OVERDOSAGE SECTION.

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 nasal spray solution. There is no known specific antidote for desmopressin acetate.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package Label/Principal Display Panel. NDC 24208-342-05DesmopressinNasal SpraySolution USP,10 mcg/0.1 mLFOR INTRANASALUSE ONLY50 sprays10 mcg per sprayRx only5 mLBAUSCH LOMB. carton.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious reactions are described below and elsewhere in the labeling:oHyponatremia [see Warnings and Precautions (5.1)].oAltered 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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: oxybutynin and imipramine [see Drug Interactions (7.1)].Severe allergic reactions and anaphylaxis [see Contraindications (4)]. oHyponatremia [see Warnings and Precautions (5.1)].. oAltered Absorption in Patients with Changes in Nasal Mucosa [see Warnings and Precautions (5.2)].. Adverse reactions that have been identified in patients administered desmopressin nasal spray solution 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 Bausch Lomb Incorporated at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Desmopressin nasal spray solution is indicated as antidiuretic replacement therapy in the management of central diabetes insipidus in pediatric patients years of age and older. Desmopressin nasal spray solution is not indicated in pediatric patients less than years of age.Use of desmopressin nasal spray solution in pediatric patients 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)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The antidiuretic effects of desmopressin are mediated by stimulation of vasopressin (V2) receptors, thereby increasing water re-absorption in the kidney, and hence reducing urine production. Desmopressin is replacement hormone for antidiuretic hormone in the treatment of central diabetes insipidus. The change in structure of arginine vasopressin to desmopressin acetate resulted in 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 nasal spray solution 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 biphasic elimination profile, with half-lives of 7.8 and 75.5 minutes for the initial and terminal phases, respectively.Specific PopulationsRenal Impairment: Desmopressin acetate is mainly excreted in the urine. pharmacokinetic study was conducted in subjects with normal renal function and patients with mild, moderate, and severe renal impairment (n=24, subjects each group) with single mcg dose of desmopressin acetate injection (this results in approximately 20 times the exposure of 10 mcg of desmopressin nasal spray solution). 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)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Desmopressin nasal spray solution is contraindicated in patients with:oKnown hypersensitivity to desmopressin acetate or to any of the components of desmopressin nasal spray solution. Severe allergic reactions and anaphylaxis have been reported [see Adverse Reactions (6)].oRenal 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)].oHyponatremia or history of hyponatremia [see Warnings and Precautions (5.1)].. oKnown hypersensitivity to desmopressin acetate or to any of the components of desmopressin nasal spray solution. Severe allergic reactions and anaphylaxis have been reported [see Adverse Reactions (6)].. oRenal 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)].. oHyponatremia or history of hyponatremia [see Warnings and Precautions (5.1)].. oKnown hypersensitivity to desmopressin acetate or to any of the components of desmopressin nasal spray solution (4, 6)oPatients with renal impairment (creatinine clearance below 50 mL/min) (4, 8.6, 12.3)oHyponatremia or history of hyponatremia (4,5.1). oKnown hypersensitivity to desmopressin acetate or to any of the components of desmopressin nasal spray solution (4, 6). oPatients with renal impairment (creatinine clearance below 50 mL/min) (4, 8.6, 12.3). oHyponatremia or history of hyponatremia (4,5.1).

DESCRIPTION SECTION.

