations ( 8.6 )].

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3 DOSAGE FORMS AND STRENGTHS Desmopressin acetate nasal solution (nasal spray), 10 mcg/ 0.1 mL per spray is available in a 5 mL bottle with spray pump delivering 50 sprays of 10 mcg. Nasal Spray: 10 mcg per 0.1 mL spray, available in a 5 mL bottle with spray pump delivering 50 sprays ( 3 )

Desmopressin Acetate Desmopressin Acetate DESMOPRESSIN ACETATE DESMOPRESSIN SODIUM CHLORIDE CITRIC ACID MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, DIHYDRATE BENZALKONIUM CHLORIDE WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with desmopressin acetate have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with desmopressin acetate have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

ANDA091345

Desmopressin Acetate

Desmopressin Acetate

68382-384

HUMAN PRESCRIPTION DRUG

NASAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 68382-384-01 Desmopressin Acetate Nasal Solution (Nasal Spray), 10 mcg/ 0.1 mL per spray 5 mL Rx only Zydus container label

Manufactured by: Zydus Lifesciences Ltd. Ahmedabad, India. Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev.: 07/22

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use) Administration Inform caregivers for pediatric patients that administration should be supervised to ensure the patient receives the prescribed dose. Inform patients that the pump must be primed prior to first use and again if not used for greater than one week. Inform patients that the desmopressin acetate nasal solution (nasal spray) bottle delivers 50 sprays of 10 mcg each following the initial 4 priming pumps. Inform patients to discard any solution remaining after 50 sprays since the amount delivered thereafter may be substantially less than 10 mcg of drug. Monitoring Educate patients about the signs and symptoms of hyponatremia and advise them to contact a healthcare provider if such symptoms occur. Discuss downward adjustment of fluid intake and monitoring of urine output with patients.

8.5 Geriatric Use Clinical studies of desmopressin acetate nasal solution (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 [see Contraindications ( 4 ), Use in Specific Populations ( 8.6 )]. Use of desmopressin acetate nasal solution (nasal spray) in geriatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings and Precautions ( 5.1 )].

8.4 Pediatric Use Desmopressin acetate nasal solution (nasal spray) is indicated as antidiuretic replacement therapy in the management of central diabetes insipidus in pediatric patients 4 years of age and older. Desmopressin acetate nasal solution (nasal spray) is not indicated in pediatric patients less than 4 years of age. Use of desmopressin acetate nasal solution (nasal spray) in pediatric patients 4 years of age and older is supported by evidence from adults and pediatric patients with central diabetes insipidus. Use in pediatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings and Precautions ( 5.1 )].

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 ).

8 USE IN SPECIFIC POPULATIONS Pediatric Use: Use requires careful fluid intake restriction to prevent hyponatremia with water intoxication ( 5.1 , 8.4 ) Geriatric Use : Carefully monitor renal function; restrict fluid intake to prevent hyponatremia with water intoxication ( 5.1 , 8.5 ) 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 ). 8.2 Lactation Risk Summary Breastfeeding is not expected to result in clinically relevant exposure of the infant to desmopressin following maternal intranasal administration. Desmopressin is poorly transferred into human breastmilk at negligible amounts (see Data). There is no information on the effects of desmopressin on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for desmopressin acetate nasal solution (nasal spray) and any potential adverse effects on the breastfed infant from desmopressin acetate nasal solution (nasal spray) or from the underlying maternal condition. Data A trial was conducted in six healthy lactating women, at greater than 4 months postpartum, to evaluate intranasal administration of 300 mcg single dose of another desmopressin product (7.5 times the recommended adult dose of desmopressin acetate nasal solution (nasal spray)). Samples of maternal plasma and breastmilk were obtained at 0, 30, 60, 120, 240, 360 and 480 min after the drug administration. At 8 hours after dose intake, the levels in the milk ranged between 4.16 and 101 pg/ml, and the plasma levels ranged between 40 and 242 pg/ml. The total amount of desmopressin present in the milk over the 8 hours ranged between 491 pg and 16 ng, which corresponds to 0.0001 to 0.005% of the administered dose to the breastfeeding mother. 8.4 Pediatric Use Desmopressin acetate nasal solution (nasal spray) is indicated as antidiuretic replacement therapy in the management of central diabetes insipidus in pediatric patients 4 years of age and older. Desmopressin acetate nasal solution (nasal spray) is not indicated in pediatric patients less than 4 years of age. Use of desmopressin acetate nasal solution (nasal spray) in pediatric patients 4 years of age and older is supported by evidence from adults and pediatric patients with central diabetes insipidus. Use in pediatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings and Precautions ( 5.1 )]. 8.5 Geriatric Use Clinical studies of desmopressin acetate nasal solution (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 [see Contraindications ( 4 ), Use in Specific Populations ( 8.6 )]. Use of desmopressin acetate nasal solution (nasal spray) in geriatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings and Precautions ( 5.1 )]. 8.6 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 solution (nasal spray) is contraindicated in patients with estimated CLcr by Cockcroft-Gault equation less than 50 mL/min [see Clinical Pharmacology ( 12.1 , 12.3 ), Contraindications ( 4 )].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Desmopressin acetate nasal solution (nasal spray), 10 mcg/ 0.1 mL per spray is available in a 5 mL bottle with the spray pump delivering 50 sprays of 10 mcg. NDC 68382-384-01 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. STORE BOTTLE IN UPRIGHT POSITION.

16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. STORE BOTTLE IN UPRIGHT POSITION.