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CLINICAL PHARMACOLOGY Stimate® Nasal Spray contains as active substance, desmopressin acetate, which is a synthetic analogue of the natural hormone arginine vasopressin. One spray or 0.1 mL (150 mcg) of Stimate® Nasal Spray solution has an antidiuretic activity of about 600 IU. Desmopressin acetate has been shown to be more potent than arginine vasopressin in increasing plasma levels of Factor VIII activity in patients with hemophilia and von Willebrand's disease Type I. Dose-response studies were performed in healthy persons using doses of 150 to 450 mcg, administered as one to three sprays. The response to Stimate® Nasal Spray is dose-related, with maximal plasma levels of 150 to 250 percent of initial concentrations achieved for both Factor VIII and von Willebrand factor. The increase is rapid and evident within 30 minutes, reaching a maximum at about 1.5 hours. The percentage increase of Factor VIII and von Willebrand factor levels in patients with mild hemophilia A and von Willebrand's disease was not notably different from that observed in normal healthy individuals when treated with 300 mcg of Stimate® Nasal Spray. In patients with von Willebrand's disease, levels of Factor VIII coagulant activity and von Willebrand factor antigen remained greater than 30 U/dL for 8 hours after a 300 mcg dose of Stimate® Nasal Spray.1 After 300 mcg of Stimate® Nasal Spray, the percentage increase of Factor VIII and von Willebrand factor levels in patients with mild hemophilia A and von Willebrand's disease was less than observed after 0.3 mcg/kg of intravenous desmopressin acetate. Plasminogen activator activity increases rapidly after intravenous desmopressin acetate infusion, but there has been no clinically significant fibrinolysis in patients treated with desmopressin acetate. The effect of repeated intravenous desmopressin acetate administration when doses were given every 12 to 24 hours has generally shown a diminution of the Factor VIII activity increase noted after a single dose. It is possible to reproduce the initial response in some patients after an interval of one week, but other patients may require as long as 6 weeks.2 The half-life of Stimate® Nasal Spray was between 3.3 and 3.5 hours, over the range of intranasal doses, 150 to 450 mcg. Plasma concentrations of Stimate® Nasal Spray were maximal approximately 40 to 45 minutes after dosing. The bioavailability of Stimate® Nasal Spray when administered by the intranasal route as a 1.5 mg/mL solution is between 3.3 and 4.1 percent. The change in structure of arginine vasopressin to desmopressin acetate has 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 are usually below threshold levels for effects on vascular or visceral smooth muscle. REFERENCES 1. Lethagen S, Harris AS and Nilsson IM: Intranasal desmopressin (DDAVP) by spray in mild hemophilia A and von Willebrand's disease type I. Blut, 60:187-191, 1990. 2. Lethagen S, Harris AS, Sjörin E and Nilsson IM: Intranasal and intravenous administration of desmopressin: Effect on FVIII/vWF, pharmacokinetics and reproducibility. Thromb. Haemost., 58:1033-1036, 1987.

CLINICAL PHARMACOLOGY Mechanism Of Action Desmopressin is a synthetic analog of vasopressin. Desmopressin is a selective agonist at V2 receptors on renal cells in the collecting ducts, increasing water re-absorption in the kidneys, and reducing urine production. Pharmacokinetics Absorption Following nasal spray administration of NOCTIVA, the median time to peak plasma concentrations (Tmax) was 0.25 hour for the 0.83 mcg dose and 0.75 hour for the 1.66 mcg dose. The mean (± S.D.) peak plasma concentration (Cmax) was 4.00 (± 3.85) pg/mL for the 0.83 mcg dose and 9.11 (± 6.90) pg/mL for the 1.66 mcg dose. Plasma NOCTIVA concentrations generally declined below 2 pg/mL (lower limit of quantitation) between four to six hours post-dose. Elimination Following an intranasal dose of 1.66 mcg of NOCTIVA, the median apparent terminal half-life (T1/2) was 2.8 hours. The distribution of T1/2 in patients with an eGFR above 50 mL/min/1.73 m2 ranged from 1.4-3.8 hours. Excretion Desmopressin is mainly excreted in urine. Specific Populations Sex And Age There were no significant differences in systemic exposure (AUC and Cmax) with respect to patient sex or age, among subjects 50 years and older. Renal Impairment The pharmacokinetics of NOCTIVA were evaluated in 8 renally impaired patients with an eGFR less than 50 mL/min/1.73 m2 , matched to 8 patients with an eGFR greater than 50 mL/min/1.73 m2. The AUC and T1/2 of desmopressin were approximately 3 to 4 fold higher for the group with eGFR below 50 mL/min/1.73 m2. Therefore, NOCTIVA is contraindicated in patients who have renal impairment with an eGFR below 50 mL/min/1.73 m2 [see CONTRAINDICATIONS]. Clinical Studies The efficacy of NOCTIVA in patients with nocturia due to nocturnal polyuria was established in two 12-week randomized, double-blind, placebo-controlled, multi-center trials in adults at least 50 years of age. At baseline, patients were required to have a six-month history of at least two nocturic episodes per night, on average, and at least 13 documented nocturia episodes over 6 nights during screening. The majority of patients in these trials were Caucasian (79%). The mean age was 67 years (range 50-90 years), 57% were men and 43% were women. In Trial 1, a total of 612 patients with nocturia due to nocturnal polyuria were randomized to receive either NOCTIVA 1.66 mcg (n=199), NOCTIVA 0.83 mcg (n=209) or placebo (n=204). In Trial 2, a total of 433 patients were randomized to receive NOCTIVA 1.66 mcg (n=143), 0.83 mcg (n=145) or placebo (n=145). In both trials, nocturnal polyuria was defined as a night-time urine production exceeding one-third of the 24-hour urine production confirmed with a 24-hour urine frequency/volume chart. Each trial had two co-primary efficacy endpoints: (1) The change in mean number of nocturic episodes per night from baseline during the 12-week treatment period, and (2) The percentage of patients who achieved at least a 50% reduction from baseline in the mean number of nocturia episodes per night during the 12-week treatment period. Secondary efficacy endpoints in both trials included the percentage of nights during the treatment period with no nocturia and the percentage of nights during the treatment period with at most one nocturia episode. Trial 1 included a patient-reported outcome instrument known as the INTU (Impact of Nighttime Urination) questionnaire as the first-ranked secondary efficacy endpoint that assessed the impacts of nocturia on some aspects of patients’ daily lives, with an overall impact score ranging from 0 to 100 points. Many conditions can cause nocturia. The efficacy and safety of NOCTIVA have not been established for all causes of nocturia. NOCTIVA is indicated only for patients who have nocturia due to nocturnal polyuria. The results for the co-primary efficacy endpoints among patients with nocturia due to nocturnal polyuria are shown in Table 5. Table 5: Co-Primary Efficacy Endpoints in the Pivotal Trials (Intent-to-Treat Population* with Nocturia Due to Nocturnal Polyuria) Trial 1 Trial 2 NOCTIVA 1.66 mcg (N=199) NOCTIVA 0.83 mcg (N=209) Placebo (N=204) NOCTIVA 1.66 mcg (N=143) NOCTIVA 0.83 mcg (N=145) Placebo (N=145) Change in Mean Number of Nocturic Episodes Per Night from Baseline Baseline (mean) 3.4 3.4 3.2 3.3 3.4 3.4 Change from baseline † -1.5 -1.5 -1.2 -1.5 -1.4 -1.1 Difference from placebo † -0.3 -0.3 - -0.4 -0.3 - 95% CI † -0.5 to -0.1 -0.4 to 0.0 - -0.6 to -0.2 -0.5 to -0.1 - Percentage of Patients Achieving at Least a 50% Reduction in Nocturic Episodes per Night from Baseline 47% 35% 27% 49% 41% 29% Difference from placebo ‡ 21% 8% - 20% 12% - 95% CI ‡ 12% to 30% -0.4% to 17% 9% to 31% 1% to 23% *Intent-to-treat population: all randomized patients who received study drug and had at least three days of post-randomization efficacy data recorded in their diary. CI: confidence interval †: obtained from ANCOVA model; ‡ obtained from stratified Cochran-Mantel-Haenszel (CMH) analysis. Figure 1 shows the percentage of patients in each treatment arm who achieved various reductions from baseline in the mean number of nightly nocturic episodes. In both trials, there was consistent separation between the NOCTIVA 1.66 mcg and placebo curves. Figure 1: Percentage of Patients Achieving Various Reductions From Baseline in Mean Number of Nightly Nocturic Episodes (Intent-to-Treat Population* with Nocturia Due to Nocturnal Polyuria) *Intent-to-treat population: all randomized patients who received study drug and had at least three days of post-randomization efficacy data recorded in their diary. The results for selected secondary efficacy endpoints among patients with nocturia due to nocturnal polyuria are shown in Table 6. Table 6: Selected Secondary Efficacy Endpoints in the Pivotal Trials (Intent-to-Treat* Population with Nocturia Due to Nocturnal Polyuria) Trial 1 Trial 2 NOCTIVA 1.66 mcg (n=199) NOCTIVA 0.83 mcg (n=209) Placebo (n=204) NOCTIVA 1.66 mcg (n=143) NOCTIVA 0.83 mcg (n=145) Placebo (n=145) Change from Baseline in Overall Impact Score for the INTU Questionnaire (Range 0-100) Baseline (mean) 33 30 32 The INTU Questionnaire was not used in Trial 2 Change from baseline † -15 -13 -11 Difference from placebo † -4 -2 - 95% CI † -6 to -1 -4 to 1 - Change from Baseline in Percentage of Nights with No Nocturia Episodes Baseline (mean) 0% 0% 0% 0% 0% 0% Change from baseline † 11% 7% 5% 9% 8% 4% Difference from placebo † 6% 2% - 5% 4% - 95% CI † 2% to 10% -1% to 6% - 1% to 9% 0.4% to 8% Change from Baseline in Percentage of Nights with at Most One Nocturia Episode Baseline (mean) 1% 1% 1% 1% 2% 1% Change from baseline † 44% 40% 34% 45% 40% 30% Difference from placebo † 9% 6% - 15% 10% - 95% CI † 2% to 17% -1% to 13% - 6% to 23% 1% to 18% *Intent-to-treat population: all randomized patients who received study drug and had at least three days of post-randomization efficacy data recorded in their diary. CI: confidence interval †: obtained from ANCOVA model