11 DESCRIPTION Desmopressin Nasal Spray Solution, USP is vasopressin 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: 1183.34Empirical formula: C46H64N14O12S2oC2H4O2o3H2O1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.Desmopressin Nasal Spray Solution, USP is an aqueous solution for intranasal use. Each mL contains:ACTIVE: Desmopressin Acetate 0.1 mg (0.01%); INACTIVES: Purified Water and Sodium Chloride. Hydrochloric Acid may be added to adjust pH (3.5 6.0). PRESERVATIVE ADDED: Chlorobutanol 0.5%.. chemstructure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oFor intranasal use only (2.1)oInstruct patients to prime pump prior to use (2.1)oAdults: 10 mcg to 40 mcg daily (either as single dose or divided into two or three daily doses) (2.2)oPediatrics: 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)oSee the Full Prescribing Information for recommendations for switching between desmopressin acetate formulations (2.3). oFor intranasal use only (2.1). oInstruct patients to prime pump prior to use (2.1). oAdults: 10 mcg to 40 mcg daily (either as single dose or divided into two or three daily doses) (2.2). oPediatrics: 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). oSee the Full Prescribing Information for recommendations for switching between desmopressin acetate formulations (2.3). 2.1 Important Administration Instructions. Administer desmopressin nasal spray solution by intranasal use only. Instruct patients about appropriate fluid restriction during desmopressin nasal spray solution treatment [see Warnings and Precautions (5.1)]. Must prime the spray pump prior to the first use. Instruct patients to:oPrime pump by pressing down on pump five times (if the spray pump is not used for one week, re-prime the pump by pressing down on the pump once).oDiscard desmopressin nasal spray solution after 50 sprays since the amount delivered thereafter may be substantially less than the recommended dosage.. oPrime pump by pressing down on pump five times (if the spray pump is not used for one week, re-prime the pump by pressing down on the pump once).. oDiscard desmopressin nasal spray solution 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 solution 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 solution 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 solution 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.AdultsThe 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 day, adjust for an adequate diurnal rhythm of urine output.Pediatric Patients For pediatric patients requiring doses less than 10 mcg, desmopressin nasal spray solution is not indicated. For pediatric patients years of age and older, the recommended starting dosage of desmopressin nasal spray solution 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 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 solution if patients demonstrate decreased response over long period of time.. For pediatric patients requiring doses less than 10 mcg, desmopressin nasal spray solution is not indicated.. For pediatric patients years of age and older, the recommended starting dosage of desmopressin nasal spray solution 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 day, adjust for an adequate diurnal rhythm of urine output.. 2.3 Switching Between Desmopressin Acetate Formulations When switching from the desmopressin acetate injection to desmopressin nasal spray solution, 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 solution, individual dose titration is required because intranasal desmopressin is approximately 10 to 40 fold more potent than oral (tablet) desmopressin.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Desmopressin Nasal Spray Solution, USP pump delivers 10 mcg (0.1 mL) of desmopressin acetate per spray.Desmopressin Nasal Spray Solution, USP is available as 5 mL bottle with spray pump delivering 50 sprays.. Nasal Spray: 10 mcg per 0.1 mL spray, available in 5 mL bottle with spray pump delivering 50 sprays (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oDrugs that Increase Risk of Hyponatremia: Requires more frequent monitoring of serum sodium (7.1)oOther Vasoconstrictors: Concomitant use may elevate blood pressure and require reduction in desmopressin acetate nasal spray solution dosage (7.2). oDrugs that Increase Risk of Hyponatremia: Requires more frequent monitoring of serum sodium (7.1). oOther Vasoconstrictors: Concomitant use may elevate blood pressure and require reduction in desmopressin acetate nasal spray solution dosage (7.2). 7.1 Other Drugs that may Increase Risk of Hyponatremia The concomitant administration of desmopressin nasal spray solution 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 solution with other vasoconstrictors may require reduction of the desmopressin nasal spray solution dosage [see Adverse Reactions (6)].

PHARMACODYNAMICS SECTION.

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

GERIATRIC USE SECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Desmopressin Nasal Spray Solution, USP is available as 5 mL bottle containing an aqueous solution with the spray pump delivering 50 sprays of 10 mcg (0.1 mL) (NDC 24208-342-05).. 16.2 Storage and Handling Store in refrigerator at to 8C (36 to 46F).When traveling, product will maintain stability for up to weeks when stored at room temperature, 22C (72F).STORE BOTTLE IN UPRIGHT POSITION.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

