DDAVP Injection

Patient Information

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Description

DDAVP® Injection (desmopressin acetate) 4 mcg/mL 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 Injection (desmopressin acetate injection) 4 mcg/mL is provided as a sterile, aqueous solution for injection. Each mL provides:

Desmopressin acetate 4.0 mcg
Sodium chloride          9.0 mg
Hydrochloric acid to adjust pH to 4.

The 10 mL vial contains chlorobutanol as a preservative (5.0 mg/mL).

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.

Limitations Of Use

DDAVP is ineffective and not indicated for the treatment of nephrogenic diabetes insipidus.

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.

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.

Limitations Of Use

DDAVP is not indicated for the treatment of severe von Willebrand’s disease (Type I) and when there is evidence of an abnormal molecular form of factor VIII antigen [see WARNINGS AND PRECAUTIONS].

Dosage And Administration

Pretreatment Testing And On-Treatment Monitoring

Diabetes Insipidus

Prior to treatment with DDAVP, assess serum sodium, urine volume and osmolality. Intermittently during treatment, assess serum sodium, urine volume and osmolality or plasma osmolality.

Hemophilia A

Prior to treatment with DDAVP Injection, verify that factor VIII coagulant activity levels are >5% and exclude the presence of factor VIII autoantibodies. Also assess serum sodium and aPTT prior to treatment. In certain clinical situations, it may be justified to try DDAVP in patients with factor VIII levels between 2% to 5%; however, these patients should be carefully monitored.

Von Willebrand’s Disease (Type I)

Prior to treatment with DDAVP Injection, verify that factor VIII coagulant activity levels are >5% and exclude severe von Willebrand’s disease (Type I) and presence of abnormal molecular form of factor VIII antigen.

During treatment with DDAVP Injection, assess serum sodium, bleeding time, factor VIII coagulant activity, ristocetin cofactor activity, and von Willebrand antigen to ensure that adequate levels are being achieved.

For All Patients Receiving Repeated Doses

Restrict free water intake and monitor for hyponatremia. Ensure that serum sodium is normal prior to initiating or resuming treatment with DDAVP Injection.

Recommended Dosage

Initiate fluid restriction during treatment with DDAVP Injection [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Diabetes Insipidus

Treatment Naïve Patients

The recommended starting daily dosage is 2 mcg to 4 mcg administered as one or two divided doses by subcutaneous or intravenous injection. Do not dilute DDAVP Injection for the Diabetes Insipidus population. The morning and evening doses should be separately adjusted for an adequate diurnal rhythm of water turnover. Adjust dose based upon response to treatment estimated by two parameters: adequate duration of sleep and adequate, not excessive, water turnover.

Patients Changing From Intranasal Desmopressin

The recommended starting dose of DDAVP Injection is 1/10th the daily maintenance intranasal dose administered by subcutaneous or intravenous injection as one or two divided doses

Hemophilia A And Von Willebrand’s Disease (Type I):

The recommended dosage is 0.3 mcg/kg actual body weight (to a maximum of 20 mcg) administered by intravenous infusion over 15 minutes to 30 minutes. If used preoperatively, administer 30 minutes prior to the procedure. If used to reduce spontaneous or traumatic bleeding, doses may be repeated after 8 hours to 12 hours and once daily thereafter, if needed, based upon clinical condition and von Willebrand factor and factor VIII levels. The necessity for repeat administration of DDAVP or use of any blood products for hemostasis should be determined by laboratory response as well as the clinical condition of the patient.

Tachyphylaxis (lessening of response) with repeated administration (i.e., given more frequently than every 48 hours) may occur. The initial response is reproducible if DDAVP is administered every 2 to 3 days.

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.

Table 1: Volume of Diluent Required

Monitor blood pressure and pulse during infusion.

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 dieresis (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.

How Supplied

Dosage Forms And Strengths

Injection: DDAVP is a sterile, aqueous, colorless solution available as:

• 4 mcg/mL in single-dose ampule
• 40 mcg/10 mL (4 mcg/mL) in multiple-dose vial

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.

Storage And Handling

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

Manufactured for: FERRING PHARMACEUTICALS INC., PARSIPPANY, NJ 07054 USA. Revised: Jul 2022

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hyponatremia [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]
• Hypotension and Hypertension [see WARNINGS AND PRECAUTIONS]
• Increased risk of thrombosis in patients with von Willebrand’s Disease Type IIB [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
• Fluid retention [see WARNINGS AND PRECAUTIONS]

The following adverse reactions have been identified during post-approval use of DDAVP Injection. 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.

Cardiovascular: Hypertension, hypotension, tachycardia, thrombotic events, fluid retention

Digestive: Nausea, abdominal cramps

Immune: Hypersensitivity reactions

Integumentary: Erythema, swelling, burning pain, facial flushing

Laboratory: Hyponatremia

Nervous: Headache, hyponatremic seizures

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, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, Use In Specific Populations].

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, ADVERSE REACTIONS].

