DDAVP- desmopressin acetate spray
For Healthcare Providers >

1. Patient Information
2. What Is Ddavp?
3. Do Not Use Ddavp If You:
4. Ddavp May Cause Serious Side Effects Including:
5. Active Ingredient:
6. Inactive Ingredients:

Patient Information ⮝

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Administration

• Inform caregivers for pediatric patients that administration should be supervised to ensure the patient receives the prescribed dose.
• Inform patients that the pump must be primed prior to first use and again if not used for greater than one week. Inform patients that the DDAVP Nasal Spray bottle delivers 50 sprays of 10 mcg each following the initial 4 priming pumps.
• Inform patients to discard any solution remaining after 50 sprays since the amount delivered thereafter may be substantially less than 10 mcg of drug.

Monitoring

• Educate patients about the signs and symptoms of hyponatremia and advise them to contact a healthcare provider if such symptoms occur.
• Discuss downward adjustment of fluid intake and monitoring of urine output with patients.

U.S. Pat. Nos. 5,500,413, 5,596,078, and 5,674,850

Manufactured for:
Ferring Pharmaceuticals Inc.
Parsippany, NJ 07054 USA
Origin Sweden

XXXXXXXXXX

This Patient Information has been approved by the Food and Drug Administration			09/18
Patient Information DDAVP (phonetic spelling) Nasal Spray, 10 mcg per 0.1 mL for Intranasal Use Only

What Is Ddavp? ⮝

DDAVP is a prescription medicine called a vasopressin analog used as an antidiuretic replacement to manage central diabetes insipidus.

• DDAVP is not effective in the treatment of nephrogenic diabetes insipidus.
• DDAVP should not be used in people with nasal problems that may keep them from using a nasal spray.

Do Not Use Ddavp If You: ⮝

• are allergic to DDAVP or any of the ingredients in DDAVP. Some people have had severe allergic reactions while taking DDAVP.
  • Read theInstructions for Usethat comes with your DDAVP.
  • Use DDAVP exactly as your healthcare provider tells you to use it.
  • Your healthcare provider may change your dose of DDAVP if needed.

Ddavp May Cause Serious Side Effects Including: ⮝

• low levels of sodium in the blood (hyponatremia).People using DDAVP are at risk for low sodium levels in the blood, water intoxication, and fluid overload. Follow your healthcare provider's instructions on limiting the amount of fluid you can drink when using DDAVP.
  • Do notdrink 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 the elderly are at higher risk for these problems and should follow their healthcare provider's limits on drinking fluids.
  • Call your healthcare provider right away if you have any of the following symptoms while using DDAVP. They may mean that your blood sodium level is too low.

• headache
• restlessness
• disorientation
• feeling irritable
• hallucinations

• nausea, vomiting
• tiredness
• loss of appetite
• feeling weak
• confusion

• weight gain
• sleepiness
• muscle cramps

• nasal scarring or swelling.Some people using DDAVP for long periods of time may have nasal problems such as scarring or swelling. This may affect how well DDAVP works for you.

The most common side effects of DDAVP include: headache, stuffy nose, runny nose, nosebleed, sore throat, cough, upper respiratory infections, nausea, flushing, and stomach cramps.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of DDAVP.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use DDAVP for a condition for which it was not prescribed. Do not give DDAVP to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about DDAVP that is written for health professionals. For more information call1-888-FERRING (1-888-337-7464).

Active Ingredient: ⮝

desmopressin acetate

Inactive Ingredients: ⮝

benzalkonium chloride solution (50%), sodium chloride, citric acid monohydrate, disodium phosphate dihydrate, purified water

