Source: Health Products and Food Branch (CA) Revision Year: 2021
OCTOSTIM (desmopressin acetate) is a synthetic structural analogue of the natural human hormone, arginine vasopressin with deamination of 1-cysteine and substitution of 8-L-arginine by 8-D-arginine.
OCTOSTIM administration causes a transient increase in all components of the Factor VIII complex (Factor VIII coagulant activity, Factor VIII related antigen, and ristocetin cofactor) and in plasminogen activator. Either directly or indirectly, OCTOSTIM causes these factors to be released very rapidly from their endothelial cell storage sites. In addition, OCTOSTIM may have a direct effect on the vessel wall, with increased platelet spreading and adhesion at injury sites.
A second dose given before endothelial cell stores are replenished will not have as great an effect as the initial dose. Responses as great as the initial one usually are seen if 48 hours or more have elapsed between doses.
The pharmacokinetic and pharmacodynamic profiles after subcutaneous or intravenous administration to healthy volunteers are equivalent. The plasma half-life following subcutaneous and intravenous administration ranges from 3.2 to 3.6 hours.
Desmopressin causes a dose-dependent increase in plasma Factor VIII (antihemophilic factor), plasminogen activator, and, to a smaller degree, Factor VIII-related antigen and ristocetin cofactor activities. The mechanism by which desmopressin lowers bleeding time remains speculative.
Structural modifications of vasopressin present in desmopressin result in reduced smooth muscle contracting and vasopressor properties compared with vasopressin and lypressin. Initial studies of intranasal desmopressin at a subtherapeutic dose of 20 mcg resulted in no effect on blood pressure or pulse rate, but mean arterial pressure increases as much as 15 mm Hg were observed with doses of 40 mcg or more. In the therapeutic dose range, cardiovascular changes in normal, healthy volunteers were not considered to be clinically meaningful, but 27 of 32 volunteers had notable changes in systolic and/or diastolic blood pressure, and 8 had notable changes in pulse. Some volunteers experienced increases in diastolic blood pressure of greater than or equal to 20%; one volunteer experienced an increase in systolic blood pressure of 35% (40 mm Hg); and others experienced decreases in diastolic blood pressure, in some cases with compensatory tachycardia.
Desmopressin has been shown to interact with renal (V2) vasopressin receptors which mediate its antidiuretic effect on renal tubes. The extrarenal effects of Desmopressin in normal persons, which include stimulation of the release of Factor VIII coagulant and von Willebrand factory (ristocetin cofactor) and a decrease in blood pressure, may be mediated by interaction with receptors in other tissues which are similar to the renal V2 receptors.
Desmopressin has not been reported to stimulate uterine contractions.
Dose-response studies were performed in healthy persons, using doses of 0.1 to 0.4 mcg/kg. OCTOSTIM provokes an average increase in Factor VIII coagulant activity two to five times baseline levels.
Plasminogen activator activity increases about threefold, after OCTOSTIM infusion, but is of such short duration of action that there has been no clinically significant fibrinolysis in patients treated with OCTOSTIM . The Factor VIII related antigen and ristocetin cofactor activity were also increased to a smaller degree, but still were dose dependent. The above responses reach a maximum at a point ranging from one to two hours.
The effect of repeated OCTOSTIM administration when doses were given every 12 to 24 hours has generally shown a gradual diminution of the Factor VIII activity increase, noted with a single dose. The initial dose is reproducible in any particular patient if there are 2 or 3 days between administration, when endothelial cell storage sites are replenished.
The percentage increase of Factor VIII levels in patient with mild haemophilia 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 OCTOSTIM infused over 10 minutes.
Desmopressin has also reportedly increased Factor VIII activity and to a lesser extent, Factor VIII related antigen and ristocetin cofactor in patients with uremia; these changes were accompanied by a shortening of bleeding time. In addition, the drug induced release into the plasma of the larger multimers of Factor VIII/von Willebrand factor in these patients.
After 300 µg of OCTOSTIM spray, the percentage increase of Factor VIII and von Willebrand factor levels in patients with mild hemophilia A and von Willebrand’s disease was less than observed after 0.3 mcg/kg of intravenous OCTOSTIM.
In a trial comparing intranasal and intravenous Desmopressin in patients with mild/moderate hemophilia A or von Willebrand’s disease, an intranasal dose of 300 mcg desmopressin resulted in a 54% and 75% respective increase in Factor VIII:C and von Willebrand antigen, compared to intravenous desmopressin. The mean maximum percent decrease in bleeding time following intranasal desmopressin was 1.5 times that observed following intravenous desmopressin.