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 nasal spray solution bottle delivers 50 sprays of 10 mcg each following the initial 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 healthcare provider if such symptoms occur. Discuss downward adjustment of fluid intake and monitoring of urine output with patients.Distributed by:Bausch Lomb, division of Bausch Health US, LLCBridgewater, NJ 08807 USAManufactured by: Bausch Health Companies Inc. Laval, Quebec H7L 4A8, Canada(C) 2021 Bausch Lomb Incorporated or its affiliates9685502Rev. 09/2021. 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 nasal spray solution bottle delivers 50 sprays of 10 mcg each following the initial 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 healthcare provider if such symptoms occur.. Discuss downward adjustment of fluid intake and monitoring of urine output with patients.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use. Desmopressin Nasal Spray Solution, 10 mcg per 0.1 mLFor Intranasal Use OnlyRead these instructions before using desmopressin nasal spray solution, and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.Children should be helped by an adult when using desmopressin nasal spray solution, to make sure the right amount of medicine is used.The parts of your desmopressin nasal spray solution pump (see Figure A):Priming your desmopressin nasal spray solution:Your desmopressin nasal spray pump must be primed before you use it for the first time.oRemove the protective cap (see Figure B).oPress down on the shoulders at the top of your desmopressin nasal spray solution pump times. Hold the spray nozzle tip away from your face and eyes (see Figure C).oAfter your desmopressin nasal spray pump is primed, it will spray 10 micrograms (1 dose) of medicine each time it is pressed.Using your desmopressin nasal spray: Step 1. Remove the protective cap. Step 2. To make sure you get the right dose of medicine, hold bottle upright as shown in Figure and place the spray nozzle tip of your desmopressin nasal spray solution into your nostril. Press the spray pump time for dose. If doses are prescribed, spray each nostril time. It is very important that you hold the bottle upright while giving the medicine. You may need to lean your head slightly forward to prevent tilting the bottle. Tilting the bottle, especially when less than half of the solution is left in the bottle, may cause the pump to not work the right way (see Figure E). Step 3. Put the spray nozzle tip of your desmopressin nasal spray solution into your nostril and press the spray pump time for dose (see Figure F). If doses are prescribed, spray each nostril time. Step 4. Put the protective cap back on the spray nozzle tip when you finish using your desmopressin nasal spray.Keeping track of your Nasal Sprays:oUse the check-off chart to help you keep track of the number of sprays of desmopressin nasal spray solution used (see Figure G).oKeep this chart with your desmopressin nasal spray solution or put it in place where you can easily get it.oCheck off number on the chart with your first dose of desmopressin nasal spray solution. Check off the numbers after each use of your desmopressin nasal spray solution. If your healthcare provider prescribed dose of sprays, then numbers should be checked off.oYour desmopressin nasal spray solution holds 50 sprays with the right amount of medicine in each spray.oIf any medicine is left in your desmopressin nasal spray solution after 50 sprays, do not use it. You may not get the right amount of medicine.oThrow away your desmopressin nasal spray solution after 50 sprays.oDo not count the priming sprays. Your desmopressin nasal spray solution has been filled with extra medicine for your priming sprays.oDo not try to remove any medicine from your desmopressin nasal spray solution pump and place it in another bottle.How should store desmopressin nasal spray solutionoStore desmopressin nasal spray solution in the refrigerator between 36F to 46F (2C to 8C).oWhen traveling, desmopressin nasal spray solution can be stored at room temperature up to 72F (22C for up to weeks.oStore desmopressin nasal spray solution standing upright.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Distributed by:Bausch Lomb, division ofBausch Health US, LLCBridgewater, NJ 08807 USAManufactured by: Bausch Health Companies Inc. Laval, Quebec H7L 4A8, Canada(C) 2021 Bausch Lomb Incorporated or its affiliates9685502Rev: September 2021. oRemove the protective cap (see Figure B).. oPress down on the shoulders at the top of your desmopressin nasal spray solution pump times. Hold the spray nozzle tip away from your face and eyes (see Figure C).. oAfter your desmopressin nasal spray pump is primed, it will spray 10 micrograms (1 dose) of medicine each time it is pressed.. Step 1. Remove the protective cap.. Step 2. To make sure you get the right dose of medicine, hold bottle upright as shown in Figure and place the spray nozzle tip of your desmopressin nasal spray solution into your nostril. Press the spray pump time for dose. If doses are prescribed, spray each nostril time. It is very important that you hold the bottle upright while giving the medicine. You may need to lean your head slightly forward to prevent tilting the bottle. Tilting the bottle, especially when less than half of the solution is left in the bottle, may cause the pump to not work the right way (see Figure E). Step 3. Put the spray nozzle tip of your desmopressin nasal spray solution into your nostril and press the spray pump time for dose (see Figure F). If doses are prescribed, spray each nostril time. Step 4. Put the protective cap back on the spray nozzle tip when you finish using your desmopressin nasal spray.. oUse the check-off chart to help you keep track of the number of sprays of desmopressin nasal spray solution used (see Figure G).. oKeep this chart with your desmopressin nasal spray solution or put it in place where you can easily get it.. oCheck off number on the chart with your first dose of desmopressin nasal spray solution. Check off the numbers after each use of your desmopressin nasal spray solution. If your healthcare provider prescribed dose of sprays, then numbers should be checked off.. oYour desmopressin nasal spray solution holds 50 sprays with the right amount of medicine in each spray.. oIf any medicine is left in your desmopressin nasal spray solution after 50 sprays, do not use it. You may not get the right amount of medicine.. oThrow away your desmopressin nasal spray solution after 50 sprays.. oDo not count the priming sprays. Your desmopressin nasal spray solution has been filled with extra medicine for your priming sprays.. oDo not try to remove any medicine from your desmopressin nasal spray solution pump and place it in another bottle.. oStore desmopressin nasal spray solution in the refrigerator between 36F to 46F (2C to 8C).. oWhen traveling, desmopressin nasal spray solution can be stored at room temperature up to 72F (22C for up to weeks.. oStore desmopressin nasal spray solution standing upright.. figurea. figureb. figurec. figure-d-e. figuref. figureg.

