WARNING: HYPONATREMIA NOCTIVA can cause hyponatremia. Severe hyponatremia can be life-threatening, leading to seizures, coma, respiratory arrest, or death ( 5.1 , 6.1 ). 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 ( 4 , 5.1 ). Ensure serum sodium concentrations are normal before starting or resuming NOCTIVA. Measure serum sodium within 7 days and approximately 1 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 ( 2.3 , 5.1 ). If hyponatremia occurs, NOCTIVA may need to be temporarily or permanently discontinued ( 5.1 ). WARNING: HYPONATREMIA See full prescribing information for complete boxed warning. NOCTIVA can cause hyponatremia, which may be life-threatening if severe. ( 5.1 , 6.1 ) 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. ( 4 , 5.1 ) Ensure serum sodium is normal before starting or resuming NOCTIVA. Measure serum sodium within 7 days and approximately 1 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. ( 2.3 , 5.1 ) If hyponatremia occurs, NOCTIVA may need to be temporarily or permanently discontinued. ( 5.1 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Fluid retention: Not recommended in patients at risk of increased intracranial pressure or history of urinary retention. Monitor volume status in patients with NYHA Class I congestive heart failure. ( 5.2 ) Nasal conditions: Discontinue in patients with concurrent nasal conditions that may increase absorption, until resolved. ( 5.3 ) 5.1 Risk of Hyponatremia NOCTIVA can cause hyponatremia [see Boxed Warning and Adverse Reactions ( 6.1 )]. 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 Boxed Warning , Contraindications ( 4 ), and Drug Interactions ( 7.1 )]. 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 ( 2.3 , 2.2 ) and Clinical Studies ( 14 )]. When NOCTIVA is administered, fluid intake in the evening and nighttime hours should be moderated to decrease the risk of hyponatremia. Monitor the serum sodium concentration within 7 days and approximately 1 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 ( 7.2 )]. 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 ( 2.3 )]. 5.2 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 ( 4 )] . 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. 5.3 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.
6 ADVERSE REACTIONS The following adverse reaction is described elsewhere in the labeling: Hyponatremia [see Boxed Warning and Warnings and Precautions ( 5.1 )] Common adverse reactions in clinical trials (incidence >2%) included nasal discomfort, nasopharyngitis, nasal congestion, sneezing, hypertension/blood pressure increased, back pain, epistaxis, bronchitis, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avadel at 1-877-638-4579 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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, multicenter 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 nighttime 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 2 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%) Dysuria 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 2 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 2 placebo-controlled trials. Table 3: Hyponatremia in 2, 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 5 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 3 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 2 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%)