CLINICAL PHARMACOLOGY DDAVP contains as active substance desmopressin acetate, a synthetic analogue of the natural hormone arginine vasopressin. One mL (0.1 mg) of intranasal DDAVP has an antidiuretic activity of about 400 IU; 10 mcg of desmopressin acetate is equivalent to 40 IU. The biphasic half-lives for intranasal DDAVP were 7.8 and 75.5 minutes for the fast and slow phases, compared with 2.5 and 14.5 minutes for lysine vasopressin, another form of the hormone used in this condition. As a result, intranasal DDAVP provides a prompt onset of antidiuretic action with a long duration after each administration. The change in structure of arginine vasopressin to DDAVP has 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 are usually below threshold levels for effects on vascular or visceral smooth muscle. DDAVP administered intranasally has an antidiuretic effect about one-tenth that of an equivalent dose administered by injection. Human Pharmacokinetics: DDAVP is mainly excreted in the urine. A pharmacokinetic study conducted in healthy volunteers and patients with mild, moderate, and severe renal impairment (n=24, 6 subjects in each group) receiving single dose desmopressin acetate (2mcg) injection demonstrated a difference in DDAVP terminal half-life. Terminal half-life significantly increased from 3 hours in normal healthy patients to 9 hours in patients with severe renal impairment. (See CONTRAINDICATIONS)

Find Lowest Prices on Stimate® (desmopressin acetate) Nasal Spray, 1.5 mg/mL DESCRIPTION Stimate® (desmopressin acetate) is a synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation. Stimate® Nasal Spray contains 1.5 mg/mL desmopressin acetate in an aqueous solution at a pH of approximately 5.0. Stimate® Nasal Spray's compression pump delivers 0.1 mL (150 mcg) of solution per spray. It is chemically defined as follows: Mol. Wt. 1183.34 Empirical formula: C46H64N14O12S2 •C2H4O2•3H2O 1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate. Stimate® Nasal Spray is provided as an aqueous solution for intranasal use. Each mL contains: Active ingredient: Desmopressin acetate 1.5 mg Inactive ingredients: Sodium chloride 7.5 mg Buffer: Citric acid monohydrate 1.7 mg Disodium phosphate dihydrate 3.0 mg Preservative: Benzalkonium chloride 0.1 mg Purified water To 1 mL

NOCTIVA™ (desmopressin acetate) Spray, for Nasal Administration WARNING HYPONATREMIA NOCTIVA can cause hyponatremia. Severe hyponatremia can be life-threatening, leading to seizures, coma, respiratory arrest or death (WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS). NOCTIVA is contraindicated in patients at increased risk of severe hyponatremia, such as patients with excessive fluid intake, illnesses that can cause fluid or electrolyte imbalances, and in those using loop diuretics or systemic or inhaled glucocorticoids (CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS). Ensure serum sodium concentrations are normal before starting or resuming NOCTIVA. Measure serum sodium within seven days and approximately one month after initiating therapy or increasing the dose, and periodically during treatment. More frequently monitor serum sodium in patients 65 years of age and older and in patients at increased risk of hyponatremia (DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS). If hyponatremia occurs, NOCTIVA may need to be temporarily or permanently discontinued (WARNINGS AND PRECAUTIONS). DESCRIPTION Desmopressin acetate is a synthetic analogue of 8-arginine vasopressin, an endogenous pituitary hormone also known as antidiuretic hormone (ADH). Its chemical name is 1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate, and its molecular weight is 1183.31. Its molecular formula is C48H68N14O14S2·3H2O. Its chemical structure is: Desmopressin acetate is a white powder that is freely soluble in water. It is also soluble in alcohol and glacial acetic acid. NOCTIVA (desmopressin acetate) nasal spray is formulated for intranasal use as a milky white emulsion without preservatives at pH 5.5. NOCTIVA is available as an oil-in-water emulsion at two dose strengths, 0.83 mcg and 1.66 mcg of desmopressin acetate per spray, for nasal administration. Each spray is 0.1 mL. The dose strengths are expressed as desmopressin acetate and are equivalent to 0.75 mcg and 1.5 mcg of desmopressin free base per spray, respectively. Both formulations also contain the following inactive ingredients: cyclopentadecanolide; cottonseed oil; sorbitan monolaurate; polysorbate 20; citric acid, anhydrous; sodium citrate dihydrate; and water for injection. After initial priming, each actuation of NOCTIVA 0.83 mcg/0.1 mL or 1.66 mcg/0.1 mL delivers a dose of 0.83 mcg or 1.66 mcg of desmopressin acetate, respectively.

DDAVP® Nasal Spray (desmopressin acetate) DESCRIPTION DDAVP® Nasal Spray (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: Mol. Wt. 1183.34.............................Empirical Formula: C46H64N14O12S2•C2H4O2•3H2O 1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate. DDAVP Nasal Spray (desmopressin acetate nasal spray) is provided as an aqueous solution for intranasal use. Each mL contains: Desmopressin acetate ..... 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 The DDAVP Nasal Spray compression pump delivers 0.1 mL (10 mcg) of DDAVP (desmopressin acetate) per spray.

INDICATIONS Before the initial therapeutic administration of Stimate® Nasal Spray, the physician should establish that the patient shows an appropriate change in the coagulation profile following a test dose of intranasal administration of Stimate® Nasal Spray. Desmopressin acetate is also available as a solution for injection (DDAVP® Injection) when the intranasal route may be compromised. These situations include nasal congestion and blockage, nasal discharge, atrophy of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may also be inappropriate where there is an impaired level of consciousness. Hemophilia A Stimate® Nasal Spray is indicated for patients with hemophilia A with Factor VIII coagulant activity levels greater than 5%. Desmopressin acetate will also stop bleeding in patients with hemophilia A with episodes of spontaneous or trauma-induced injuries such as hemarthroses, intramuscular hematomas or mucosal bleeding. In the outpatient setting during two clinical trials where patients recorded bleeding episodes, Stimate® Nasal Spray provided effective hemostasis 100% of the time in 2 of the 5 patients. For those patients not responding in 100% of bleeding occasions, 45% (14 of 31) of bleeding episodes were effectively controlled with Stimate® Nasal Spray.  Desmopressin acetate is not indicated for the treatment of hemophilia A with Factor VIII coagulant activity levels equal to or less than 5%, or for the treatment of hemophilia B, or in patients who have Factor VIII antibodies. von Willebrand's Disease (Type I) Stimate® Nasal Spray is indicated for patients with mild to moderate classic von Willebrand's disease (Type I) with Factor VIII levels greater than 5%. Desmopressin acetate will also stop bleeding in mild to moderate von Willebrand's disease patients with episodes of spontaneous or trauma-induced injuries such as hemarthroses, intramuscular hematomas, mucosal bleeding or menorrhagia. In the outpatient setting during two clinical trials where patients recorded bleeding episodes, Stimate® Nasal Spray provided effective hemostasis 100% of the time in 75% of the patients (n=16). For those patients not responding in 100% of bleeding occasions, 78% (64 of 82) of bleeding episodes were effectively controlled with Stimate® Nasal Spray. Patients may respond in a variable fashion depending on the type of molecular defect they have. Bleeding time and Factor VIII coagulant activity, ristocetin cofactor activity, and von Willebrand factor antigen should be checked after initial administration of Stimate® Nasal Spray to ensure that adequate levels have been achieved. Stimate® Nasal Spray is not indicated for the treatment of severe classic von Willebrand's disease (Type I) and when there is evidence of an abnormal molecular form of Factor VIII antigen. See WARNINGS. DOSAGE AND ADMINISTRATION Hemophilia A and von Willebrand's Disease (Type I) Stimate® Nasal Spray is administered by nasal insufflation, one spray per nostril, to provide a total dose of 300 mcg. In patients weighing less than 50 kg, 150 mcg administered as a single spray provided the expected effect on Factor VIII coagulant activity, Factor VIII ristocetin cofactor activity and skin bleeding time. If Stimate® Nasal Spray is used preoperatively, it should be administered 2 hours prior to the scheduled procedure.3,4 The necessity for repeat administration of Stimate® Nasal Spray or use of any blood products for hemostasis should be determined by laboratory response as well as the clinical condition of the patient. Fluid restriction should be observed, and fluid intake should be limited to a minimum, from 1 hour before desmopressin administration, until at least 24 hours after administration. The tendency toward tachyphylaxis (lessening of response) with repeated administration given more frequently than once every 48 hours should be considered in treating each patient. The nasal spray pump can only deliver doses of 0.1 mL (150 mcg) or multiples of 0.1 mL. If doses other than these are required, DDAVP® Injection may be used. The spray pump must be primed prior to the first use. To prime pump, press down 4 times. The bottle should be discarded after 25 doses since the amount delivered thereafter per spray may be substantially less than 150 mcg of drug. HOW SUPPLIED A 2.5 mL bottle with spray pump capable of delivering 25 doses of 150 mcg (NDC 0053-6871-00). Store at room temperature not to exceed 25°C (77°F) for the period indicated by the expiration date on the label. Discard six months after being opened. Store bottle in upright position. REFERENCES 3. Chistolini A, Dragoni F, Ferrari A, La Verde G, Arcieri R, Mohamud AE and Mazzucconi MG: Intranasal DDAVP: Biological and clinical evaluation in mild Factor VIII deficiency. Haemostasis, 21:273-277, 1991. 4. Rose EH and Aledort LM: Nasal spray desmopressin (DDAVP) for mild hemophilia A and von Willebrand's disease. Ann. Int. Med., 114:563-568, 1991. Manufactured for: By: CSL Behring LLC Ferring GmbH, King of Prussia, PA 19406-0901 Kiel, Germany, US License No. 1767. Revised November 2012 IN-8155-08