LACTATION SECTION.

8.2 Lactation Risk SummaryBreastfeeding 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 mothers clinical need for desmopressin nasal spray solution and any potential adverse effects on the breastfed infant from desmopressin nasal spray solution or from the underlying maternal condition.DataA trial was conducted in six healthy lactating women, at greater than months postpartum, to evaluate intranasal administration of 300 mcg single dose of another desmopressin product (7.5 times the recommended adult dose of desmopressin nasal spray solution). Samples of maternal plasma and breastmilk were obtained at 0, 30, 60, 120, 240, 360 and 480 min after the drug administration. At 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 hours ranged between 491 pg and 16 ng, which corresponds to 0.0001 0.005% of the administered dose to the breastfeeding mother.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action The antidiuretic effects of desmopressin are mediated by stimulation of vasopressin (V2) receptors, thereby increasing water re-absorption in the kidney, and hence reducing urine production. Desmopressin is replacement hormone for antidiuretic hormone in the treatment of central diabetes insipidus. The change in structure of arginine vasopressin to desmopressin acetate resulted in 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.

NONCLINICAL TOXICOLOGY SECTION.

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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption: Desmopressin acetate is absorbed through the nasal mucosa.Elimination: Desmopressin acetate exhibits biphasic elimination profile, with half-lives of 7.8 and 75.5 minutes for the initial and terminal phases, respectively.Specific PopulationsRenal Impairment: Desmopressin acetate is mainly excreted in the urine. pharmacokinetic study was conducted in subjects with normal renal function and patients with mild, moderate, and severe renal impairment (n=24, subjects each group) with single mcg dose of desmopressin acetate injection (this results in approximately 20 times the exposure of 10 mcg of desmopressin nasal spray solution). 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)].

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryProlonged experience with desmopressin in pregnant women over several decades, based on the available published data and case reports, did not identify 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/m2) (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 2-4% and 15-20%, respectively.DataAnimal DataDesmopressin acetate at up to 50 ng/kg/day was given by subcutaneous injection to pregnant rats, from gestation day 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 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/m2).

RENAL IMPAIRMENT SUBSECTION.

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 nasal spray solution 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)].