1. Highlights Of Prescribing Information
2. Indications And Usage
3. Dosage And Administration
4. Dosage Forms And Strengths
5. Contraindications
6. Warnings And Precautions
7. Adverse Reactions
8. Drug Interactions
9. Use In Specific Populations
10. 1 Indications And Usage
11. 2 Dosage And Administration
12. 3 Dosage Forms And Strengths
13. 4 Contraindications
14. 5 Warnings And Precautions
15. 6 Adverse Reactions
16. 7 Drug Interactions
17. 8 Use In Specific Populations
18. 10 Overdosage
19. 11 Description
20. 12 Clinical Pharmacology
21. 13 Nonclinical Toxicology
22. 16 How Supplied/storage And Handling
23. Instructions For Use
24. Principal Display Panel - 5 Ml Bottle Carton
25. Description
26. Clinical Pharmacology
27. Warnings
28. Precautions
29. Overdosage
30. How Supplied
31. Patient Instruction Guide
32. Principal Display Panel - 2.5 Ml Bottle Carton

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use DDAVP NASAL SPRAY safely and effectively. See full prescribing information for DDAVP NASAL SPRAY.

DDAVP (desmopressin acetate) nasal spray
Initial U.S. Approval: 1978

Indications And Usage ⮝

Central Cranial Diabetes Insipidus

DDAVP Rhinal Tube 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 Rhinal Tube 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

This drug is administered into the nose through a soft, flexible plastic rhinal tube which has four graduation marks on it that measure 0.2, 0.15, 0.1, 0.05 and 0.025 mL. DDAVP Rhinal Tube 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.)

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.)

Dosage Forms And Strengths ⮝

Nasal Spray: 10 mcg per 0.1 mL spray, available in a 5 mL bottle with spray pump delivering 50 sprays (3)

Contraindications ⮝

DDAVP Rhinal Tube is contraindicated in individuals with known hypersensitivity to desmopressin acetate or to any of the components of DDAVP Rhinal Tube.

DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as a creatinine clearance below 50 mL/min).

DDAVP is contraindicated in patients with hyponatremia or a history of hyponatremia.

Warnings And Precautions ⮝

• Hyponatremia: Instruct patients about proper fluid restriction and monitor serum sodium as needed (2.1, 5.1)
• Altered Absorption in Patients with Nasal Mucosa Abnormalities: May occur with chronic administration, and require use of other formulations instead (5.2)

Adverse Reactions ⮝

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 percent 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 ⮝

• Drugs that Increase Risk of Hyponatremia: Requires more frequent monitoring of serum sodium (7.1)
• Other Vasocontrictors: Concomitant use may elevate blood pressure and require a reduction in DDAVP Nasal Spray dosage (7.2)

Use In Specific Populations ⮝

• Pediatric Use: Use requires careful fluid intake restriction to prevent hyponatremia with water intoxication (5.1, 8.4)
• Geriatric Use: Carefully monitor renal function; restrict fluid intake to prevent hyponatremia with water intoxication (5.1, 8.5)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 9/2018

1 Indications And Usage ⮝

DDAVP Nasal Spray is indicated as antidiuretic replacement therapy in the management of central diabetes insipidus in adults and pediatric patients 4 years of age and older.

Limitations of Use:

DDAVP Nasal Spray is not indicated for:

• Treatment of nephrogenic diabetes insipidus,
• Treatment of primary nocturnal enuresis [see Warnings and Precautions (5.1)],
• Use in patients with conditions that compromise the intranasal route of administration (e.g., severe nasal congestion and blockage, nasal mucosa atrophy, severe atrophic rhinitis, recent nasal surgery such as transsphenoidal hypophysectomy) [see Warnings and Precautions (5.2)].
• Use in patients with an impaired level of consciousness,
• Use in patients requiring doses less than 10 mcg or doses that are not multiples of 10 mcg [see Dosage Forms and Strengths (3)].

2 Dosage And Administration ⮝

2.1 Important Administration Instructions

Administer DDAVP Nasal Spray by intranasal use only. Instruct patients about appropriate fluid restriction during DDAVP Nasal Spray treatment [see Warnings and Precautions (5.1)].

Must prime the spray pump prior to the first use. Instruct patients to:

• Prime pump by pressing down on pump four times (if the spray pump is not used for one week, re-prime the pump by pressing down on the pump once).
• Discard DDAVP Nasal Spray after 50 sprays since the amount delivered thereafter may be substantially less than the recommended dosage.

