DDAVP Rhinal Tube

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of low sodium levels like headache, trouble focusing, memory problems, feeling confused, weakness, seizures, or change in balance.
• Upset stomach or throwing up.
• Mood changes.
• Change in how you act.
• Hallucinations (seeing or hearing things that are not there).
• Feeling tired or weak.
• Restlessness.
• Muscle pain or weakness.
• Muscle spasm.
• Not hungry.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Very bad headache.
• Very bad dizziness or passing out.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Chest pain or pressure or a fast heartbeat.
• Coughing up blood.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• A heartbeat that does not feel normal.
• Bad nosebleeds.

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	5.0 mg
	Sodium Chloride	9.0 mg
	Hydrochloric acid to adjust pH to approximately 4

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.)

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.

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.

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.

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.

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 and 0.05 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.)

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.

1. Pull plastic tag on neck of bottle. 2. Break security seal and remove plastic cap. 3. 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. 4. The drug is administered by a soft, flexible, plastic rhinal tube which has dose marks at 0.2, 0.15, 0.1 and 0.05 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. 5. Hold the tube with the fingers approximately ¾ inch from the end and insert into a nostril until the tips of the fingers reach the nostril. 6. 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. 7. 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

Origin Sweden

Rev. 12/2014

2009053646

NDC 55566-2400-0

DDAVP®
Rhinal
Tube
desmopressin
acetate

10 mcg/0.1 mL

FOR INTRANASAL USE ONLY

Rx ONLY

2.5 mL Bottle

FERRING
PHARMACEUTICALS

DDAVP  desmopressin acetate spray

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

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Desmopressin Acetate (desmopressin) Desmopressin Acetate 0.1 ug  in 1 mL

Inactive Ingredients Ingredient Name Strength Sodium Chloride 9 mg  in 1 mL Chlorobutanol   Hydrochloric Acid

Packaging # Item Code Package Description 1 NDC:55566-2400-0 1 BOTTLE, PUMP in 1 CARTON 1 2.5 mL in 1 BOTTLE, PUMP

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	Operations
Ferring GmbH		328609615	MANUFACTURE(55566-2400), ANALYSIS(55566-2400), PACK(55566-2400), LABEL(55566-2400)

Establishment
Name	Address	ID/FEI	Operations
Rechon Life Science AB		775207769	MANUFACTURE(55566-2400), ANALYSIS(55566-2400), PACK(55566-2400), LABEL(55566-2400)

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

Revised: 12/2014   Ferring Pharmaceuticals Inc.