1.1 Central Diabetes Insipidus

DDAVP Injection is indicated as antidiuretic replacement therapy in the management of central (cranial) diabetes insipidus and for the management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region.

1.2 Hemophilia A

DDAVP Injection is indicated for patients with hemophilia A with factor VIII coagulant activity levels greater than 5% without factor VIII antibodies to:

• Maintain hemostasis during surgical procedures and postoperatively
• Reduce bleeding with episodes of spontaneous or traumatic injuries such as hemarthroses, intramuscular hematomas, or mucosal bleeding.

1.3 von Willebrand's Disease (Type I)

DDAVP Injection is indicated for patients with mild to moderate von Willebrand's disease (Type I) with factor VIII levels greater than 5% to:

• Maintain hemostasis during surgical procedures and postoperatively
• Reduce bleeding with episodes of spontaneous or traumatic injuries such as hemarthroses, intramuscular hematomas, or mucosal bleeding.

2.1 Pretreatment Testing and On-Treatment Monitoring

2.2 Recommended Dosage

Initiate fluid restriction during treatment with DDAVP Injection [see Warnings and Precautions (5.1), Use in Specific Populations (8.4, 8.5)].

2.3 Preparation and Administration for Patients with Hemophilia A and von Willebrand's Disease (Type I)

Prepare the solution for infusion using aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw the necessary volume of DDAVP Injection from the vial and dilute by adding to the infusion bag of 0.9% Sodium Chloride Injection, USP per Table 1. Dilute DDAVP Injection in sterile 0.9% Sodium Chloride Injection, USP and infuse slowly over 15 minutes to 30 minutes.

The volume of diluent is weight-based. See Table 1 for volume of diluent to use.

Monitor blood pressure and pulse during infusion.

2.4 Switching Between Desmopressin Acetate Formulations

DDAVP is also available as nasal spray and tablet dosage forms.

When switching between formulations, the below text is meant as guidance for starting dose. However, dose should always be titrated individually according to the diuresis (antidiuretic response) and electrolyte status (serum sodium) of the patient.

When switching from DDAVP Nasal Spray to DDAVP Injection, the starting dose is one-tenth times the DDAVP Nasal Spray dose.

When switching from DDAVP Tablets to DDAVP Injection, titrate dose individually according to the diuresis (antidiuretic response) and electrolyte status (serum sodium) due to the large variability in both PK and PD. Monitor patients closely during the initial dose titration period.

5.1 Hyponatremia

DDAVP Injection can cause hyponatremia. Severe hyponatremia can be life-threatening if it is not promptly diagnosed and treated, leading to seizures, coma, respiratory arrest, or death [see Boxed Warning].

DDAVP Injection is contraindicated in patients with hyponatremia (or a history of hyponatremia), with excessive fluid intake (e.g., polydipsia), using loop diuretics or systemic or inhaled glucocorticoids, with known or suspected SIADH, and/or illnesses that can cause fluid or electrolyte imbalances [see Contraindications (4), Drug Interactions (7)]. Avoid concomitant treatments that also cause hyponatremia.

Prior to starting or resuming DDAVP Injection, ensure that the serum sodium concentration is normal. Limit fluid intake to a minimum from 1 hour before administration until 8 hours after administration. Use of DDAVP Injection without concomitant reduction of fluid intake may lead to fluid retention and hyponatremia.

Monitor the serum sodium concentration within 1 week and approximately 1 month of initiating DDAVP Injection, and periodically thereafter [see Dosage and Administration (2.1)]. Base the frequency of serum sodium monitoring on the patient's risk of hyponatremia.

Patients with conditions associated with fluid and electrolyte imbalance (i.e., cystic fibrosis, heart failure, and renal disorders), geriatric and pediatric patients, patients receiving concomitant treatments that also cause hyponatremia (i.e., tricyclic antidepressants, selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs, chlorpromazine, opiate analgesics, carbamazepine, lamotrigine, thiazide diuretics and chlorpropamide), and patients with habitual or psychogenic polydipsia who may drink excessive amounts of water, may be at increased risk of hyponatremia [see Contraindications (4)].

If hyponatremia occurs, DDAVP Injection 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.

5.2 Hypotension and Hypertension

DDAVP may cause hypotension (with compensatory increase in heart rate) or hypertension. Monitor blood pressure during DDAVP administration, particularly in patients with a history of coronary artery insufficiency and/or hypertensive cardiovascular disease [see Adverse Reactions (6), Drug Interactions (7.2)]

5.3 Increased Risk of Thrombosis in Patients with von Willebrand's Disease Type IIB

Use of DDAVP in patients with Type IIB von Willebrand's disease may result in platelet aggregation, thrombocytopenia, and possibly thrombosis.