2.2 Recommended Dosage

The use of DDAVP Nasal Spray is not indicated for patients who require less than 10 mcg doses or doses that are not multiples of 10 mcg because the spray pump can only deliver doses of 10 mcg [see Indications and Usage (1)]. If other doses are required, use another desmopressin acetate product.

Individualize the dosage of DDAVP Nasal Spray for each patient with particular attention in pediatric and elderly patients and adjust according to the diurnal pattern of response to limit nocturia and to ensure fluid intake with respect to urine output is not excessive [see Warnings and Precautions (5.1)]. Monitor continued response to DDAVP Nasal Spray by urine volume and osmolality to ensure adequate diuresis to limit the risk of hyponatremia, and include measurements of serum sodium and plasma osmolality as needed.

Adults

The recommended dosage in adults is 10 mcg once daily into one nostril up to 40 mcg once daily (or 40 mcg divided into two or three daily doses). If administered more than once a day, adjust for an adequate diurnal rhythm of urine output.

Pediatric Patients

• For pediatric patients requiring doses less than 10 mcg, DDAVP Nasal Spray is not indicated.
• For pediatric patients 4 years of age and older, the recommended starting dosage of DDAVP Nasal Spray is 10 mcg once daily into one nostril. The dose can be titrated up to 30 mcg once daily (or 30 mcg divided into two daily doses, typically with 20 mcg given in the morning and 10 mcg given at nighttime). If administered more than once a day, adjust for an adequate diurnal rhythm of urine output.

Because administration of desmopressin acetate can been associated with decreased responsiveness with prolonged use, consider increasing the dosage of DDAVP Nasal Spray if patients demonstrate decreased response over a long period of time.

2.3 Switching Between Desmopressin Acetate Formulations

When switching from the desmopressin acetate injection to DDAVP Nasal Spray, administer 10 times the amount of desmopressin acetate, rounding down to the nearest 10 mcg.

When switching from the desmopressin acetate tablets to DDAVP Nasal Spray individual dose titration is required because intranasal desmopressin is approximately 10 to 40 fold more potent than oral (tablet) desmopressin.

3 Dosage Forms And Strengths ⮝

DDAVP Nasal Spray pump delivers 10 mcg (0.1 mL) of desmopressin acetate per spray.

DDAVP Nasal Spray is available as a 5 mL bottle with spray pump delivering 50 sprays.

4 Contraindications ⮝

DDAVP Nasal Spray is contraindicated in patients with:

• Known hypersensitivity to desmopressin acetate or to any of the components of DDAVP Nasal Spray. Severe allergic reactions and anaphylaxis have been reported [see Adverse Reactions (6)].
• Renal impairment defined as estimated creatinine clearance (CLcr) by Cockcroft-Gault equation less than 50 mL/min [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
• Hyponatremia or a history of hyponatremia [see Warnings and Precautions (5.1)].

5 Warnings And Precautions ⮝

5.1 Hyponatremia

Excessive fluid intake when urine output is limited by the antidiuretic effect of desmopressin may lead to water intoxication with hyponatremia. Cases of hyponatremia have been reported from postmarketing experience in patients treated with desmopressin acetate. Unless properly diagnosed and treated, hyponatremia can be fatal.

All patients receiving DDAVP Nasal Spray should be observed for the following signs or symptoms associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium, weight gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss appetite, irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as hallucinations, decreased consciousness, and confusion. Severe symptoms due to an extreme decrease in serum sodium and plasma osmolality may include one or a combination of the following: seizure, coma, and/or respiratory arrest.

In order to decrease the risk of water intoxication with hyponatremia, fluid restriction is recommended. Careful fluid intake restriction is particularly important in pediatric and geriatric patients because these patients are at greater risk of developing hyponatremia [see Use in Specific Populations (8.4, 8.5)]. More frequent monitoring of serum sodium levels is recommended in the following patients: those with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure, renal disorders, habitual or psychogenic polydipsia or those taking concomitant drugs that may cause hyponatremia [see Drug Interactions (7.1)].

