Desmopressin nasal spray

Desmopressin is sometimes used in mild Hemophilia A and Von Willebrand s disease. In December 2007, US drug regulators banned using desmopressin nasal sprays for treating bedwetting after two children died from hyponatremia. 

Joukhader C, Schenk B, Kaehler S T, et al. (2003). A replicate study design for testing bioequivglence A case study on two desmopressin nasal spray preparations. Pharma-cokinet. Dispos. 59 631-636. 

Desmopressin may be given orally, intranasally, SC, or IV. The oral dose must be determined for each individual patient and adjusted according to the patient s response to therapy. When the drug is administered nasally, a nasal tube is used for administration. The nasal tube delivery system comes with a flexible calibrated plastic tube called a rhinyle. The solution is drawn into the rhinyle. One end is inserted into the nostril and the patient (if condition allows) blows the other end to deposit solution deep into the nasal cavity. A nasal spray pump may also be used. Most adults require 0.2 mL daily in two divided doses to control diabetes insipidus. The drug may also be administered via the SC route or direct IV injection. 

Educating the Patient and Family If lypressin or desmopressin is to be used in the form of a nasal spray or is to be instilled intranasally usingthe nasal tube delivery system, the nurse demonstrates the technique of instillation (see Fhtient and Family Teaching Checklist Self-Adnrinistering Nasal Vasopressin). The nurse includes illustrated patient instructions with the drug and reviews them with the patient. If possible, the nurse lias the patient demonstrate the technique of administration. The nurse should discuss the need to take the drug only as directed by the primary health care provider. The patient should not increase the dosage (ie, the number or frequency of sprays) unless advised to do so by the primary health care provider. 

Primary therapy is based on disease severity and type of hemorrhage.7 Most patients with mild to moderate disease and a minor bleeding episode can be treated with l-desamino-8-D-arginine vasopressin [desmopressin acetate (DDAVP)], a synthetic analog of the antidiuretic hormone vasopressin. DDAVP causes release of von Willebrand factor (vWF) and factor VIII from endogenous storage sites. This formulation increases plasma factor VIII levels by three- to fivefold within 30 minutes. The recommended dose is 0.3 mcg/kg intravenously (in 50 mL normal saline infused over 15 to 30 minutes) or subcutaneously or 300 meg intranasally via concentrated nasal spray every 12 hours. Peak effect with intranasal administration occurs 60 to 90 minutes after administration, which is somewhat later than with intravenous administration. Desmopressin infusion may be administered daily for up to 2 to 3 days. Tachyphylaxis, an attenuated response with repeated administration, may occur after several doses.8... 

Oral administration of 0.1-0.2 mg desmopressin provides an antidiuretic effect lasting for 8-12 hours. Desmopressin does not cross blood brain barrier and maximal plasma concentrations are reached within 2 hours. After oral administration, varies between 2.0 hours and 3.2 hours. 65% of oral desmopressin absorbed is excreted unchanged in the urine. It is also used as a nasal spray. 

Vasopressin and desmopressin are treatments of choice for pituitary diabetes insipidus. The dosage of desmopressin is 10-40 meg (0.1-0.4 mL) in two to three divided doses as a nasal spray or, as an oral tablet, 0.1-0.2 mg two to three times daily. The dosage by injection is 1-4 meg (0.25-1 mL) every 12-24 hours as needed for polyuria, polydipsia, or hypernatremia. Bedtime desmopressin therapy, by intranasal or oral administration, ameliorates nocturnal enuresis by decreasing nocturnal urine production. Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic diverticular bleeding. 

Intravenous injection is the most common route although subcutaneous injection may also be used. A concentrated nasal spray formulation has been proved to be efficient for home treatment of patients with bleeding episodes or even minor surgical procedures and has also been used prophylacticly (4). The nasal spray used to treat diabetes insipidus (Desmospray) is too dilute for use in disorders of hemostasis. Similarly, desmopressin in tablet form (Desmotabs) is intended for treatment of nocturnal enuresis in children and is of no use in the treatment of hemostatic disorders. 

In 64 women mean age 53 years enrolled in a randomized, placebo-controlled, crossover study of desmopressin 40 micrograms by nasal spray for the treatment of severe daytime urinary incontinence, there were drug-related adverse events in 25 women taking desmopressin and 24 adverse drug reactions in 15 women taking placebo (35). The most common adverse event with desmopressin was headache (36%). Nausea occurred in 10%. 

An 11-year-old girl was given desmopressin 10 micrograms by nasal spray per nostril for nocturnal enuresis (46). On the second night she took 3 puffs and at 3 a.m. awoke with a tonic-clonic fit. Her serum sodium concentration was 115 mmol/1. 

The synthetic vasopressin peptide, desmopressin, has been extensively investigated and shown to be effective as tricyclic antidepressants in the control of nocturnal enuresis and to enhace the enuretic night alarm treatment. The side effects are relatively few (nasal pain, conjunctivitis) when given by nasal spray. The precise mechanism of action of this peptide is unknown. 

The volume of drug solution delivered to the nose also seems to have an effect on the bioavailability of the dmg. For example, the bioavailability of desmopressin was doubled when it was delivered as two 50 pi actuations from a metered nasal spray in comparison to the delivery of one 100 //I actuation. This may be attributed to prolonged retention of the dose at the administration site. 

Intranasal Desmopressin is administered intranasally in the treatment of diabetes insipidus salmon calcitonin, a peptide hormone used in the treatment of of osteoporosis, is available as a nasal spray. The abused drug, cocaine, is generally taken by sniffing. 