INDICATIONS NOCTIVA is indicated for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least 2 times per night to void. Nocturnal polyuria was defined in the NOCTIVA clinical trials as night-time urine production exceeding one-third of the 24-hour urine production. Before starting NOCTIVA: Evaluate the patient for possible causes for the nocturia, including excessive fluid intake prior to bedtime, and optimize the treatment of underlying conditions that may be contributing to the nocturia. Confirm the diagnosis of nocturnal polyuria with a 24-hour urine collection, if one has not been obtained previously. Limitation Of Use NOCTIVA has not been studied in patients less than 50 years of age. DOSAGE AND ADMINISTRATION Important Administration And Priming Instructions Only administer NOCTIVA intranasally. Do not shake the bottle. Prime NOCTIVA before using for the first time by pumping 5 actuations into the air away from the face. Re-prime by pumping 2 actuations into the air if the product has not been used for more than 3 days. If a dose is missed, do not double the dose at next use. Two sprays of NOCTIVA 0.83 mcg are not interchangeable with one spray of NOCTIVA 1.66 mcg. Prescribe the NOCTIVA nasal spray 1.66 mcg/0.1 mL bottle for patients who are or will be taking the 1.66 mcg dose. Recommended Dosage For patients younger than 65 years of age who are not at increased risk for hyponatremia: The recommended dose is one spray of NOCTIVA 1.66 mcg in either the left or right nostril approximately 30 minutes before going to bed. For patients ≥65 years of age, or younger patients at increased risk for hyponatremia: The recommended starting dose is one spray of NOCTIVA 0.83 mcg in either the left or right nostril approximately 30 minutes before going to bed. After at least 7 days of treatment, the dose can be increased to 1.66 mcg, if needed, provided the serum sodium is within the normal range during treatment with the 0.83 mcg dose. The 0.83 mcg dose did not meet all prespecified efficacy endpoints in clinical trials but may have a lower risk of hyponatremia [see ADVERSE REACTIONS and Clinical Studies]. Monitoring Of Serum Sodium Concentration Check serum sodium concentrations: Prior to initiating or resuming NOCTIVA or increasing the dose. NOCTIVA is contraindicated in patients with hyponatremia or a history of hyponatremia [see CONTRAINDICATIONS]. Within 7 days and approximately one month after initiating therapy or increasing the dose. Periodically during NOCTIVA therapy, as clinically appropriate. More frequent serum sodium monitoring is recommended for patients 65 years and older and for those at increased risk of hyponatremia. If the patient develops hyponatremia, NOCTIVA may need to be temporarily or permanently discontinued, and treatment for the hyponatremia instituted, depending on the clinical circumstances, including the duration and severity of the hyponatremia [see WARNINGS AND PRECAUTIONS]. HOW SUPPLIED Dosage Forms And Strengths Preservative-free desmopressin acetate nasal spray. Each spray delivers 0.1 mL of NOCTIVA. Each spray of the 0.83 mcg/0.1 mL strength of desmopressin acetate contains 0.83 mcg of desmopressin acetate (equivalent to 0.75 mcg of desmopressin). Each spray of the 1.66 mcg/0.1 mL strength of desmopressin acetate contains 1.66 mcg of desmopressin acetate (equivalent to 1.5 mcg of desmopressin). Storage And Handling NOCTIVA (desmopressin acetate) nasal spray is available in a 3.5 mL amber glass bottle (nominal volume) fitted with a nasal actuator, a cartridge pump, and a dip tube, delivering a dose of either 0.83 mcg or 1.66 mcg of desmopressin acetate (equivalent to 0.75 mcg or 1.5 mcg of desmopressin) per spray (0.1 mL). Each bottle contains a target amount of 3.8 g formulation with 30 effective doses in addition to the initial priming (5 actuations), equivalent to 30 days of medication when used as one spray once a day. 0.83 mcg/0.1 mL of desmopressin acetate NDC 0023-5227-35 1.66 mcg/0.1 mL of desmopressin acetate NDC 0023-5670-35 Storage And Handling Before opening, store upright in a refrigerator, 2°C to 8°C (36°F to 46°F); excursion permitted between 0°C and 15°C (32°F and 59°F) [See USP Controlled Cold Temperature]. After opening, store upright at room temperature 20°C to 25°C (68°F to 77°F). Discard NOCTIVA 60 days after opening. Manufactured by: Renaissance Lakewood, LLC for Serenity, Renaissance Lakewood, LLC, Lakewood, NJ, U.S.A. Serenity Pharmaceuticals, LLC, Milford, PA, U.S.A. Revised: March 2017

INDICATIONS Central Cranial Diabetes Insipidus: DDAVP Nasal Spray (desmopressin acetate nasal spray) is indicated as antidiuretic replacement therapy in the management of central cranial diabetes insipidus and for management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region. It is ineffective for the treatment of nephrogenic diabetes insipidus. The use of DDAVP Nasal Spray (desmopressin acetate nasal spray) in patients with an established diagnosis will result in a reduction in urinary output with increase in urine osmolality and a decrease in plasma osmolality. This will allow the resumption of a more normal life-style with a decrease in urinary frequency and nocturia. There are reports of an occasional change in response with time, usually greater than 6 months. Some patients may show a decreased responsiveness, others a shortened duration of effect. There is no evidence this effect is due to the development of binding antibodies but may be due to a local inactivation of the peptide. Patients are selected for therapy by establishing the diagnosis by means of the water deprivation test, the hypertonic saline infusion test, and/or the response to antidiuretic hormone. Continued response to intranasal DDAVP can be monitored by urine volume and osmolality. DDAVP is also available as a solution for injection when the intranasal route may be compromised. These situations include nasal congestion and blockage, nasal discharge, atrophy of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may also be inappropriate where there is an impaired level of consciousness. In addition, cranial surgical procedures, such as transsphenoidal hypophysectomy create situations where an alternative route of administration is needed as in cases of nasal packing or recovery from surgery. DOSAGE AND ADMINISTRATION Central Cranial Diabetes Insipidus: DDAVP Nasal Spray (desmopressin acetate nasal spray) dosage must be determined for each individual patient and adjusted according to the diurnal pattern of response. Response should be estimated by two parameters: adequate duration of sleep and adequate, not excessive, water turnover. Patients with nasal congestion and blockage have often responded well to intranasal DDAVP. The usual dosage range in adults is 0.1 to 0.4 mL daily, either as a single dose or divided into two or three doses. Most adults require 0.2 mL daily in two divided doses. The morning and evening doses should be separately adjusted for an adequate diurnal rhythm of water turnover. For children aged 3 months to 12 years, the usual dosage range is 0.05 to 0.3 mL daily, either as a single dose or divided into two doses. About 1/4 to 1/3 of patients can be controlled by a single daily dose of DDAVP administered intranasally. Fluid restriction should be observed. (See WARNINGS, PRECAUTIONS, Pediatric Use and Geriatric Use.) The nasal spray pump can only deliver doses of 0.1 mL (10 mcg) or multiples of 0.1 mL. If doses other than these are required, the rhinal tube delivery system may be used. The spray pump must be primed prior to the first use. To prime pump, press down four times. The bottle will now deliver 10 mcg of drug per spray. Discard DDAVP Nasal Spray (desmopressin acetate nasal spray) after 50 sprays since the amount delivered thereafter per spray may be substantially less than 10 µg of drug. Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY, Human Pharmacokinetics, CONTRAINDICATIONS, and PRECAUTIONS, Geriatric Use.) HOW SUPPLIED DDAVP Nasal Spray (desmopressin acetate nasal spray) is available in a 5-mL bottle with spray pump delivering 50 sprays of 10 mcg (NDC 0075-2452-01). Desmopressin acetate is also available as DDAVP Rhinal Tube, a refrigerated product with 2.5 mL per bottle, packaged with two rhinal tube applicators per carton (NDC 0075-2450-01). Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP]. STORE BOTTLE IN UPRIGHT POSITION. Keep out of the reach of children. Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 Rev. July 2007. FDA Rev date: 10/26/2007

