Desmopressin dosing

The desmopressin dose should be adjusted to achieve adequate urinary concentration during sleep to prevent nocturia, to result in a daily urine volume of approximately 1.5 to 2 L, and to maintain the serum sodium concentration in the 137 to 142 mEq/L range. The serum sodium concentration should be measured every 3 to 4 days during the initial dose titration period, and then every 2 to 4 months. 

Syndrome of inappropriate antidiuretic hormone is defined by water retention, dilutional hyponatraemia and decreased volume of highly concentrated urine. There are several causes which can result in SIADH, neoplasms ectopic secreting AVP, ectopic release of AVP by various diseases or drugs, exogenous administration of AVP, desmopressin, lysipressin or large doses of OT (iatrogenic SLADH). 

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. 

These chromatographic performance tests are carried out in order to ensure that all impurities to be controlled are well separated from the substance to be examined (HPLC, GC andTLC). Forthis reason, preferably such reference substances are chosen which elute dose to the main compoxmd (HPLC, GC) or which have a similar Rf-value (TLC) but can stiU be separated. These may be structurally related compoimds which shall be separated with a minimum requirement for the resolution using the chromatographic system described, e.g. such as in the monograph for desmopressin (Monograph 07121999), Figure 5.3. 

Desmopressin (DDAVP) increases the release of factor VIII (von Willebrand factor) from endothelial tissue in the vessel wall. Bleeding time is promptly reduced, within 1 hour of administration, and is sustained for 4 to 8 hours.42 Doses used for uremic bleeding are 0.3 to 0.4 mcg/kg intravenously over 20 to 30 minutes, 0.3 mcg/kg subcutaneously, or 2 to 3 mcg/kg intranasally. Repeated doses can cause tachyphylaxis by... 

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... 

Most patients with type 1 vWD (functionally normal vWF) and a minor bleeding episode can be treated successfully with desmopressin, which induces secretion of autologous factor VIII and vWF into plasma. The recommended dose is the same as that used to treat mild factor VIII deficiency (0.3 mcg/kg intravenously in 50 mL of normal saline infused over 15 to 30 minutes). This therapy generally is ineffective in type 2A patients who secrete qualitatively abnormal vWF and is controversial in type 2B patients because it may increase the risk of postinfusion thrombocytopenia. Type 3 vWD patients who lack releasable stores of vWF do not respond to DDAVP therapy.18... 

The individual responsiveness to desmopressin is consistent, and a test dose administered at the time of diagnosis or prior to therapy is the best predictor of response. Generally, DDAVP is more effective in vWD than in hemophilia patients, with an average 30% to 50% increase in vWF and factor VIII levels. In patients with an adequate response, desmopressin is first-line therapy because it allows for once-daily administration (elevates plasma levels for 8-10 hours), does not pose a threat in terms of viral transmission, and the cost is substantially less than that of the plasma-derived products. Fibrinolysis inhibitors (50-60 mg/kg of aminocapriotic acid every 4—6 hours or trenex-amic acid 10-15 mg/kg every 8-12 hours) and OCs are used successfully in the management of epistaxis and menorrhagia or as adjuvant treatments. 

Desmopressin (the synthetic analog of vasopressin) acts by increasing water retention and urine concentration in the distal tubules of the kidney. This drug is administered intranasally (20-40 pg or one to two sprays) using a unit-dose, spray pump delivery system. The duration of action is 10 to 12 hours. The medication is expensive. 

Desmopressin acetate increases the factor VIII activity of patients with mild hemophilia A or von Willebrand disease. It can be used in preparation for minor surgery such as tooth extraction without any requirement for infusion of clotting factors if the patient has a documented adequate response. High-dose intranasal desmopressin (see Chapter 17) is available and has been shown to be efficacious and well tolerated by patients. 

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%. 

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. 

At higher doses desmopressin also has significant hematological effects and can significantly boost concentrations of factor VIII and von Willebrand factor (VWF) in the blood. Desmopressin is therefore a valuable agent for the treatment of mild and moderate hemophilia A (congenital or acquired) and type 1 von Willebrand disease, in which the VWF protein structure is normal but... 

In an open trial of high-dose desmopressin 1.5 mg intra-nasally to control bleeding in 278 patients with congenital bleeding disorders, headache occurred in 3.6% and flushing in 3.2% of patients (18). Dizziness and nausea were reported in 1-1.5% and edema in 0.3% of patients. 

Facial flushing occurred in two of 25 children with either hemophilia or von Willebrand disease given high-dose intranasal desmopressin (150 micrograms) in a singledose open study (19). 

A 59-year-old man with mild hemophilia A was given a test dose of desmopressin 30 micrograms (0.19 micrograms/kg) in 100 ml of saline by intravenous infusion over 30 minutes (29). Shortly afterwards, having had a cigarette, he developed chest pain. An electrocardiogram showed ST elevation, and a myocardial infarction was confirmed. 

The pharmacokinetics of one dose of desmopressin 400 micrograms have been investigated in 15 men and nine women with nocturia aged over 65 years (40). They then entered a placebo-controlled crossover evaluation period. Peak concentrations occurred at 1-2 hours after administration and gradually fell over 6-7 hours. The women had significantly higher concentrations than the men, even after adjustment for body weight. Four women were withdrawn from the crossover period because of hyponatremia. 

In 224 women aged 20-89 years, desmopressin 0.1—0.4 mg/day was used for treating nocturia (43). There were five adverse events, four of which were reported in the dose-titration period. Of these four events, two were deaths that were not thought to be due to hyponatremia and two were due to serious hyponatremia. The fifth case occurred during the double-blind period in the placebo group. In 27 patients serum sodium concentrations were below the reference range and in 13 they were less than 130 mmol/1 11 of the 13 were aged 65 years or older. 