1. 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.
2. When DDAVP Injection (desmopressin acetate injection) is administered to patients who do not have need of antidiuretic hormone for its antidiuretic effect, in particular in pediatric and geriatric patients, fluid intake should be adjusted downward 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 of 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.
3. DDAVP should not be used to treat patients with Type IIB von Willebrand’s disease since platelet aggregation may be induced.
4. 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.

General: For injection use only.

DDAVP Injection (desmopressin acetate) 4 mcg/mL has infrequently produced changes in blood pressure causing either a slight elevation in blood pressure or a transient fall in blood pressure and a compensatory increase in heart rate. The drug should be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease.

DDAVP (desmopressin acetate) 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.

There have been rare reports of thrombotic events following DDAVP Injection (desmopressin acetate injection) 4 mcg/mL in patients predisposed to thrombus formation. No causality has been determined, however, the drug should be used with caution in these patients.

Severe allergic reactions have been reported rarely. Anaphylaxis has been reported rarely with intravenous and intranasal DDAVP, including isolated cases of fatal anaphylaxis with intravenous DDAVP. It is not known whether antibodies to DDAVP Injection 4 mcg/mL are produced after repeated injections.

Hemophilia A: Laboratory tests for assessing patient status include levels of factor VIII coagulant, factor VIII antigen and factor VIII ristocetin cofactor (von Willebrand factor) as well as activated partial thromboplastin time. Factor VIII coagulant activity should be determined before giving DDAVP for hemostasis. If factor VIII coagulant activity is present at less than 5% of normal, DDAVP should not be relied on.

von Willebrand’s Disease: Laboratory tests for assessing patient status include levels of factor VIII coagulant activity, factor VIII ristocetin cofactor activity, and factor VIII von Willebrand factor antigen. The skin bleeding time may be helpful in following these patients.

Diabetes Insipidus: Laboratory tests for monitoring the patient include urine volume and osmolality. In some cases, plasma osmolality may be required.

Carcinogenicity, Mutagenicity, 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 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: 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.) DDAVP Injection (desmopressin acetate injection) 4 mcg/mL should not be used in infants less than three months of age in the treatment of hemophilia A or von Willebrand’s disease; safety and effectiveness in pediatric patients under 12 years of age with diabetes insipidus have not been established.

Geriatric Use: Clinical studies of DDAVP Injection (desmopressin acetate 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 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 50ml/min). (See CLINICAL PHARMACOLOGY, Human Pharmacokinetics and CONTRAINDICATIONS )

Use of DDAVP injection (desmopressin acetate 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.)

Overdosage of DDAVP Injection leads to prolonged duration of action with an increased risk of water retention and hyponatremia. Signs of overdose may include headaches, abdominal cramps, nausea, facial flushing, confusion, drowsiness, problems with passing urine and rapid weight gain due to fluid retention [see WARNINGS AND PRECAUTIONS]. In case of overdosage, the dosage should be reduced, frequency of administration decreased, or the drug withdrawn according to the severity of the condition, serum sodium assessed, and hyponatremia treated appropriately.

There is no known specific antidote for desmopressin acetate or DDAVP Injection 4 mcg/mL.

Contraindications

DDAVP Injection is contraindicated in patients with known hypersensitivity to desmopressin acetate or to any of the components of DDAVP Injection [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, DESCRIPTION].

DDAVP Injection is contraindicated in patients with the following conditions due to an increased risk of hyponatremia:

• Moderate to severe renal impairment defined as a creatinine clearance below 50 mL/min [see Use In Specific Populations and CLINICAL PHARMACOLOGY].
• Hyponatremia or a history of hyponatremia [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS], Use In Specific Populations].
• Known or suspected syndrome of inappropriate antidiuretic hormone (SIADH) secretion [see WARNINGS AND PRECAUTIONS].
• Polydipsia [see WARNINGS AND PRECAUTIONS].
• Concomitant use with loop diuretics [see BOXED WARNING].
• Concomitant use with systemic or inhaled glucocorticoids [see BOXED WARNING].
• During illnesses that can cause fluid or electrolyte imbalance, such as gastroenteritis, salt-wasting nephropathies, or systemic infection [see BOXED WARNING].

DDAVP Injection is contraindicated in patients with the following conditions because fluid retention increases the risk of worsening the underlying condition:

• Heart failure
• Uncontrolled hypertension

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.

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.

Pharmacokinetics

Elimination

The geometric mean terminal half-life is 2.8 hours.

Metabolism

Desmopressin is not metabolized by human CYP450 system.

Excretion

After intravenous administration of 2 mcg, 52% of the dose was recovered in the urine within 24 hours as unchanged desmopressin.

Drug Interaction Studies

In vitro studies in human liver microsome preparations have shown that desmopressin does not inhibit the human CYP450 system. No in vivo interaction studies have been performed with DDAVP Injection.

Specific Populations

Patients With Renal Impairment

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 intravenous injection. The geometric mean terminal half-life was 2.8 hours in subjects with normal renal function, and 4, 6.6, and 8.7 hours in patients with mild, moderate, and severe renal impairment, respectively. In patients with mild, moderate and severe renal impairment, mean desmopressin area under the plasma drug concentration time curve (AUC) was 1.5 fold, 2.4 fold and 3.6 fold higher, respectively compared to that of subjects with normal renal function.