Prescription Drugs

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

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.

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

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.

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.

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.