Noctiva: Package Insert / Prescribing Info

2.1 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 1 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.

2.2 Recommended Dosage

• For patients younger than 65 years of age who are not at increased risk for hyponatremia:
  • The recommended dose is 1 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 1 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 (6.1) and Clinical Studies (14)].

2.3 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 (4)].
• Within 7 days and approximately 1 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 (5.1)].

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.

6.1 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.

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.

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.

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).

7.1 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 Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. NOCTIVA can be started or resumed 3 days or 5 half-lives after the glucocorticoid is discontinued, whichever is longer.

7.2 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 reuptake inhibitors, chlorpromazine, opioid analgesics, NSAIDs, lamotrigine, and carbamazepine) [see Warnings and Precautions (5.1)].

7.3 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.

8.1 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% to 4% and 15% to 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.

8.2 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.

8.4 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 desmopressin. Studies of NOCTIVA have not been conducted in pediatric patients [see Contraindications (4)].

8.5 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 (2.2), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

8.6 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 eGFR 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 (4) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of desmopressin has not been studied.

12.1 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 reabsorption in the kidneys, and reducing urine production.

12.3 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 4 to 6 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 to 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 (4)].

13.1 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.

16.1 How Supplied

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 1 spray once a day.

16.2 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.