DDAVP Nasal Spray is not an indicated formulation for the treatment of primary nocturnal enuresis due to a higher risk of hyponatremia and hyponatremic convulsions with the use of the nasal spray formulation compared to desmopressin tablets seen in postmarketing reports [see Indications and Usage (1)].

5.2 Altered Absorption in Patients with Nasal Mucosa Abnormalities

Chronic administration of DDAVP Nasal Spray may result in changes to nasal mucosa. Nasal mucosa abnormalities (such as scarring and edema) due to chronic administration, or due to other causes (nasal blockage, nasal mucosal atrophy, severe atrophic rhinitis, recent nasal surgery such as transsphenoidal hypophysectomy) may cause erratic, unreliable absorption. Avoid use of DDAVP Nasal Spray in such patients [see Indications and Usage (1)] and consider use of other formulations of desmopressin acetate given by other routes of administration.

6 Adverse Reactions ⮝

The following serious reactions are described below and elsewhere in the labeling:

• Hyponatremia [see Warnings and Precautions (5.1)].
• Altered Absorption in Patients with Changes in Nasal Mucosa [see Warnings and Precautions (5.2)].

The following adverse reactions have been identified during post-approval use of desmopressin acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Increase in blood pressure, headache, nasal congestion, rhinitis, nosebleed, sore throat, cough, upper respiratory infections, nausea, flushing, and abdominal cramps.

Water intoxication with hyponatremia

Hyponatremic convulsions associated with concomitant use of the following medications: oxybutinin and imipramine [see Drug Interactions (7.1)].

Severe allergic reactions and anaphylaxis [see Contraindications (4)]

7 Drug Interactions  ⮝

7.1 Other Drugs that may Increase Risk of Hyponatremia

The concomitant administration of DDAVP Nasal Spray with other drugs that may increase the risk of water intoxication with hyponatremia, (e.g., tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine, oxybutynin and carbamazepine) requires more frequent serum sodium monitoring [see Warnings and Precautions (5.1) and Adverse Reactions (6)].

7.2 Other Vasoconstrictors

Desmopressin acetate can elevate blood pressure. Use of large doses of DDAVP Nasal Spray with other vasocontrictors may require a reduction of the DDAVP dosage [see Adverse Reactions (6)].

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk summary

Prolonged experience with desmopressin in pregnant women over several decades, based on the available published data and case reports, did not identify a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In addition, in vitro studies with human placenta demonstrate poor placental transfer of desmopressin. No adverse developmental outcomes were observed in animal reproduction studies with administration of desmopressin during organogenesis to pregnant rats and rabbits at doses approximately <1 and 38 times, respectively, the maximum recommended human dose based on body surface area (mg/m2) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Desmopressin acetate at up to 50 ng/kg/day was given by subcutaneous injection to pregnant rats, from gestation day 1 to 20 during the period of early embryonic development and organogenesis without teratogenic effects. Desmopressin acetate at up to 10 mcg/kg/day was given to pregnant rabbits by subcutaneous injection from gestation day 6 to 18 during fetal organogenesis without teratogenic effects. These doses of desmopressin acetate represent approximately <1 times (rat) and 38 times (rabbit) the maximum recommended human dose based on body surface area (mg/m2).

8.2 Lactation

Risk Summary

Breastfeeding is not expected to result in clinically relevant exposure of the infant to desmopressin following maternal intranasal administration. Desmopressin is poorly transferred into human breastmilk at negligible amounts (see Data). There is no information on the effects of desmopressin on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DDAVP Nasal Spray and any potential adverse effects on the breastfed infant from DDAVP Nasal Spray or from the underlying maternal condition.

Data

A trial was conducted in six healthy lactating women, at greater than 4 months postpartum, to evaluate intranasal administration of 300 mcg single dose of another desmopressin product (7.5 times the recommended adult dose of DDAVP Nasal Spray). Samples of maternal plasma and breastmilk were obtained at 0, 30, 60, 120, 240, 360 and 480 min after the drug administration. At 8 hours after dose intake, the levels in the milk ranged between 4.16 and 101 pg/ml, and the plasma levels ranged between 40 and 242 pg/ml. The total amount of desmopressin present in the milk over the 8 hours ranged between 491 pg and 16 ng, which corresponds to 0.0001 - 0.005% of the administered dose to the breastfeeding mother.