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. Desmopressin (DEZ-mo-press-in) Nasal Spray Solution, USP10 mcg per 0.1 mLFor Intranasal Use OnlyWhat is desmopressin nasal spray solution, 0.01%Desmopressin nasal spray solution is prescription medicine called vasopressin analog used as an antidiuretic replacement to manage central diabetes insipidus.oDesmopressin nasal spray solution is not effective in the treatment of nephrogenic diabetes insipidus.oDesmopressin nasal spray solution should not be used in people with nasal problems that may keep them from using nasal spray.Who should not use desmopressin nasal spray solution, 0.01%Do not use desmopressin nasal spray solution if you:oare allergic to desmopressin nasal spray solution or any of the ingredients in desmopressin nasal spray solution. Some people have had severe allergic reactions while taking desmopressin nasal spray solution. See the end of this Patient Information for complete list of ingredients in desmopressin nasal spray solution.ohave kidney problemsohave or have had low levels of sodium in your blood (hyponatremia) What should tell my healthcare provider before using desmopressin nasal spray solution, 0.01%Before using desmopressin nasal spray solution, tell your healthcare provider about all your medical conditions including if you:ohave or have had nasal sores, nasal surgery, nasal injury, or have problems such as stuffy nose or trouble breathing through your nose.ohave or have had any heart, blood circulation, or blood pressure problemsohave condition that causes fluid or water imbalance problems such as cystic fibrosis, or heart failure.ohave or have had condition that causes you to be very thirstyoare pregnant or plan to become pregnant. It is not known if desmopressin nasal spray solution will harm your unborn baby.oare breastfeeding or plan to breastfeed. It is not known if desmopressin nasal spray solution passes into your breast milk. You and your healthcare provider should decide if you will use desmopressin nasal spray solution.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should use desmopressin nasal spray solution, 0.01oRead the Instructions for Use that comes with your desmopressin nasal spray solution.oUse desmopressin nasal spray solution exactly as your healthcare provider tells you to use it.oYour healthcare provider may change your dose of desmopressin nasal spray solution if needed.What are the possible side effects of desmopressin nasal spray solution, 0.01%Desmopressin nasal spray solution may cause serious side effects including:olow levels of sodium in the blood (hyponatremia). People using desmopressin nasal spray solution are at risk for low sodium levels in the blood, water intoxication, and fluid overload. Follow your healthcare providers instructions on limiting the amount of fluid you can drink when using desmopressin nasal spray solution.oDo not drink more than you need to satisfy your thirst. You can have serious side effects such as seizures, coma, and death from drinking too much fluid.oChildren and the elderly are at higher risk for these problems and should follow their healthcare providers limits on drinking fluids.oCall your healthcare provider right away if you have any of the following symptoms while using desmopressin nasal spray solution. They may mean that your blood sodium level is too low. oheadache nausea, vomiting weight gainorestlessness tiredness sleepinessodisorientation loss of appetite muscle crampsofeeling irritable feeling weakohallucinations confusiononasal scarring or swelling. Some people using desmopressin nasal spray solution for long periods of time may have nasal problems such as scarring or swelling. This may affect how well desmopressin nasal spray solution works for you.The most common side effects of desmopressin nasal spray solution include: headache, stuffy nose, runny nose, nosebleed, sore throat, cough, upper respiratory infections, nausea, flushing, and stomach cramps.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of desmopressin nasal spray solution, 0.01%.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use desmopressin nasal spray solution for condition for which it was not prescribed. Do not give desmopressin nasal spray solution to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about desmopressin nasal spray solution that is written for health professionals. For more information call 1-800-321-4576.What are the ingredients in desmopressin nasal spray solution, 0.01%Active ingredient: desmopressin acetateInactive ingredients: purified water and sodium chloride; hydrochloric acid may be added to adjust pH (3.5 6.0) Preservative: chlorobutanolDistributed by:Bausch Lomb, division of Bausch Health US, LLCBridgewater, NJ 08807 USAManufactured by:Bausch Health Companies Inc.Laval, Quebec H7L 4A8, CanadaThis Patient Information has been approved by the U.S. Food and Drug Administration.(C) 2021 Bausch Lomb Incorporated or its affiliates9685502Issued: September 2021. oDesmopressin nasal spray solution is not effective in the treatment of nephrogenic diabetes insipidus.. oDesmopressin nasal spray solution should not be used in people with nasal problems that may keep them from using nasal spray.. oare allergic to desmopressin nasal spray solution or any of the ingredients in desmopressin nasal spray solution. Some people have had severe allergic reactions while taking desmopressin nasal spray solution. See the end of this Patient Information for complete list of ingredients in desmopressin nasal spray solution.. ohave kidney problems. ohave or have had low levels of sodium in your blood (hyponatremia) ohave or have had nasal sores, nasal surgery, nasal injury, or have problems such as stuffy nose or trouble breathing through your nose.. ohave or have had any heart, blood circulation, or blood pressure problems. ohave condition that causes fluid or water imbalance problems such as cystic fibrosis, or heart failure.. ohave or have had condition that causes you to be very thirsty. oare pregnant or plan to become pregnant. It is not known if desmopressin nasal spray solution will harm your unborn baby.. oare breastfeeding or plan to breastfeed. It is not known if desmopressin nasal spray solution passes into your breast milk. You and your healthcare provider should decide if you will use desmopressin nasal spray solution.. oRead the Instructions for Use that comes with your desmopressin nasal spray solution.. oUse desmopressin nasal spray solution exactly as your healthcare provider tells you to use it.. oYour healthcare provider may change your dose of desmopressin nasal spray solution if needed.. olow levels of sodium in the blood (hyponatremia). People using desmopressin nasal spray solution are at risk for low sodium levels in the blood, water intoxication, and fluid overload. Follow your healthcare providers instructions on limiting the amount of fluid you can drink when using desmopressin nasal spray solution.. oDo not drink more than you need to satisfy your thirst. You can have serious side effects such as seizures, coma, and death from drinking too much fluid.. oChildren and the elderly are at higher risk for these problems and should follow their healthcare providers limits on drinking fluids.. oCall your healthcare provider right away if you have any of the following symptoms while using desmopressin nasal spray solution. They may mean that your blood sodium level is too low. oheadache nausea, vomiting weight gain. orestlessness tiredness sleepiness. odisorientation loss of appetite muscle cramps. ofeeling irritable feeling weak. ohallucinations confusion. onasal scarring or swelling. Some people using desmopressin nasal spray solution for long periods of time may have nasal problems such as scarring or swelling. This may affect how well desmopressin nasal spray solution works for you.