PATIENT INFORMATION Stimate® Nasal Spray (Pronounced Stim-ate) (desmopressin acetate) Read this patient information leaflet before you start taking Stimate® Nasal Spray and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about Stimate® Nasal Spray? All patients using Stimate® Nasal Spray are at risk for water intoxication, fluid overload and low sodium levels in the blood. You must follow your healthcare provider's instructions on limiting the amount of fluid you can drink when taking Stimate® Nasal Spray. Do 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. Children and elderly patients are at higher risk for these conditions and must follow their healthcare provider's restrictions on drinking fluids. Call your healthcare provider right away if you have any of the following symptoms while using Stimate® Nasal Spray. They may mean that your blood sodium level is low: Headache Loss of appetite Nausea Irritability Vomiting Muscle weakness Weight gain Muscle spasms or cramps Restlessness Hallucinations Tiredness Confusion Using Stimate® Nasal Spray the wrong way may cause it not to work to control bleeding. Call your healthcare provider right away if you have any uncontrolled bleeding. What is Stimate® Nasal Spray? Stimate® Nasal Spray is a prescription medicine used to stop some types of bleeding in people with mild hemophilia A or mild to moderate von Willebrand's disease Type 1. Stimate® Nasal Spray should not be used in children under 11 months of age. What should I tell my healthcare provider before I use Stimate® Nasal Spray? Before taking Stimate® Nasal Spray, tell your healthcare provider about all of your medical conditions, including if you: Have any nasal problems such as a stuffy nose, have ever had surgery on your nose, or have trouble breathing through your nose. You may need to use another form of this medicine. Have or have had any heart, blood circulation, or blood pressure problems. Have a condition that causes fluid or water imbalance problems such as: Cystic fibrosis Heart failure Kidney problems Have or have had a condition that causes you to be very thirsty. Are pregnant or plan to become pregnant. It is not known if Stimate® Nasal Spray will harm your unborn baby. Are breast-feeding or plan to breast-feed. It is not known if Stimate® Nasal Spray passes into your breast milk. You and your healthcare provider should decide if you will take Stimate® Nasal Spray. Tell your healthcare provider and pharmacist about all the medicines you take, including prescription and non-prescription medicines, such as over-the-counter medicines, vitamins, supplements and herbal remedies. Using Stimate® Nasal Spray with certain other medicines can affect the way Stimate® Nasal Spray works. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. It is especially important to tell your healthcare provider if you take: Blood pressure or heart medicines Antidepressants Anti-anxiety medicines Antihistamines Pain relievers such as narcotics or non-steroidal anti-inflammatory medicines (NSAIDs) Seizure medicines Medicines for over-active urinary bladder Ask your healthcare provider or pharmacist if you are not sure if your medicine is one of these. How should I use Stimate® Nasal Spray? Use Stimate® Nasal Spray exactly as your healthcare provider told you. Do not use more Stimate® Nasal Spray or take it more often than your healthcare provider told you. The Stimate® Nasal Spray pump provides the correct dose of your medicine. For detailed instructions on how to use the nasal spray pump, see the Patient Instructions for Use at the end of this leaflet. The nasal spray pump delivers 25 doses of Stimate® Nasal Spray and each spray contains a measured amount of medicine. Any medicine left in the spray pump after 25 sprays should be thrown away because, at that time, the amount of medicine in each spray may be a lot less than the correct amount. Do not put any leftover medicine into another bottle. If your symptoms do not improve, or if they become worse, contact your healthcare provider. Do not stop taking Stimate® Nasal Spray without talking to your healthcare provider. If you use too much Stimate® Nasal Spray, call your healthcare provider or go to the nearest hospital emergency department right away. What are the possible side effects of Stimate® Nasal Spray? Stimate® Nasal Spray may cause serious side effects, that come from having too much water in the body. See “What is the most important information I should know about Stimate® Nasal Spray?”. Common side effects of Stimate Nasal Spray include: Occasional facial flushing Nasal congestion Runny nose Nosebleed Sore throat Cough Upper respiratory infections. Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of Stimate® Nasal Spray. If you have questions, talk to your healthcare provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Stimate® Nasal Spray? Store at room temperature, but not higher than 77°F (25°C). Throw away Stimate® Nasal Spray six months after it is opened, or when the expiration date has passed, if this date is before the six months is up. Store Stimate® Nasal Spray standing upright. Keep Stimate® Nasal Spray and all medicines out of the reach of children. General information about Stimate® Nasal Spray Medicines are sometimes prescribed for conditions that are not mentioned in the patient leaflet. Do not use Stimate® Nasal Spray for a condition for which it was not prescribed. Do not give Stimate® Nasal Spray to other people, even if they have the same symptoms you have. It may harm them. This patient information leaflet summarizes the most important information about Stimate® Nasal Spray. If you would like more information about Stimate® Nasal Spray, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Stimate® Nasal Spray that is written for health professionals. For more information, go to www.stimate.com or call CSL Behring Medical Affairs at 1-800-504-5434. What are the ingredients in Stimate® Nasal Spray? Active ingredients: desmopressin acetate Inactive ingredients: sodium chloride, citric acid monohydrate, disodium phosphate dihydrate, benzalkonium chloride, purified water. Patient Instructions for Use Read these instructions carefully before you use your Stimate® Nasal Spray pump. The following instructions tell you how to prepare, or prime, your Stimate® Nasal Spray pump so that it is ready to use. Using your Stimate® Nasal Spray Pump 1. Remove the protective cap. 2. When using Stimate® Nasal Spray for the first time, the spray pump must be primed by pressing down on the ring at the top of the pump 4 times. Hold the spray tip away from your face and eyes. See Figure A. Figure A 3. When primed, the Stimate® Nasal Spray pump delivers one dose of medicine each time it is pressed. For the right dose, tilt your Stimate® Nasal Spray pump so that the tube inside the spray pump draws the medicine up from the deepest part of the medicine inside the container. See Figures A and B. Figure B 4. Put the spray nozzle tip into your nostril and press the spray pump one time for one dose (150-micrograms). If two doses are prescribed, spray each nostril one time (for a dose of 300-micrograms). 5. When you finish using your Stimate® Nasal Spray, put the cap over the tip of the pump. 6. If Stimate® Nasal Spray has not been used for one week, you will need to prime the pump again by pressing one time, or until you see a fine mist. Use this check-off chart to help you keep track of the number of sprays used. This will help make sure that you receive 25 doses with each bottle of Stimate® Nasal Spray. There is extra medicine in the bottle to allow for priming. When using the chart to check off sprays, do not count the priming sprays. Stimate® Nasal Spray 25 Spray Check-off Chart 1. Keep this chart with your Stimate® Nasal Spray or put it someplace where you can easily get it. 2. Check off number 1 on the chart with your first dose of Stimate® Nasal Spray. Check off the numbers after each use of Stimate® Nasal Spray. If your healthcare provider prescribed a 2-spray dose (300-micrograms), then two numbers should be checked off. 3. Throw away the Stimate® Nasal Spray after 25 doses.