8.4 Pediatric Use

DDAVP Nasal Spray is indicated as antidiuretic replacement therapy in the management of central diabetes insipidus in pediatric patients 4 years of age and older. DDAVP Nasal Spray is not indicated in pediatric patients less than 4 years of age.

Use of DDAVP Nasal Spray in pediatric patients 4 years of age and older is supported by evidence from adults and pediatric patients with central diabetes insipidus. Use in pediatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Clinical studies of DDAVP Nasal Spray did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at a low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

Because elderly patients are more likely to have renal impairment, care should be taken in dose selection, and monitoring renal function is recommended [see Contraindications (4), Use in Specific Populations (8.6)].

Use of DDAVP Nasal Spray in geriatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings and Precautions (5.1)].

8.6 Renal Impairment

Desmopressin acetate is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment than patients with normal renal function. DDAVP Nasal Spray is contraindicated in patients with estimated CLcr by Cockcroft-Gault equation less than 50 mL/min [see Clinical Pharmacology (12.1, 12.3), Contraindications (4)].

10 Overdosage ⮝

Signs of desmopressin acetate overdosage may include confusion, drowsiness, continuing headache, problems with passing urine, and rapid weight gain due to fluid retention [see Warnings and Precautions (5.1)]. In case of overdosage, reduce the dosage, decrease the frequency of administration, or discontinue DDAVP Nasal Spray. There is no known specific antidote for desmopressin acetate.

11 Description ⮝

DDAVP Nasal Spray is a vasopressin analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation. It is chemically defined as follows:

Molecular weight: 1183.34

Empirical formula: C46H64N14O12S2 C2H4O2 3H2O

1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.

DDAVP Nasal Spray is 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 mg
• Benzalkonium chloride solution (50%) 0.2 mg

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

The antidiuretic effects of desmopressin are mediated by stimulation of vasopressin 2 (V2) receptors, thereby increasing water re-absorption in the kidney, and hence reducing urine production. Desmopressin is a replacement hormone for antidiuretic hormone in the treatment of central diabetes insipidus. The change in structure of arginine vasopressin to desmopressin acetate 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 were usually below threshold levels for effects on vascular or visceral smooth muscle.

12.2 Pharmacodynamics

The use of DDAVP Nasal Spray in patients with central diabetes insipidus reduces urinary output, increases urine osmolality, and decreases plasma osmolality.

12.3 Pharmacokinetics

Absorption: Desmopressin acetate is absorbed through the nasal mucosa.

Elimination: Desmopressin acetate exhibits a biphasic elimination profile, with half-lives of 7.8 and 75.5 minutes for the initial and terminal phases, respectively.

Specific Populations

Renal Impairment: Desmopressin acetate is mainly excreted in the urine. A pharmacokinetic study was conducted in subjects with normal renal function and patients with mild, moderate, and severe renal impairment (n=24, 6 subjects each group) with a single 2 mcg dose of desmopressin acetate injection (this results in approximately 20 times the exposure of 10 mcg of DDAVP Nasal Spray). The terminal half-life was 2.8 hours in subjects with normal renal function, 4.0 hours in mild renal impairment, 6.6 hours in moderate renal impairment and 8.7 hours in severe renal impairment. In patients with mild, moderate and severe renal impairment, mean desmopressin exposure was 1.5 fold, 2.4 fold and 3.6 fold higher, respectively compared to that of subjects with normal renal function [see Contraindications (4), Use in Specific Populations (8.6)].

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with desmopressin acetate have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

16 How Supplied/storage And Handling ⮝

16.1 How Supplied

DDAVP Nasal Spray is available as a 5 mL bottle containing an aqueous solution with the spray pump delivering 50 sprays of 10 mcg (0.1 mL) (NDC 55566-2500-0).