SPL UNCLASSIFIED SECTION.

2.1 Important Administration Instructions. Administer desmopressin nasal spray solution by intranasal use only. Instruct patients about appropriate fluid restriction during desmopressin nasal spray solution treatment [see Warnings and Precautions (5.1)]. Must prime the spray pump prior to the first use. Instruct patients to:oPrime pump by pressing down on pump five times (if the spray pump is not used for one week, re-prime the pump by pressing down on the pump once).oDiscard desmopressin nasal spray solution after 50 sprays since the amount delivered thereafter may be substantially less than the recommended dosage.. oPrime pump by pressing down on pump five times (if the spray pump is not used for one week, re-prime the pump by pressing down on the pump once).. oDiscard desmopressin nasal spray solution after 50 sprays since the amount delivered thereafter may be substantially less than the recommended dosage.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPediatric Use: Use requires careful fluid intake restriction to prevent hyponatremia with water intoxication (5.1, 8.4)oGeriatric Use: Carefully monitor renal function; restrict fluid intake to prevent hyponatremia with water intoxication (5.1, 8.5). oPediatric Use: Use requires careful fluid intake restriction to prevent hyponatremia with water intoxication (5.1, 8.4). oGeriatric Use: Carefully monitor renal function; restrict fluid intake to prevent hyponatremia with water intoxication (5.1, 8.5). 8.1 Pregnancy Risk SummaryProlonged experience with desmopressin in pregnant women over several decades, based on the available published data and case reports, did not identify 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/m2) (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 2-4% and 15-20%, respectively.DataAnimal DataDesmopressin acetate at up to 50 ng/kg/day was given by subcutaneous injection to pregnant rats, from gestation day 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 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/m2).. 8.2 Lactation Risk SummaryBreastfeeding 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 mothers clinical need for desmopressin nasal spray solution and any potential adverse effects on the breastfed infant from desmopressin nasal spray solution or from the underlying maternal condition.DataA trial was conducted in six healthy lactating women, at greater than months postpartum, to evaluate intranasal administration of 300 mcg single dose of another desmopressin product (7.5 times the recommended adult dose of desmopressin nasal spray solution). Samples of maternal plasma and breastmilk were obtained at 0, 30, 60, 120, 240, 360 and 480 min after the drug administration. At 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 hours ranged between 491 pg and 16 ng, which corresponds to 0.0001 0.005% of the administered dose to the breastfeeding mother.. 8.4 Pediatric Use Desmopressin nasal spray solution is indicated as antidiuretic replacement therapy in the management of central diabetes insipidus in pediatric patients years of age and older. Desmopressin nasal spray solution is not indicated in pediatric patients less than years of age.Use of desmopressin nasal spray solution in pediatric patients 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 nasal spray solution 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 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 nasal spray solution 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 nasal spray solution 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHyponatremia: Instruct patients about proper fluid restriction and monitor serum sodium as needed (2.1, 5.1)oAltered Absorption in Patients with Nasal Mucosa Abnormalities: May occur with chronic administration, and require use of other formulations instead (5.2). oHyponatremia: Instruct patients about proper fluid restriction and monitor serum sodium as needed (2.1, 5.1). oAltered 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 solution 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 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 solution is not an indicated formulation for the treatment of primary nocturnal enuresis due to 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 solution 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 solution in such patients [see Indications and Usage (1)] and consider use of other formulations of desmopressin acetate given by other routes of administration.