A dose of 1 pg desmopressin acetate has antidiuretic activity that is equivalent to 4U arginine vasopressin. Desmopressin acetate has recently been evaluated in normal horses. The author and coworkers diluted desmopressin acetate (0.1 mg/ml) nasal spray in sterile water and administered 0.05pg/kg i.v. (25 pg, equivalent to 100 U of antidiuretic activity in a 500 kg horse) to horses with polyuria induced by repeated nasogastric intubation of water for 3 days. Urine was collected for 8h after desmopressin acetate administration and there was an increase in urine specific gravity to >1.020 from 2 to 7h after administration (Fig. 10.2). The drug had no effects on heart rate or systemic blood pressure. These preliminary data demonstrate that the i.v. administration of desmopressin acetate appears to be safe and a useful tool for the evaluation of horses with DI. 

Desmopressin may be administered intranasaUy via a concentrated nasal spray. It effectively increases factor VIE levels, but its peak eEect occurs 60 to 90 minutes after administration, somewhat longer than with desmopressin administered intravenously. The dosage is one spray (150 meg) for children who weigh less than 50 kg and two sprays (300 meg) for those who weigh more than 50 kg. The nasal spray may serve as an altemative to the intravenous formulation, especially in patients with nuld bleeding episodes. 

Various studies (Bond et al. 1984 Newman et al. 1987a) have found droplet size distributions of aqueous nasal spray products to have mass mean (median) diameter values between 44 and 62 pun. These studies showed that the majority of the dose was deposited locally in the anterior one-third of the nose. The relationship between retention time and viscosity has shown that the addition of various concentrations of methylcellulose (MC) to a metered spray pump containing desmopressin resulted in a dose-related increase in mean particle size from 51 pan (0 percent MC) to 81 pan (0.25 percent MC) to 200 pirn (0.5 percent MC), without a change in mean spray weight. The longest retention time was observed for the 0.25 percent MC solution, which was attributed to its particle size (81 p,m) and not to an increase in viscosity, since a decrease in retention time was observed for the highest viscosity (0.5 percent MC) solution... 

Only two antidiuretic peptides are available for clinical use in the United States (1) Vasopressin (synthetic 8-l-arginine vasopressin Pitressin) is available as a sterile aqueous solution it may be administered subcutaneously, intramuscularly, or intranasally. (2) Desmopressin acetate (synthetic l-deamino-8-D-arginine vasopressin DDAVP, others) is available as a sterile aqueous solution packaged for intravenous or subcutaneous injection, in a nasal solution for intranasal administration with either a nasal spray pump or rhinal tube delivery system, and in tablets for oral administration. The therapeutic uses of vasopressin and its congeners can be divided into two main categories according to the type of vasopressin receptor involved. 

Protein and peptide therapeutics currently represent eight of the top 100 prescription pharmaceuticals in the U.S., and biotechnology products are projected to account for 15% of the total US. prescription drug market by 2003. Of the protein and peptide products now on the market, many are administered as daily injections, though several are delivered by noninvasive routes. For example, desmopressin is delivered as a nasal spray, and deoxyribonuclease I is administered by inhalation. Although cyclosporin A is orally active, as yet there are no general means to confer oral bioavailability to peptides and proteins. A major advance in delivery of peptides was achieved with the introduction of a monthly injectable, biodegradable microsphere formulation of LHRH. 

Commercially available peptide hormones delivered as nasal spray solutions include Synarel (nafare-lin), Stimate NS (desmopressin), Suprefact (buserelin acetate), and Miacalcin (salmon calcitonin). A list of current drugs in the market, doses, and bioavailability along with a comparative bioavailability profile for oral desmopressin is presented in Table 86.3. 

Desmopressin can be administered intravenously, subcutaneously, intranasally, or orally. The half-life of circulating desmopressin is 1.5-2.5 hours. Nasal desmopressin is available as a unit dose spray that delivers 0.1 mL per spray it is also available with a calibrated nasal tube that can be used to deliver a more precise dose. Nasal bioavailability of desmopressin is 3-4%, whereas oral bioavailability is less than 1%. 

Formulation and dosage form aspects that can impact the site of deposition within the nasal cavity are a key consideration for nasal delivery. The site of deposition can impact absorption due to the differences in the permeability and residence time of the anterior and posterior portions of the nose. A variety of dosage forms such as nasal drops, sprays, gels, powders, or microspheres are available for administering pharmaceuticals by the nasal route, and these options need to be carefully evaluated because the type of dosage form can impact where the formulation is deposited in the nasal cavity and, in turn, the systemic absorption. For example, the bioavailability of nasally administered desmopressin was significantly increased in a spray formulation compared with drops, " likely... 

Infrequent adverse effects of desmopressin spray include nasal irritation, epistaxis, rhinitis, and nasal congestion, whereas desmopressin tablets or spray may cause transient headache, chills, dizziness, nausea, and abdominal pain. Rarely, water intoxication, hyponatremia, and subsequent tonic-clonic seizures have been reported, " particularly in children with concurrent physical disorders, intentional overdoses, or excessive fluid intake. When desmopressin is administered, evening fluids should be limited to 8 ounces to prevent hyponatremia or water intoxication. ... 

Usually, desmopressin is administered intranasally by use of sprays or drops. This administration route of desmopressin was considered to be more efficacious than the oral route, because bypassing the gastrointestinal tract increases the absolute bioavailability from less than 1% to approximately 5%. However, nasal application of desmopressin is accompanied by high intersubject and intrasubject variability in plasma pharmacokinetics [215]. Therefore, there have been several pharmaceutical research efforts to improve nasal delivery of desmopressin. 

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