16.2 Storage and Handling

Store at Controlled Room Temperature 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. STORE BOTTLE IN UPRIGHT POSITION.

Instructions For Use ⮝

DDAVP
Nasal Spray, 10 mcg per 0.1 mL
For Intranasal Use Only

Read these instructions before using DDAVP 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 treatment.

Children should be helped by an adult when using DDAVP Nasal Spray, to make sure the right amount of medicine is used.

The parts of your DDAVP Nasal Spray pump (see Figure A):

Figure A

Priming your DDAVP Nasal Spray:

Your DDAVP Nasal Spray pump must be primed before you use it for the first time.

• Remove the protective cap (see Figure B).

Figure B

• Press down on the shoulders at the top of your DDAVP Nasal Spray pump 4 times. Hold the spray tip away from your face and eyes (see Figure C).

Figure C

• After your DDAVP Nasal Spray pump is primed, it will spray 10 micrograms (1 dose) of medicine each time it is pressed.

Using your DDAVP Nasal Spray:

Step 1. Remove the protective cap.

Step 2. To make sure you get the right dose of medicine tilt your DDAVP Nasal Spray pump so the dip tube inside the bottle draws the medicine up from the deepest part of the medicine inside the bottle (see Figures D and E).

Figure D	Figure E

Step 3. Put the spray nozzle tip of your DDAVP Nasal Spray into your nostril and press the spray pump 1 time for 1 dose. (see Figure F). If 2 doses are prescribed, spray each nostril 1 time.

Figure F

Step 4. Put the protective cap back on the spray nozzle tip when you finish using your DDAVP Nasal Spray.

Keeping track of your Nasal Sprays:

• Use the check-off chart to help you keep track of your DDAVP Nasal Sprays used (see Figure G).

DDAVP Nasal Spray
50-Spray Check-off Chart
Figure G

• Keep this chart with your DDAVP Nasal Spray or put it someplace where you can easily get it.
• Check off number 1 on the chart with your first dose of DDAVP Nasal Spray. Check off the numbers after each use of your DDAVP Nasal Spray. If your healthcare provider prescribed a 2-spray dose, then 2 numbers should be checked off.
• Your DDAVP Nasal Spray holds 50 sprays with the right amount of medicine in each spray.
• If any medicine is left in your DDAVP Nasal Spray after 50 sprays, do not use it. You may not get the right amount of medicine.
• Throw away your DDAVP Nasal Spray after 50 sprays.
• Do not count the priming sprays. Your DDAVP Nasal Spray has been filled with extra medicine for your priming sprays.
• Do not try to remove any medicine from your DDAVP Nasal Spray pump and place it in another bottle.

How should I store DDAVP Nasal Spray?

• Store DDAVP Nasal Spray at room temperature between 68 F to 77 F (20 C to 25 C).
• Store DDAVP Nasal Spray standing upright.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Ferring Pharmaceuticals Inc.
Parsippany, NJ 07054 USA
Origin Sweden

Rev. 09/18

XXXXXXXXXX

Principal Display Panel - 5 Ml Bottle Carton ⮝

NDC 55566-2500-0

DDAVP
Nasal
Spray
desmopressin
acetate

10 mcg/0.1 mL

FOR INTRANASAL USE ONLY

5 mL Bottle (50 Doses)

Rx ONLY

FERRING
PHARMACEUTICALS

DDAVP desmopressin acetate spray

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55566-2500 Route of Administration NASAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Desmopressin Acetate (UNII: XB13HYU18U) (desmopressin - UNII:ENR1LLB0FP) Desmopressin Acetate 0.1 ug in 1 mL

Inactive Ingredients Ingredient Name Strength Sodium Chloride (UNII: 451W47IQ8X) 7.5 mg in 1 mL Citric Acid Monohydrate (UNII: 2968PHW8QP) Sodium Phosphate, Dibasic, Dihydrate (UNII: 94255I6E2T) Benzalkonium Chloride (UNII: F5UM2KM3W7)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55566-2500-0 1 in 1 CARTON 02/21/1978 1 5 mL in 1 BOTTLE, PUMP; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA017922 02/21/1978