PATIENT INFORMATION NOCTIVA™ (nok-tee-va) (desmopressin acetate) Nasal Spray 0.83 mcg/0.1 mL and 1.66 mcg/0.1 mL Important: NOCTIVA is for use in your nose (intranasal) only. What is the most important information I should know about NOCTIVA? NOCTIVA may cause serious side effects, including: Low levels of salt (sodium) in your blood (hyponatremia) can happen with NOCTIVA. If you develop very low salt levels in your blood, this may lead to serious or life threatening side effects, including seizure, coma, trouble breathing, or death if not treated early. Call your doctor if you have any of the following symptoms of low salt levels in your blood: headache nausea or vomiting feeling restless fatigue drowsiness dizziness muscle cramps change in your mental condition, such as confusion, or decreased awareness or alertness Low salt levels in the blood happen more often in people who are treated with NOCTIVA and are 65 years old or older than in people treated with NOCTIVA who are younger than 65 years old. Your doctor should check the salt levels in your blood before you start taking NOCTIVA, during treatment with NOCTIVA, before increasing your dose, and before you restart taking NOCTIVA if your treatment with NOCTIVA was stopped for a period of time. To help decrease your risk of developing low levels of sodium in your blood: Limit the amount of fluids you drink in the evening and night-time. Stop taking NOCTIVA and tell your doctor right away if you have a stomach or intestinal virus with vomiting or diarrhea or if you have an infection or fever. Stop taking NOCTIVA and tell your doctor right away if you develop any nose problems, such as a blockage, stuffy nose, runny nose, or drainage. Your doctor may stop your treatment with NOCTIVA for a period of time or stop your treatment completely if you have low levels of salt in your blood during treatment with NOCTIVA. What is NOCTIVA? NOCTIVA is a prescription medicine used in adults who wake up two or more times during the night to urinate due to a condition called nocturnal polyuria. Nocturnal polyuria is a condition where your body makes too much urine at night. There are other conditions that could cause you to wake up during the night to urinate. NOCTIVA is only approved for the treatment of nocturnal polyuria. Your doctor should have you measure your urine and the times that you urinate for 24 hours to determine if you have nocturnal polyuria if you have not already done this. NOCTIVA is not for use in children who wet the bed while sleeping at night. NOCTIVA has not been studied in people under 50 years of age. Do not use NOCTIVA if you: have or have had low salt levels in your blood are thirsty much of the time and drink large amounts of fluids (polydipsia) wet the bed while sleeping at night are taking a type of water-pill called a loop-diuretic are taking a glucocorticoid (steroid) medicine, including an inhaled glucocorticoid (steroid) medicine have moderate to severe kidney problems have or may have a condition called syndrome of inappropriate antidiuretic hormone (SIADH) secretion have an illness that can cause you to have low levels of fluid or electrolytes in your blood, such as vomiting, diarrhea, an infection, or a kidney problem that causes you to lose too much salt have symptoms from a heart problem called congestive heart failure have high blood pressure that is not controlled Ask your doctor if you are not sure you have any of these conditions or take any of the medicines listed. Before using NOCTIVA, tell your doctor about all of your medical conditions, including if you: have vomiting, diarrhea, fever, or infection have kidney or heart problems have diabetes mellitus have had a head injury have a heart problem called congestive heart failure have a history of not being able to empty your bladder all of the way (urinary retention) have any nose problems, such as a blockage, stuffy nose, runny nose, or drainage are pregnant or plan to become pregnant. It is not known if NOCTIVA can harm your unborn baby. are breastfeeding or plan to breastfeed. Desmopressin, an ingredient in NOCTIVA, passes into breast milk. Talk to your doctor about the best way to feed your baby if you use NOCTIVA. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using NOCTIVA with certain other medicines may cause serious side effects. Do not start taking any new medicines until you talk to your doctor. Especially tell your doctor if you take a: water pill (diuretic) glucocorticoid (steroid) medicine, including an inhaled glucocorticoid (steroid) medicine Your doctor should stop your treatment with NOCTIVA for a period of time while you are taking and after you stop taking an oral or inhaled glucocorticoid (steroid) medicine. medicine used to treat depression called a tricyclic antidepressant or selective serotonin reuptake inhibitor (SSRI) medicine used to treat mood disorders, such as schizophrenia or bipolar disorder called chlorpromazine medicine used to treat seizures, nerve pain, or bipolar disorder called carbamazepine non-steroidal anti-inflammatory medicine (NSAID) medicine that you use in your nose Ask your doctor or pharmacist if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine. How should I use NOCTIVA? See the Instructions for Use that come with NOCTIVA for information about the right way to use NOCTIVA. Use NOCTIVA exactly as your doctor tells you to use it. NOCTIVA comes in two strengths. Your doctor has prescribed the strength that is best for you. If your dose of NOCTIVA is changed from 0.83 mcg/0.1 mL to 1.66 mcg/0.1 mL your doctor will give you a prescription for NOCTIVA 1.66 mcg/0.1 mL. You should not use 2 sprays of NOCTIVA 0.83 mcg/0.1 mL instead of 1 spray of NOCTIVA 1.66 mcg/0.1 mL. Use 1 spray of NOCTIVA in your left or right nostril 1 time each night, about 30 minutes before you go to bed. If you take too much NOCTIVA, stop taking NOCTIVA and call your doctor or get medical help right away. If you miss a dose of NOCTIVA, take the next dose at your regular time. Do not take 2 doses at the same time to make up for a missed dose. What should I avoid while taking NOCTIVA? Do not drink large amounts of fluids close to bedtime during treatment with NOCTIVA. What are the possible side effects of NOCTIVA? NOCTIVA can cause serious side effects. See "What is the most important information I should know about NOCTIVA?" Fluid retention. Your body may hold too much fluid (fluid retention). The most common side effects of NOCTIVA include: nose discomfort pain or swelling (inflammation) in your nose or throat stuffy nose sneezing high blood pressure back pain nosebleed inflammation of the lining of the bronchial tubes that carry air to and from your lungs that causes a cough (bronchitis) dizziness These are not all the possible side effects of NOCTIVA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store NOCTIVA? Before opening, store NOCTIVA upright in a refrigerator between 36°F to 46°F (2°C to 8°C). After opening, store NOCTIVA upright at room temperature between 68°F to 77°F (20°C to 25°C). Throw away (discard) NOCTIVA 60 days after opening. Write the date the bottle is opened on the bottle label. Keep NOCTIVA and all medicines out of the reach of children. General information about the safe and effective use of NOCTIVA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NOCTIVA for a condition for which it was not prescribed. Do not give NOCTIVA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about NOCTIVA that is written for health professionals. What are the ingredients in NOCTIVA? Active ingredient: desmopressin acetate Inactive ingredients: cyclopentadecanolide, cottonseed oil, sorbitan monolaurate, polysorbate 20, citric acid anhydrous, sodium citrate dihydrate, and water for injection Instructions for Use NOCTIVA™ (nok-tee-va) (desmopressin acetate) nasal spray 0.83 mcg/0.1 mL and 1.66 mcg/0.1 mL Read this Instructions for Use before you start using NOCTIVA and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. Important information: NOCTIVA is for use in your nose only. You will need to prime your bottle of NOCTIVA before using it for the first time. See “Before your first use, follow these instructions to prime your bottle of NOCTIVA”. If you do not use NOCTIVA for more than 3 days, you will need to re-prime the bottle of NOCTIVA before you start using it again. See “Re-priming NOCTIVA”. Parts of your NOCTIVA nasal spray (See Figure A). Figure A Before your first use, follow these instructions to prime your bottle of NOCTIVA Prime your bottle of NOCTIVA before using it for the first time. Do not shake the bottle. Step 1. Pull the cap off and set it aside (See Figure B). Figure B Step 2. Remove and throw away (discard) the clip (See Figure C). Figure C Step 3. Hold the bottle upright and away from your face. Place 1 finger on each side of the base of the nasal applicator and your thumb underneath the bottle (See Figure D). Figure D Step 4. Completely press (pump) the nasal applicator 5 times by squeezing your fingers and thumb together (See Figure E). Keep nasal applicator pointed away from your face. Figure E Your NOCTIVA is now ready to use. Using NOCTIVA Use only 1 spray of NOCTIVA in 1 nostril each night about 30 minutes before going to bed. Step 1. Blow your nose to clear your nostrils (See Figure F). Figure F Step 2. Hold the bottle upright (See Figure G). Figure G Step 3. Tilt your head back slightly (See Figure H). Figure H Nasal applicator must be in an upright position to deliver the correct dose. Do not lie down or tilt your head too far back while giving your dose of NOCTIVA. Step 4. Insert the nasal applicator into your left or right nostril. Keep the nasal applicator upright. Close your open nostril with a finger from your empty hand (See Figure I). Figure I Step 5. Breathe in (inhale) gently while you pump the nasal applicator 1 time (See Figure J). Figure J Avoid spraying in your eyes. Gently breathe in through your nose and out through your mouth several times. Step 6. Wipe the nasal applicator with a clean tissue (See Figure K). Figure K Step 7. Replace the cap on the bottle (See Figure L). Figure L Re-priming NOCTIVA If you do not use NOCTIVA for more than 3 days, you will need to re-prime the bottle before you start using it again. If you miss a dose, take the next dose at your regular time. Do not take 2 doses at the same time. To re-prime your bottle of NOCTIVA, hold the bottle upright and away from your face. Completely press (pump) the nasal applicator 2 times. Your NOCTIVA is now ready to use. Storage: Before opening, store NOCTIVA upright in a refrigerator between 36°F to 46°F (2°C to 8°C). After opening, store NOCTIVA upright at room temperature between 68°F to 77°F (20°C to 25°C). Throw away (discard) NOCTIVA 60 days after opening. Write the date the bottle is opened on the bottle label. Keep NOCTIVA and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration.

PATIENT INFORMATION DDAVP® Nasal Spray (desmopressin acetate) A better way to deliver DDAVP Delivering DDAVP more efficiently Your doctor has prescribed DDAVP as antidiuretic hormone replacement therapy. Follow the dosage schedule that is specified. The convenient nasal spray pump provides an efficient, reliable way to administer your medication. It is important, however, to adhere completely to the following instructions so that you will always receive a consistent dose of your medication. CAUTION: The nasal spray pump accurately delivers 50 doses of 10 micrograms each. Any solution remaining after 50 doses should be discarded since the amount delivered thereafter per actuation may be substantially less than 10 micrograms of drug. Do not transfer any remaining solution to another bottle. Please read the following instructions carefully before using the spray pump. Ensure that in children administration is under adult supervision in order to control the dose intake. If you accidentally deliver/administer too much of a dose, immediately telephone your doctor or a certified Regional Poison Center for advice. Possible signs of overdose may include confusion, drowsiness, continuing headache, problems with passing urine and rapid weight gain due to fluid retention. Using your DDAVP Nasal Spray (desmopressin acetate nasal spray) Pump Remove protective cap. The spray pump must be primed prior to the first use. To prime pump, press down 4 times. Once primed, the spray pump delivers 10 micrograms of medication each time it is pressed. To ensure dosing accuracy, tilt bottle so that dip tube inside the bottle draws from the deepest portion of the medication. To administer a 10-microgram dose, place the spray nozzle in nostril and press the spray pump once. If a higher dose has been prescribed, spray half the dose in each nostril. The spray pump cannot be used for doses less than 10 micrograms or doses other than multiples of 10 micrograms. Replace the protective cap on bottle after use. The pump will stay primed for up to one week. If the product has not been used for a period of one week, re-prime the pump by pressing once. We have included a convenient check-off chart to assist you in keeping track of medication doses used. This will help assure that you receive 50 "full doses" of medication. Please note that the bottle has been filled with extra solution to accommodate the initial priming activity. DDAVP Nasal Spray (desmopressin acetate nasal spray) 5 0-Dose Check-off 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Retain with medication or affix in convenient location. Starting with dose #1, check off after each administration. Discard medication after 50 doses. Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP]. STORE BOTTLE IN UPRIGHT POSITION.