A prolonged bleeding time is shortened to the same extent after doses of either 300 mcg desmopressin intranasally, or intravenous doses of 0.3 mcg/kg body weight.
Following IV infusion of desmopressin, the increase in plasma Factor VIII activity occurs within 15-30 minutes and peaks between 90 minutes and 3 hours after administration; the increase in Factor VIII activity is dose dependent, with a 300-400% maximum increase reportedly occurring after IV infusion of 0.4 mcg/kg dose. Plasma Factor VIII-related antigen activity has also been reported to peak within 3 hours after IV infusion of the drug. The subcutaneous route of OCTOSTIM administered has been compared with the intravenous route in healthy volunteers and found to produce a bioequivalent response in terms of pharmacokinetic profile.
Desmopressin acetate was administered to 10 healthy volunteers in a randomized cross-over study at a dose of 0.4 mcg/kg by intravenous infusion and subcutaneous injection. The pharmacokinetic data are summarized in Table 1.
Table 1. Pharmacokinetics of OCTOSTIM after subcutaneous and intravenous administration to 10 healthy volunteers. Mean ± S.D.:
| Dose and route of administration | AUC (pg/h/mL-1) | Cmax (pg/mL) | Tmax (min) | Half-life (min-1) |
|---|---|---|---|---|
| 0.4-mcg/Kg i.v. | 3109 ± 1056 | 3.62 ± 0.42 | ||
| 0.4-mcg /Kg s.c. (4 mcg /mL ampoule) | 3492 ± 659 | 568 ± 203 | 87 ± 66 | 3.50 ± 0.39 |
| 0.4-mcg /Kg s.c.(40 mcg/mL ampoule) | 3164 ± 393 | 544 ± 46 | 60 ± 7 | 3.17 ± 0.33 |
Subcutaneous administration of OCTOSTIM showed the same plasma half-life, from 3.2 to 3.6 hours, as intravenous OCTOSTIM. The plasma profile indicates that the elimination of OCTOSTIM from plasma follow first order kinetics. There is no significant difference in AUC between subcutaneous and intravenous OCTOSTIM. A similar study in 14 hemophiliac patients also showed that the subcutaneous route of administration is bioequivalent to the intravenous route.
The acute toxicity of desmopressin acetate is low (Table 2). Mice tolerate IV doses of 2 mg/kg. At IV doses of 30 mcg/kg in rates and 40 mcg/kg in rabbits, only transient changes in clinical behaviour were observed. Intravenous doses up to 24 mcg/kg in dogs did not produce any cardiovascular changes.
Table 2. Acute Toxicity of OCTOSTIM:
| Species | Number | LD50 Dose | Route |
|---|---|---|---|
| Mice | 10 both sexes | <2 mg/kg | IV |
| Rats | 12 both sexes | >30 mcg/kg | IV |
| Dogs | 5 males | >24 mcg/kg | IV |
Results from 14-day studies show that the drug given intravenously to rates at 18 mcg/kg/day and to rabbits at 6 mcg /kg/day, causes no biologically significant changes in hemotological and clinical chemistry parameters. Post-mortem examinations did not reveal any abnormalities.
Rats which received 5 mg/kg/day subcutaneously for 3 weeks did not show any significant changes in weight, blood count, or organ changes.
In a controlled 8 week experiment, 20 rats received 2 mcg /kg/day subcutaneous desmopressin acetate. No increase in blood glucose nor morphological or histological pancreatic changes occurred.
Rats (20 per group) which received desmopressin acetate doses of 5, 50, or 500 ng/kg/day, for 6 months did not show any significant changes in weight, blood values, or levels of transaminases. The weight of heart, lungs, and kidneys decreased in female animals in the lower dose groups but not in the higher ones. In male animals, a decrease in non-esterifiable fatty acids was noted.
Dogs (3 per group) which received subcutaneous doses of 10 and 100 ng/kg/day desmopressin acetate for 6 months did not show any significant changes in comparison with control groups in blood sugar or transaminases and did not show histological or morphological organ changes.
In teratogenicity testing in Wistar rats, no teratologic or embryotoxic effects were observed in 369 fetuses from 40 females dosed with up to 50 ng/kg/day desmopressin acetate subcutaneously on Day 1 through Day 20 of gestation.
In a study of 78 Dutch belted rabbits which received subcutaneous desmopressin acetate up to 10 mcg/kg/day on Day 6 through Day 18 of pregnancy, no teratogenic or embryotoxic effects were observed in 296 fetuses. Weaning was unaffected.
There have been no long-term studies in animals to assess the impairment of fertility potential of OCTOSTIM (desmopressin acetate injection).
There have been no long-term studies in animals to assess the carcinogenic or mutagenic potential of OCTOSTIM.
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