DDAVP® Rhinal Tube (desmopressin acetate) 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

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.

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 is available in a 2.5 mL bottle, packaged with two rhinal tube applicators per carton (NDC 0075-2450-01). Also available in a 5.0 mL pump bottle with spray pump delivering 50 doses of 10 mcg (NDC 0075-2452-01).

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).

Keep out of the reach of children.

MILITARY: DDAVP Rhinal Tube, 1 x 2.5 mL (NSN 6505-01-145-6338).

Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807. Rev. July 2007. FDA rev date: 10/26/2007

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.

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.

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.

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.

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.

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 50ml/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.)

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.

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 50ml/min).

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

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. 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 (2mcg) 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
(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.

IMPORTANT: Replace Knurled Seal

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).

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DESMOPRESSIN SOLUTION - NASAL

(dess-mow-PRESS-in)

COMMON BRAND NAME(S): DDAVP

USES: This medication is used to reduce urination in certain cases (e.g., diabetes insipidus, surgery). It is a man-made form of a certain natural hormone made by the body (vasopressin). It works by making your kidneys concentrate your urine, so you produce less of it.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using desmopressin and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

This medication is given into the nose. Draw up the proper dose in the marked, flexible tube provided with the medication, and use as directed by your doctor. Your doctor will prescribe the total daily dose and how it should be taken. Follow these instructions exactly. Do not use it more frequently than prescribed without your doctor's approval. Wash the tube with water after use. Shake the tube thoroughly to dry.

A parent or other responsible adult should supervise a child using this medication. If you have any questions, consult your doctor or pharmacist.

Limit drinking of water or other fluids while using this medication. Consult your doctor for details.

Dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, use it at the same time(s) each day.

Tell your doctor if your condition persists or worsens. After taking desmopressin for 6 months or more, some patients may notice that the medicine does not work as well or last as long. Consult your doctor if this medication stops working well.

SIDE EFFECTS: Headache, runny nose, nausea, stomach ache, or flushing of the face may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Desmopressin can infrequently cause serious low levels of sodium. Drinking too much water or other fluids increases the risk of low sodium. Follow your doctor's directions for limiting fluids. Tell your doctor immediately if any of these unlikely symptoms of low sodium occur: loss of appetite, severe headache, muscle weakness/spasms/cramps, stomach cramps, tiredness, sudden weight gain, vomiting.

Seek immediate medical attention if any of these rare but very serious side effects occur: slow/shallow breathing, loss of consciousness, severe drowsiness/difficulty staying awake, mental/mood changes (e.g., confusion, hallucinations, irritability), seizures.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking desmopressin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: kidney disease, low sodium blood levels (hyponatremia or history of hyponatremia).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high blood pressure, breathing problems, congestion in the nose, heart disease, mineral imbalance (low potassium blood levels), unusual/extreme thirst (habitual or psychogenic polydipsia), cystic fibrosis, type 2 or 3 von Willebrand disease.

Caution is advised when using this drug in children because they may be more sensitive to the effects of the drug, especially loss of sodium in the blood (hyponatremia).

Kidney function declines with age. This medication is removed by the kidneys. Therefore, caution is advised when using this drug in the elderly.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: chlorpromazine, chlorpropamide, clofibrate, demeclocycline, drugs that increase blood pressure (e.g., dopamine, epinephrine, ephedrine, norepinephrine), fludrocortisone, heparin, lithium, narcotic pain relievers (e.g., codeine), nonsteroidal anti-inflammatory drugs (e.g., celecoxib, ibuprofen, naproxen), oxybutynin, anti-seizure drugs (e.g., carbamazepine, lamotrigine), SSRI antidepressants (e.g., fluoxetine, sertraline), tricyclic antidepressants (e.g., amitriptyline, imipramine), urea, "water pills" (diuretics such as furosemide, hydrochlorothiazide), alcohol use.

Ask your doctor how much alcohol you may drink, if any. Alcohol interferes with desmopressin by increasing urination.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: This medicine may be harmful if swallowed. If overdose or swallowing is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., urinalysis, blood tests) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose and use 1 dose daily, use it as soon as you remember, unless you do not remember until the next day. In that case, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

If you use more than 1 dose daily, use it as soon as you remember, unless it is almost time for the next dose. In that case, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the US product in the refrigerator between 36-46 degrees F (2-8 degrees C). Do not freeze. When traveling, the US product may remain at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture for 3 weeks. Discard after 3 weeks out of the refrigerator.

Store the Canadian product in the refrigerator between 36-46 degrees F (2-8 degrees C). Do not freeze.

Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.