OVERDOSE Signs of overdose may include confusion, drowsiness, continuing headache, problems with passing urine and rapid weight gain due to fluid retention. (See WARNINGS.) In cases of overdosage, the dosage should be reduced, frequency of administration decreased, or the drug withdrawn according to the severity of the condition. There is no known specific antidote for desmopressin acetate or Stimate® Nasal Spray. An oral LD50 has not been established. An intravenous dose of 2 mg/kg in mice demonstrated no effect. CONTRAINDICATIONS None.

OVERDOSE Signs of overdose may include confusion, drowsiness, continuing headache, problems with passing urine and rapid weight gain due to fluid retention. (See WARNINGS.) In case of overdosage, the dose should be reduced, frequency of administration decreased, or the drug withdrawn according to the severity of the condition. There is no known specific antidote for desmopressin acetate or DDAVP Nasal Spray. An oral LD50 has not been established. An intravenous dose of 2 mg/kg in mice demonstrated no effect. CONTRAINDICATIONS DDAVP Nasal Spray (desmopressin acetate nasal spray) is contraindicated in individuals with known hypersensitivity to desmopressin acetate or to any of the components of DDAVP Nasal Spray (desmopressin acetate nasal spray) . DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as a creatinine clearance below 50ml/min). DDAVP is contraindicated in patients with hyponatremia or a history of hyponatremia.

SIDE EFFECTS Infrequently, DDAVP® Injection has produced transient headache, nausea, mild abdominal cramps and vulval pain. These symptoms disappeared with reduction in dosage. Occasional facial flushing has been reported with the administration of DDAVP® Injection. Infrequently, high doses of intranasal DDAVP® have produced transient headache and nausea. Nasal congestion, rhinitis and flushing have also been reported occasionally along with mild abdominal cramps. These symptoms disappeared with reduction in dosage. Nosebleed, sore throat, cough and upper respiratory infections have also been reported. In addition to those listed above, the following have also been reported in clinical trials with Stimate® Nasal Spray: Somnolence, dizziness, itchy or light-sensitive eyes, insomnia, chills, warm feeling, pain, chest pain, palpitations, tachycardia, dyspepsia, edema, vomiting, agitation and balanitis. DDAVP® Injection (desmopressin acetate) has infrequently produced changes in blood pressure causing either a slight elevation or a transient fall with a compensatory increase in heart rate. Severe allergic reactions including anaphylaxis have been reported rarely with DDAVP® Injection. Post Marketing There have been rare reports of convulsions from hyponatremia associated with concomitant use of desmopressin and the following medications: oxybutynin and imipramine. See WARNINGS for the possibility of water intoxication, hyponatremia and coma. To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www. fda.gov/medwatch. DRUG INTERACTIONS Although the pressor activity of desmopressin acetate is very low, its use with other pressor agents should be done only with careful patient monitoring. The concomitant administration of drugs that may increase the risk of water intoxication with hyponatremia (e.g., tricyclic antidepressants, serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDS, lamotrigine and carbamazepine) should be performed with caution. DDAVP® Injection has been used with epsilon aminocaproic acid without adverse effects.

SIDE EFFECTS The following adverse reaction is described elsewhere in the labeling: Hyponatremia [see BOX WARNING and WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized, double-blind, placebo-controlled, multi-center trials conducted in adults 50 years of age and older evaluated the efficacy and safety of NOCTIVA nasal spray compared to placebo. At baseline, 1045 patients treated with NOCTIVA 0.83 mcg or 1.66 mcg, or placebo had nocturia due to nocturnal polyuria, wakening at least 2 times per night to urinate. Nocturnal polyuria was defined as night-time urine production exceeding one-third of the 24-hour urine production. The mean age of the patients studied with nocturia due to nocturnal polyuria was 67 years with 42% between 50 and 64 years of age, and 58% aged 65 years and older. Fifty-seven percent were men and 43% were women. Caucasians comprised 79%, Blacks 12%, Hispanics 6%, and Asians 2% of the trial population. During these trials, serious adverse reactions were reported in 2%, 2%, and 3% of patients with nocturia due to nocturnal polyuria treated with NOCTIVA 0.83 mcg, NOCTIVA 1.66 mcg, and placebo, respectively. There was one case of hyponatremia in the 1.66 mcg group and one case in the placebo group classified as serious adverse reactions. Adverse Reactions Leading To Discontinuation Among patients with nocturia due to nocturnal polyuria, the discontinuation rate due to adverse reactions was 4.0% with NOCTIVA 0.83 mcg, 4.4% with NOCTIVA 1.66 mcg, and 2.3% with placebo. Table 1 displays the most common adverse reactions leading to discontinuation in patients with nocturia due to nocturnal polyuria. Table 1: Most Common Adverse Reactions (≥2 incidences) Leading to Discontinuation in Patients with Nocturia due to Nocturnal Polyuria in Two Double-Blind, Placebo-Controlled Clinical Trials Adverse Reactions NOCTIVA 1.66 mcg (N=341) NOCTIVA 0.83 mcg (N=354) Placebo (N=349) Hyponatremia/Blood Sodium Decreased 4 (1.2%) 3 (0.9%) 1 (0.3%) Nasal Discomfort 2 (0.6%) 0 3 (0.9%) Nasal Congestion 2 (0.6%) 0 0 Atrial Fibrillation 2 (0.6%) 0 0 Dizziness 0 2 (0.6%) 1 (0.3%) Dyuria 1 (0.3%) 2 (0.6%) 0 Most Common Adverse Reactions Table 2 summarizes the most common adverse reactions reported by patients with nocturia due to nocturnal polyuria. This table shows adverse reactions reported in at least 2% of patients treated with NOCTIVA and at a higher incidence with the 1.66 mcg dose than with placebo. Table 2: Common Adverse Reactions (Reported by ≥2% of NOCTIVA-treated Patients and at a Higher Incidence with the 1.66 mcg Dose than with Placebo) in Two Double-blind, Placebo-Controlled Clinical Trials in Patients with Nocturia due to Nocturnal Polyuria Adverse Reactions NOCTIVA 1.66 mcg (N=341) NOCTIVA 0.83 mcg (N=354) Placebo (N=349) Nasal Discomfort 20 (5.9%) 12 (3.4%) 17 (4.9%) Nasopharyngitis 13 (3.8%) 8 (2.3%) 10 (2.9%) Nasal Congestion 10 (2.9%) 5 (1.4%) 5 (1.4%) Sneezing 9 (2.6%) 8 (2.3%) 5 (1.4%) Hypertension/Blood Pressure Increased 9 (2.6%) 6 (1.7%) 4 (1.1%) Back Pain 8 (2.3%) 4 (1.1%) 3 (0.9%) Epistaxis 7 (2.1%) 7 (2.0%) 4 (1.1%) Bronchitis 7 (2.1%) 3 (0.8%) 3 (0.9%) Dizziness 6 (1.8%) 7 (2.0%) 5 (1.4%) No overall changes were observed in the safety profile during the open-label, uncontrolled extension trial with up to 126 weeks of follow-up. Hyponatremia Table 3 shows the incidence of serum sodium concentrations below the normal range reported in the two placebo-controlled trials. Table 3: Hyponatremia in Two, Double-blind, Placebo-controlled Clinical Trials in Patients with Nocturia due to Nocturnal Polyuria Serum Sodium Concentrations (mmol/L) NOCTIVA 1.66 mcg (N=341) NOCTIVA 0.83 mcg (N=354) Placebo (N=349) 130-134 42 (12.3%) 33 (9.3%) 18 (5.2%) 126-129 7 (2.1%) 8 (2.3%) 0 ≤125 5 (1.5%) 0 1 (0.3%) Of the five patients on NOCTIVA 1.66 mcg with serum sodium ≤ 125 mmol/L, all were 65 years of age or older. Four were men. The onset of the hyponatremia ranged from 6 days to 12 weeks after the start of dosing. Four of these patients were taking a concomitant systemic or inhaled glucocorticoid and three were taking an NSAID. Sex The incidence of hyponatremia with NOCTIVA was similar in men and women. Age Patients 65 years of age and older treated with NOCTIVA had a higher incidence of hyponatremia compared to those younger than 65 years of age (see Table 4). Table 4: Hyponatremia, Based on Age, in Two, Double-blind, Placebo-controlled Clinical Trials in Patients with Nocturia due to Nocturnal Polyuria Serum Sodium Concentrations (mmol/L) NOCTIVA 1.66 mcg <65 years (N=146) NOCTIVA 1.66 mcg ≥65 years (N=195) NOCTIVA 0.83 mcg <65 years (N=148) NOCTIVA 0.83 mcg ≥65 years (N=206) Placebo <65 years (N=144) Placebo ≥65 years (N=205) 130-134 14 (9.6%) 28 (14.4%) 8 (5.4%) 25 (12.1%) 7 (4.9%) 11 (5.4%) 126-129 0 7 (3.6%) 2 (1.4%) 6 (2.9%) 0 0 ≤125 0 5 (2.6%) 0 0 0 1 (0.5%) DRUG INTERACTIONS No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions between NOCTIVA and other medications. Drugs That May Cause Severe Hyponatremia Concomitant use of NOCTIVA and loop diuretics or systemic or inhaled glucocorticoids is contraindicated because of the risk of severe hyponatremia [see BOX WARNING, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS]. NOCTIVA can be started or resumed three days or five half-lives after the glucocorticoid is discontinued, whichever is longer. Drugs That May Cause Water Retention Monitor serum sodium more frequently in patients taking NOCTIVA concomitantly with medications that may cause water retention and increase the risk for hyponatremia (e.g., tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opioid analgesics, NSAIDs, lamotrigine and carbamazepine) [see WARNINGS AND PRECAUTIONS]. Drugs Administered Intranasally The drug interaction potential between NOCTIVA and other intranasally administered drugs has not been studied. NOCTIVA is not recommended for use in patients who require treatment with other drugs via the nasal route.