An 80-year-old woman with a high baseline fluid intake developed severe hyponatremia, with loss of consciousness and seizures, after a single dose of desmopressin 0.2 mg (49). 

In a double-blind study of desmopressin, 10 of 224 adult men had serum sodium concentrations below 130 mmol/1 during a 3-week, open, dose-titration period. Men aged 65 years and over were more likely to develop hyponatremia (51). 

Fluid balance and plasma electrolytes should be monitored to prevent this complication, particularly if repeated doses are required. Children seem to be particularly vulnerable to this complication (55). In a longterm, open study of 245 Swedish children given intranasal desmopressin 20-40 micrograms at night for enuresis, five had an asymptomatic fall in plasma sodium (36). Mild hyponatremia, which did not cause symptoms, was found in five of 399 children in an open, multicenter trial (56). 

A 38-year-old man with von Willebrand disease type 2B developed severe thrombocytopenia after a single dose of desmopressin (66). 

In 224 adult men, mean age 65 (range 37-88) years, thrombocytopenia developed in one man during a 1-week washout period after dose titration to up to 0.4 mg of oral desmopressin daily over the preceding 3 weeks thrombocytopenia did not recur on rechallenge (51). 

A scientific registry of transplant recipients has been used to determine the effect of cadaveric organ donor treatment with desmopressin on the incidence of pancreas graft thrombosis in clinical pancreas transplantation (70). Of 2804 cases with sufficient information between 5 April 1994 and 27 September 2002, 1287 (46%) had received desmopressin. The mean follow up was 1.5 years (1 month to 8.4 years). There was pancreatic graft thrombosis in 4.3%, of whom 5.1% had received desmopressin and 3.5% had not this was just statistically significant. There was no information about dose, time-course, or duration of desmopressin use. It is not known whether this finding is clinically significant. 

There is growing evidence that desmopressin can be used safely in pregnant women and no adverse effects have been reported in either mothers with diabetes insipidus or their babies (71), or in women with clotting factor deficiencies (72). However, the manufacturers advise that it should be used with caution in women with bleeding disorders, who require high doses. 

In 103 children with cranial diabetes insipidus, 3 children who started or had an increase in dose of lamotrigine needed a larger dose of desmopressin, suggesting an effect on the renal tubule or on drug clearance (76). Lamotrigine also increased desmopressin dosage requirements in two other children with cranial diabetes insipidus (78). 

Virtanen R, Kauppila M, Itala M. Percutaneous coronary intervention with stenting in a patient with haemophilia A and an acute myocardial infarction following a single dose of desmopressin. Thromb Haemost 2004 92 1154-6. 

Molnar Z, Farkas V, Nemes L, Reusz GS, Szabo AJ. Hyponatraemic seizures resulting from inadequate postoperative intake following a single dose of desmopressin. Nephrol Dial Transplant 2005 20 2265-7. 

Lebl J, Kolska M, Zavacka A, Eliasek J, Gut J, Biolek J. Cerebral oedema in enuretic children during low-dose desmopressin treatment a preventable complication. Eur J Pediatr 2001 160(3) 159-62. 

Desmopressin has little vasoconstrictor effect but has potent antidiuretic action, through renal vasopressin V2 receptors, and at high doses hemostatic properties, by increasing concentrations of factor VIII and von Willebrand factor in the blood. 

Desmopressin is also available as an oral preparation. The usual dose is 0.1-0.2 mg every 12-24 hours. 

Results from the intranasal trials with histamine and desmopressin have been previously reported ( 12) but will be summarized here for purposes of comparison to the CMC findings. Desmopressin alone, in these trials, significantly reduced the NBF response compared to vehicle administration (Table I). The administration of 20 meg histamine immediately prior to desmopressin restored the NBF response to levels significantly greater than desmopressin alone (Table I). CMC combined with desmopressin had no effect on the NBF response compared to desmopressin alone (Table I). We have previously demonstrated a linear dose-response relationship of intranasal histamine on NBF response over a dosing range of 20 to 500 meg (42). In that study, a single intranasal histamine dose of 20 meg increased NBF response by two fold compared to vehicle. 

CMC did not enhance the ability of desmopressin to concentrate the urine, as measured by urine osmolality or volume response (Table 11). There was also no evidence of any acute effect of the combination of CMC and desmopressin on urinary electrolyte or creatinine concentration (Table 11). The intranasal administration of histamine immediately prior to desmopressin increased the antidiuretic response to desmopressin. Compared to vehicle treatment, urine flow rate response was depressed for a longer duration in response to histamine and desmopressin than after desmopressin alone (Table II). Also it was observed that only histamine and desmopressin in combination, significantly lowered (p < 0.05) cumulative 24 hour urine volume compared to vehicle. As a measure of acute antidiuretic activity, dosing with histamine immediately prior to... 

The increase in desmopressin activity observed in association with an increase in NBF due to coadministered histamine suggests that peptide absorption through the nasal mucosal membrane is in part, blood flow limited. Previous studies (15,fr3) have indicated that the duration of activity of desmopressin is directly related to the intranasal dose administered and resultant peak plasma desmopressin levels. These findings support our hypothesis that histamine enhanced desmopressin activity by increasing its mucosal absorption. 

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. 

There are two types of disturbances in vasopressin secretion. In central diabetes insipidus, vasopressin secretion is reduced it can be treated by giving vasopressin or desmopressin, which has a longer half-life, by mouth or intranasally. In nephrogenic diabetes insipidus, the plasma vasopressin concentration may be normal but the kidney fails to respond. The latter type of diabetes insipidus does not respond to vasopressin therapy but, paradoxically, can be managed by giving a thiazide diuretic, for example chlortalidone, at a maintenance dose of 50 mg daily. 

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