Labeler - Ferring Pharmaceuticals Inc. (103722955)

Establishment
Name	Address	ID/FEI	Business Operations
Ferring GmbH		328609615	MANUFACTURE(55566-2500) , ANALYSIS(55566-2500) , PACK(55566-2500) , LABEL(55566-2500)

Establishment
Name	Address	ID/FEI	Business Operations
Rechon Life Science AB		775207769	MANUFACTURE(55566-2500) , ANALYSIS(55566-2500) , PACK(55566-2500)

Establishment
Name	Address	ID/FEI	Business Operations
Ferring International Center SA		481210362	PACK(55566-2500)

Establishment
Name	Address	ID/FEI	Business Operations
PolyPeptide Laboratories (Sweden) AB		356580779	API MANUFACTURE(55566-2500) , ANALYSIS(55566-2500)

Revised: 9/2019 Document Id: c55d5585-903d-4bdc-b249-5185fd7ab7f7 34391-3 Set id: d9d8442a-4722-4b41-9faa-1ee853a4cc3b Version: 5 Effective Time: 20190911 Ferring Pharmaceuticals Inc.

Description ⮝

DDAVP Rhinal Tube 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 Rhinal Tube is provided as an aqueous solution for intranasal use.

Each mL contains:
	Desmopressin acetate	0.1 mg
	Chlorobutanol	5 mg
	Sodium Chloride	9 mg
	Hydrochloric acid to adjust pH to approximately 4

Clinical Pharmacology ⮝

DDAVP Rhinal Tube contains as active substance desmopressin acetate, a synthetic analogue of the natural hormone arginine vasopressin. One mL (0.1 mg) of intranasal DDAVP (desmopressin acetate) has an antidiuretic activity of about 400 IU; 10 mcg of desmopressin acetate is equivalent to 40 IU.

1. 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.
2. 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.
3. 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 (2 mcg) 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.)

Warnings ⮝

1. For intranasal use only.
2. DDAVP Rhinal Tube should only be used in patients where orally administered formulations are not feasible.
3. 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.
4. When DDAVP 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.
5. 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.

Ensure that in children administration is under adult supervision in order to control the dose intake.

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 Rhinal Tube 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.

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.

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.

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. 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 postpartum women demonstrated a marked change in plasma, but little if any change in assayable DDAVP (desmopressin acetate) 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 Rhinal Tube has been used in pediatric patients with diabetes insipidus. Use in infants and pediatric patients will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient and/or guardian. (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.

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.

Geriatric Use

Clinical studies of DDAVP Rhinal Tube 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 elderly and younger patients. 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 other 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 50 mL/min). (See CLINICAL PHARMACOLOGY, Human Pharmacokinetics and CONTRAINDICATIONS.)

Use of DDAVP Rhinal Tube in geriatric patients will require careful fluid intake restrictions to prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient. (See WARNINGS.)

Overdosage ⮝

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 Rhinal Tube.

An oral LD50 has not been established. An intravenous dose of 2 mg/kg in mice demonstrated no effect.

How Supplied ⮝

DDAVP Rhinal Tube is available in a 2.5 mL bottle, packaged with two rhinal tube applicators per carton (NDC 55566-2400-0). Also available in a 5.0 mL pump bottle with spray pump delivery 50 doses of 10 mcg (NDC 55566-2500-0).

Store refrigerated 2 to 8 C (36 to 46 F). When travelling, closed bottles will maintain stability for 3 weeks when stored at controlled room temperature, 20 to 25 C (68 to 77 F).

Keep out of the reach of children.

Manufactured for:

Ferring Pharmaceuticals Inc.

Parsippany, NJ 07054 USA

Origin Sweden

Rev. 04/2015

2009054185

Patient Instruction Guide ⮝

DDAVP Rhinal Tube

(desmopressin acetate)

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.

• Pull plastic tag on neck of bottle.

• Break security seal and remove plastic cap.