5.4 Hypersensitivity Reactions

Hypersensitivity reactions including anaphylaxis have been reported with intravenous and intranasal DDAVP, including cases of fatal anaphylaxis with intravenous DDAVP. DDAVP Injection is contraindicated in patients with known hypersensitivity to desmopressin acetate or to any of the components of DDAVP Injection [see Contraindications (4)]. It is not known whether antibodies to DDAVP Injection are produced after repeated injections. Monitor patients for signs or symptoms of hypersensitivity reactions during administration, interrupt treatment should a reaction occur, and manage medically. Permanently discontinue for serious hypersensitivity reaction [see Adverse Reactions (6)].

5.5 Fluid Retention

DDAVP Injection can cause fluid retention, which can worsen underlying conditions that are susceptible to volume status. Patients with heart failure or uncontrolled hypertension may be at increased risk. DDAVP Injection is not recommended in patients at risk for increased intracranial pressure or those with a history of urinary retention. Advise patients to limit fluid intake [see Patient Counseling Information (17)].

7.1 Other Drugs that may Increase Risk of Hyponatremia

The concomitant administration of DDAVP Injection 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, thiazide diuretics, NSAIDs, lamotrigine, sulfonylureas, particularly chlorpropamide, oxybutynin and carbamazepine), requires more frequent serum sodium monitoring. Monitor serum sodium more frequently in patients taking DDAVP Injection concomitantly with these drugs and when doses of these drugs are increased [see Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7.1), Use in Specific Populations (8.4, 8.5)].

7.2 Other Vasoconstrictors

DDAVP Injection can elevate blood pressure. Use of DDAVP Injection with other vasoconstrictors may require a reduction of the DDAVP Injection dosage [see Warnings and Precautions (5.2), Adverse Reactions (6)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of DDAVP have been established in pediatric patients 3 months of age and older with hemophilia A and von Willebrand's disease and pediatric patients aged 12 years and older with diabetes insipidus. The safety and effectiveness of DDAVP have not been established in infants less than 3 months of age with hemophilia A or von Willebrand's disease or pediatric patients under 12 years of age 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 and Precautions (5.1)].

8.5 Geriatric Use

Clinical studies of DDAVP Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection 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 adverse 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 Contraindications (4), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Use of DDAVP injection 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 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 is contraindicated in patients with estimated CLcr by Cockcroft-Gault equation less than 50 mL/min [see Contraindications (4), Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Desmopressin acetate increases plasma levels of factor VIII activity in patients with hemophilia and von Willebrand's disease Type I.

The antidiuretic effects of desmopressin acetate are mediated by stimulation of vasopressin 2 (V2) receptors, thereby increasing water re-absorption in the kidney, and hence reducing urine production. Desmopressin acetate 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 increased duration of action and 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 response to DDAVP of factor VIII activity and plasminogen activator is dose-related, with maximal plasma levels of 300 to 400 percent change from baseline obtained after infusion of 0.4 mcg/kg. The increase of factor VIII is rapid and evident within 30 minutes, reaching a maximum at a point ranging from 90 minutes to two hours. The duration of the hemostatic effect depends on the half-life for VIII:C which is about 8-12 hours. The percentage increase of factor VIII levels in patients with mild hemophilia A and von Willebrand's disease was not significantly different from that observed in normal healthy individuals when treated with 0.3 mcg/kg of DDAVP infused over 10 minutes.

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

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with desmopressin have not been performed to evaluate carcinogenic potential. Desmopressin was not mutagenic in bacterial mutagenicity (Ames) and mouse lymphoma assays.

16.1 How Supplied

DDAVP Injection is available as a sterile solution supplied as 4 mcg/mL in cartons of ten 1 mL single-dose, type 1 glass ampules (NDC 55566-2200-0) and 40 mcg/10 mL (4 mcg/mL) in 10 mL multiple-dose vials, type 1 glass vial with rubber stopper and a flip off seal, (NDC 55566-2300-0), each containing 4 mcg DDAVP per mL.

16.2 Storage and Handling

Store refrigerated 2° to 8°C (36° to 46°F).

Hyponatremia and Fluid Restriction

• Inform patients that DDAVP may cause severe hyponatremia, which may be life-threatening, if it is not promptly diagnosed and treated [see Warnings and Precautions (5.1)].
• Inform them about the signs and symptoms associated with hyponatremia, to undergo recommended serum sodium measurements, and to inform their health care provider about new medications.
• Advise patients to contact a healthcare provider if symptoms of hyponatremia occur.
• Discuss adjustment of fluid intake and monitoring of urine output with patients.