SIDE EFFECTS Infrequently, high dosages of intranasal DDAVP have produced transient headache and nausea. Nasal congestion, rhinitis and flushing have also been reported occasionally along with mild abdominal cramps. These symptoms disappeared with reduction in dosage. Nosebleed, sore throat, cough and upper respiratory infections have also been reported. The following table lists the percentage of patients having adverse experiences without regard to relationship to study drug from the pooled pivotal study data for nocturnal enuresis. ADVERSE REACTION PLACEBO (N=59) DDAVP 20 mcg (N=60) DDAVP 40 mcg (N=61) % % % BODY AS A WHOLE Abdominal Pain 0 2 2 Asthenia 0 0 2 Chills 0 0 2 Headache 0 2 5 NERVOUS SYSTEM Dizziness 0 0 3 RESPIRATORY SYSTEM Epistaxis 2 3 0 Nostril Pain 0 2 0 Rhinitis 2 8 3 DIGESTIVE SYSTEM Gastrointestinal Disorder 0 2 0 Nausea 0 0 2 SPECIAL SENSES Conjunctivitis 0 2 0 Edema Eyes 0 2 0 Lachrymation Disorder 0 0 2 Post Marketing: There have been rare reports of hyponatremic convulsions associated with concomitant use with the following medications: oxybutinin and imipramine. See WARNINGS for the possibility of water intoxication and hyponatremia. DRUG INTERACTIONS Although the pressor activity of DDAVP is very low compared to the antidiuretic activity, use of large doses of intranasal DDAVP with other pressor agents should only be done with careful patient monitoring. The concomitant administration of 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 and carbamazepine) should be performed with caution.

WARNINGS For intranasal use only. Very rare cases of hyponatremia have been reported from world-wide postmarketing experience in patients treated with Stimate (desmopressin acetate). Stimate is a potent antidiuretic which, when administered, may lead to water intoxication and/ or hyponatremia. Unless properly diagnosed and treated hyponatremia can be fatal. Therefore, fluid restriction is recommended and should be discussed with the patient and/ or guardian. Careful medical supervision is required. When Stimate Nasal Spray is administered, in particular in pediatric and geriatric patients, fluid intake should be adjusted downward in order to decrease the potential occurrence of water intoxication and hyponatremia (See PRECAUTIONS, Pediatric Use and Geriatric Use.) All patients receiving Stimate therapy 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 of appetite, irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as hallucinations, decreased consciousness and confusion. Severe symptoms may include one or a combination of the following: seizure, coma and/or respiratory arrest. Particular attention should be paid to the possibility of the rare occurrence of an extreme decrease in plasma osmolality that may result in seizures that could lead to coma. Stimate should be used with caution in patients with habitual or psychogenic polydipsia, who may be more likely to drink excessive amounts of fluids, putting them at greater risk of hyponatremia. Stimate® Nasal Spray should not be used to treat patients with Type IIB von Willebrand's disease since platelet aggregation may be induced. PRECAUTIONS General Desmopressin acetate has infrequently produced changes in blood pressure causing either a slight elevation in blood pressure or a transient fall in blood pressure and a compensatory increase in heart rate. The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease. Stimate® Nasal Spray should be used with caution in patients with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders because these patients are prone to hyponatremia. There have been rare reports of thrombotic events (thrombosis, acute cerebrovascular thrombosis, acute myocardial infarction) following desmopressin acetate injection in patients predisposed to thrombus formation. No causality has been determined; however, the drug should be used with caution in these patients. Severe allergic reactions have been reported rarely. Fatal anaphylaxis has been reported in one patient who received intravenous DDAVP® (desmopressin acetate). It is not known whether antibodies to desmopressin acetate are produced after repeated administration. Since Stimate® Nasal Spray is used intranasally, changes in the nasal mucosa such as scarring, edema, or other disease may cause erratic, unreliable absorption in which case Stimate® Nasal Spray should be discontinued until the nasal problems resolve. For such situations, DDAVP® Injection should be considered. Information for Patients Patients should be informed that the bottle accurately delivers 25 doses of 150 mcg each. Any solution remaining after 25 doses should be discarded since the amount delivered thereafter may be substantially less than 150 mcg of drug. No attempt should be made to transfer remaining solution to another bottle. Patients should be instructed to read accompanying directions on use of the spray pump carefully before use. Patients should also be advised that if bleeding is not controlled, the physician should be contacted. Hemophilia A Laboratory tests for assessing patient status include levels of Factor VIII coagulant, Factor VIII antigen and Factor VIII ristocetin cofactor (von Willebrand factor) as well as activated partial thromboplastin time. Factor VIII coagulant activity should be determined before giving Stimate® Nasal Spray for hemostasis. If Factor VIII coagulant activity is present at less than 5% of normal, Stimate® Nasal Spray should not be relied on. von Willebrand's Disease Laboratory tests for assessing patient status include levels of Factor VIII coagulant activity, VWF:RCo and VWF:Ag. Carcinogenicity, Mutagenicity, Impairment of Fertility There have been no long-term studies in animals to assess the carcinogenic, mutagenic or impairment of fertility potential of Stimate® Nasal Spray. Pregnancy Category B Reproduction studies performed in rats and rabbits by the subcutaneous route at doses up to 10 mcg/kg/day have revealed no evidence of harm to the fetus due to desmopressin acetate. This dose is equivalent to 10 times (for Factor VIII stimulation) or 38 times (for diabetes insipidus) the systemic human dose based on a mg/M2 surface area. There are no adequate and well-controlled studies in pregnant women. Several publications of desmopressin acetate's use in the management of diabetes insipidus during pregnancy are available; these include a few anecdotal reports of congenital anomalies and low birth weight babies. However, no causal connection between these events and desmopressin acetate has been established. A 15-year, Swedish epidemiologic study of the use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that in the general population. As opposed to preparations containing natural hormones, desmopressin acetate in antidiuretic doses has no uterotonic action and the physician will have to weigh the therapeutic advantages against the possible risks in each case. Nursing Mothers There have been no controlled studies in nursing mothers. A single study in postpartum women demonstrated a marked change in plasma, but little if any change in assayable DDAVP® in breast milk following an intranasal dose of 10 mcg. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Stimate® Nasal Spray is administered to a nursing woman. Pediatric Use Use in infants and children will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. Stimate® Nasal Spray should not be used in infants younger than 11 months in the treatment of hemophilia A or von Willebrand's disease; safety and effectiveness in children between 11 months and 12 years of age has been demonstrated. Geriatric Use Clinical studies of Stimate® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. However, other post-marketing experience has indicated the occurrence of hyponatremia with the use of desmopressin acetate and fluid overload. Therefore, in elderly patients fluid intake should be adjusted downward in an effort to decrease the potential occurrence of water intoxication and hyponatremia. Particular attention should be paid to the possibility of the rare occurrence of an extreme decrease in plasma osmolality that may result in seizures, and that could lead to coma. Patients who do not have need of antidiuretic hormone for its antidiuretic effect should be cautioned to ingest only enough fluid to satisfy thirst, in an effort to decrease the potential occurrence of water intoxication and hyponatremia. As for all patients, dosing for geriatric patients should be appropriate to their clinical condition.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Risk Of Hyponatremia NOCTIVA can cause hyponatremia [see BOX WARNING and ADVERSE REACTIONS]. Severe hyponatremia can be life-threatening if it is not promptly diagnosed and treated, leading to seizures, coma, respiratory arrest or death. NOCTIVA is contraindicated in patients at increased risk of severe hyponatremia, such as those with excessive fluid intake, those who have illnesses that can cause fluid or electrolyte imbalances, and in those using loop diuretics or systemic or inhaled glucocorticoids [see BOX WARNING, CONTRAINDICATIONS, and CLINICAL PHARMACOLOGY]. Before starting or resuming NOCTIVA, ensure that the serum sodium concentration is normal. Consider the 0.83 mcg dose as the starting dose for patients who may be at risk for hyponatremia [see DOSAGE AND ADMINISTRATION and Clinical Studies]. When NOCTIVA is administered, fluid intake in the evening and night-time hours should be moderated to decrease the risk of hyponatremia. Monitor the serum sodium concentration within seven days and approximately one month of initiating NOCTIVA or increasing the dose, and periodically thereafter. The frequency of serum sodium monitoring should be based on the patient’s risk for hyponatremia. For example, more frequent monitoring is recommended for patients 65 years of age or older or those on concomitant medications that can increase the risk of hyponatremia, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), chlorpromazine, carbamazepine, and thiazide diuretics [see DRUG INTERACTIONS]. If hyponatremia occurs, NOCTIVA may need to be temporarily or permanently discontinued, and treatment for the hyponatremia instituted, depending on the clinical circumstances, including the duration and severity of the hyponatremia [see DOSAGE AND ADMINISTRATION]. Fluid Retention NOCTIVA can cause fluid retention, which can worsen underlying conditions that are susceptible to volume status. Therefore, NOCTIVA is contraindicated in patients with New York Heart Association Class II to IV congestive heart failure or uncontrolled hypertension [see CONTRAINDICATIONS]. In addition, NOCTIVA is not recommended in patients at risk for increased intracranial pressure or those with a history of urinary retention, and should be used with caution (e.g., monitoring of volume status) in patients with New York Heart Association Class I congestive heart failure. Concurrent Nasal Conditions Discontinue NOCTIVA in patients with concurrent nasal conditions that may increase systemic absorption of NOCTIVA (e.g., atrophy of nasal mucosa, and acute or chronic rhinitis), because the increased absorption may increase the risk of hyponatremia. NOCTIVA can be resumed when these conditions resolve. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Hyponatremia Inform patients that NOCTIVA can cause hyponatremia, which may be life-threatening. Inform patients to moderate fluid intake in the evening and night-time hours, to monitor for symptoms of hyponatremia (such as headache, nausea or vomiting, restlessness, fatigue, drowsiness, dizziness, muscle cramping or altered mental status), to undergo recommended serum sodium measurements, to inform their health care provider about new medications, and to stop NOCTIVA during illnesses that can cause fluid or electrolyte imbalance. [see BOX WARNING, DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Nasal Conditions Inform patients to discontinue NOCTIVA if nasal conditions occur that may increase systemic absorption of NOCTIVA (e.g., atrophy of nasal mucosa, and acute or chronic rhinitis). NOCTIVA can be resumed when these conditions resolve [see WARNINGS AND PRECAUTIONS]. Priming And Dosing Instruct patients to prime NOCTIVA before using it for the first time by pumping 5 sprays into the air away from the face and to reprime it by pumping 2 sprays into the air if the bottle has not been used in more than 3 days [see DOSAGE AND ADMINISTRATION]. Instruct patients not to administer two sprays of the 0.83 mcg dose [see DOSAGE AND ADMINISTRATION]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility There have been no long-term studies in animals to assess the carcinogenic, mutagenic or impairment of fertility potential of NOCTIVA nasal spray. Use In Specific Populations Pregnancy Risk Summary There are no data with NOCTIVA use in pregnant women to inform any drug-associated risks. 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 31 times, respectively, the maximum recommended human dose based on nasal surface area (see Data). NOCTIVA is not recommended for the treatment of nocturia in pregnant women. Nocturia is usually related to normal, physiologic changes during pregnancy that do not require treatment with NOCTIVA. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Desmopressin acetate did not cause fetal harm in teratology studies in rats and rabbits at doses from 0.05 to 10 mcg/kg/day, which is approximately <1 times (rat) and 31 times (rabbit) the maximum recommended human dose based on nasal surface area. Lactation Desmopressin is present in small amounts in human milk and is poorly absorbed orally by an infant. There is no information on the effects of desmopressin on the breastfed infant or on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for NOCTIVA and any potential adverse effects on the breastfed infant from NOCTIVA or from the underlying maternal condition. Pediatric Use NOCTIVA is contraindicated for the treatment of primary nocturnal enuresis because of reports of hyponatremic-related seizures in pediatric patients treated with other intranasal formulations of demospressin. Studies of NOCTIVA have not been conducted in pediatric patients [see CONTRAINDICATIONS]. Geriatric Use Patients 65 years and older treated with NOCTIVA had a higher incidence of hyponatremia compared to patients less than 65 years old treated with NOCTIVA [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Renal Impairment Desmopressin is mainly excreted in the urine. The area under the concentration-time curve (AUC) and terminal half-life of desmopressin in renally impaired patients with an eGFR below 50 mL/min/1.73 m2 is 3-to 4-fold greater than in patients with an GFR above 50 mL/min/1.73 m2. Therefore, NOCTIVA is contraindicated in patients who have renal impairment with an eGFR below 50 mL/min/1.73 m2 [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY]. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of desmopressin has not been studied.