• Twist off the small knurled seal from the dropper. Use the same seal reversed to prevent subsequent leakage, especially if the bottle is not stored upright.

• The drug is administered by a soft, flexible, plastic rhinal tube which has dose marks at 0.2, 0.15, 0.1, 0.05 and 0.025 mL. Take the arrow-marked part of the tube in one hand and place the fingers of the other hand around the cylindrical part of the closure. Insert the top of the dropper in a downward position into the arrow-marked end of the tube and squeeze the dropper until the solution has reached the desired calibration mark. The dose is measured from the arrow-marked end of the tube to the appropriate calibration. Disconnect the tube from the bottle by withdrawing the bottle quickly downwards. In order to prevent air bubbles from forming in the tube, maintain constant pressure on the dropper. If difficulty is experienced in filling the tube, a diabetic or tuberculin syringe may be used to draw up the dose and load the tube.

• Hold the tube with the fingers approximately inch from the end and insert into a nostril until the tips of the fingers reach the nostril.

• Put the other end of the tube into the mouth. Hold the breath, tilt the head back and then blow with a short, strong puff through the tube so that the solution reaches the right place in the nasal cavity. Through this procedure, medication is limited to the nasal cavity and the preparation does not pass down into the throat.
  
  In very young patients, it may be necessary for an adult to blow the solution into the child's nose. In such cases, the tube will not need to be put into the nose as far as in the older child or adult. The tube should be placed in the nose gently just far enough so that the solution does not run out. A baby must be held firmly and securely.

• After use, reseal dropper tip and close the bottle with the plastic cap. Wash the tube in water and shake thoroughly, until no more water is left. The tube can then be used for the next application.

Store refrigerated 2 to 8 C (36 to 46 F). When traveling, closed bottles will maintain stability for 3 weeks when stored at controlled room temperature, 20 to 25 C (68 to 77 F).

Manufactured for:

Ferring Pharmaceuticals Inc.

Parsippany, NJ 07054 USA

Origin Sweden

Rev. 04/2015

2009054185

Principal Display Panel - 2.5 Ml Bottle Carton ⮝

NDC 55566-2400-0

DDAVP
Rhinal
Tube
desmopressin
acetate

10 mcg/0.1 mL

FOR INTRANASAL USE ONLY

2.5 mL Bottle

Rx ONLY

FERRING
PHARMACEUTICALS

DDAVP desmopressin acetate spray

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55566-2400 Route of Administration NASAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DESMOPRESSIN ACETATE (UNII: XB13HYU18U) (DESMOPRESSIN - UNII:ENR1LLB0FP) DESMOPRESSIN ACETATE 0.1 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg in 1 mL CHLOROBUTANOL (UNII: HM4YQM8WRC) HYDROCHLORIC ACID (UNII: QTT17582CB)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55566-2400-0 1 in 1 CARTON 02/21/1978 1 2.5 mL in 1 BOTTLE, PUMP; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA017922 02/21/1978

Labeler - Ferring Pharmaceuticals Inc. (103722955)

Establishment
Name	Address	ID/FEI	Business Operations
Ferring GmbH		328609615	manufacture(55566-2400) , analysis(55566-2400) , pack(55566-2400) , label(55566-2400)

Establishment
Name	Address	ID/FEI	Business Operations
Ferring International Center SA		481210362	pack(55566-2400)

Establishment
Name	Address	ID/FEI	Business Operations
Rechon Life Science AB		775207769	manufacture(55566-2400) , analysis(55566-2400) , pack(55566-2400) , label(55566-2400)

Establishment
Name	Address	ID/FEI	Business Operations
PolyPeptide Laboratories (Sweden) AB		356580779	API MANUFACTURE(55566-2400) , ANALYSIS(55566-2400)

Revised: 9/2019 Document Id: 4752722a-3675-45df-8105-cfcbf0e99d9d 34391-3 Set id: 86f040d0-a073-4fa5-8997-b2fecc4a3205 Version: 6 Effective Time: 20190911 Ferring Pharmaceuticals Inc.