WARNINGS For intranasal use only. DDAVP Nasal Spray (desmopressin acetate nasal spray) should only be used in patients where orally administered formulations are not feasible. Very rare cases of hyponatremia have been reported from world-wide postmarketing experience in patients treated with DDAVP (desmopressin acetate). DDAVP is a potent antidiuretic which, when administered, may lead to water intoxication and/or hyponatremia. Unless properly diagnosed and treated hyponatremia can be fatal. Therefore, fluid restriction is recommended and should be discussed with the patient and/or guardian. Careful medical supervision is required. When DDAVP Nasal Spray (desmopressin acetate nasal spray) is administered, in particular in pediatric and geriatric patients, fluid intake should be adjusted downward in order to decrease the potential occurrence of water intoxication and hyponatremia (See PRECAUTIONS, Pediatric Use and Geriatric Use.) All patients receiving DDAVP therapy 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 of appetite, irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as hallucinations, decreased consciousness and confusion. Severe symptoms may include one or a combination of the following: seizure, coma and/or respiratory arrest. Particular attention should be paid to the possibility of the rare occurrence of an extreme decrease in plasma osmolality that may result in seizures which could lead to coma. DDAVP should be used with caution in patients with habitual or psychogenic polydipsia who may be more likely to drink excessive amounts of water, putting them at greater risk of hyponatremia. PRECAUTIONS General: Intranasal DDAVP at high dosage has infrequently produced a slight elevation of blood pressure, which disappeared 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 rise in blood pressure. DDAVP should be used with caution in patients with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders because these patients are prone to hyponatremia. Rare severe allergic reactions have been reported with DDAVP. Anaphylaxis has been reported rarely with intravenous and intranasal administration of DDAVP. Central Cranial Diabetes Insipidus: Since DDAVP is used intranasally, changes in the nasal mucosa such as scarring, edema, or other disease may cause erratic, unreliable absorption in which case intranasal DDAVP should not be used. For such situations, DDAVP Injection should be considered. Information for Patients: Ensure that in children administration is under adult supervision in order to control the dose intake. Patients should be informed that the DDAVP Nasal Spray (desmopressin acetate nasal spray) bottle accurately delivers 50 doses of 10 mcg each. Any solution remaining after 50 doses should be discarded since the amount delivered thereafter may be substantially less than 10 mcg of drug. No attempt should be made to transfer remaining solution to another bottle. Patients should be instructed to read accompanying directions on use of the spray pump carefully before use. Fluid intake should be adjusted downward based upon discussion with the physician. Laboratory Tests: Laboratory tests for following the patient with central cranial diabetes insipidus or post-surgical or head trauma-related polyuria and polydipsia include urine volume and osmolality. In some cases plasma osmolality measurements may be required. Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with DDAVP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility. Pregnancy: Category B: Fertility studies have not been done. Teratology studies in rats and rabbits at doses from 0.05 to 10 mcg/kg/day (approximately 0.1 times the maximum systemic human exposure in rats and up to 38 times the maximum systemic human exposure in rabbits based on surface area, mg/m2) revealed no harm to the fetus due to DDAVP (desmopressin acetate). There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Several publications of desmopressin acetate's use in the management of diabetes insipidus during pregnancy are available; these include a few anecdotal reports of congenital anomalies and low birth weight babies. However, no causal connection between these events and desmopressin acetate has been established. A fifteen year Swedish epidemiologic study of the use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that in the general population; however, the statistical power of this study is low. As opposed to preparations containing natural hormones, desmopressin acetate in antidiuretic doses has no uterotonic action and the physician will have to weigh the therapeutic advantages against the possible risks in each case. Nursing Mothers: There have been no controlled studies in nursing mothers. A single study in a post-partum woman demonstrated a marked change in plasma, but little if any change in assayable DDAVP in breast milk following an intranasal dose of 10 mcg. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DDAVP is administered to a nursing woman. Pediatric Use: Central Cranial Diabetes Insipidus: DDAVP Nasal Spray has been used in children with diabetes insipidus. Use in infants and children will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. (See WARNINGS.) The dose must be individually adjusted to the patient with attention in the very young to the danger of an extreme decrease in plasma osmolality with resulting convulsions. Dose should start at 0.05 mL or less. Since the spray cannot deliver less than 0.1 mL (10 mcg), smaller doses should be administered using the rhinal tube delivery system. Do not use the nasal spray in pediatric patients requiring less than 0.1 mL (10 mcg) per dose. Geriatric Use: Clinical studies of DDAVP Nasal Spray (desmopressin acetate nasal spray) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as a creatinine clearance below 50ml/min). (See CLINICAL PHARMACOLOGY, Human Pharmacokinetics and CONTRAINDICATIONS.) Use of DDAVP Nasal Spray (desmopressin acetate nasal spray) in geriatric patients will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. (See WARNINGS). There are reports of an occasional change in response with time, usually greater than 6 months. Some patients may show a decreased responsiveness, others a shortened duration of effect. There is no evidence this effect is due to the development of binding antibodies but may be due to a local inactivation of the peptide.