OCTOSTIM Solution for injection Ref.[27769] Active ingredients: Desmopressin

OCTOSTIM (desmopressin acetate) treatment without concomitant restriction of water intake may lead to water retention/hyponatremia with or without accompanying signs and symptoms (reduced serum sodium, weight gain, and, in severe cases, convulsions). Other signs include persistent headache and nausea/vomiting. If these symptoms are present, serum sodium must be checked. The fluid intake should be restricted to the least possible and the body weight should be checked regularly. Should there be a gradual increase of the body weight, a decrease of serum sodium to below 130 mmol/L or plasma osmolality to below 270 mOsm/kg body weight, the fluid intake must be reduced drastically and the administration of OCTOSTIM interrupted.

Precautions to prevent fluid overload must be taken in:

• the very young and elderly patients
• conditions characterized by fluid and/or electrolyte imbalance
• patients at risk for increased intracranial pressure

Children, elderly and patients with serum sodium levels in the lower range of normal may have an increased risk of hyponatremia.

Treatment with desmopressin should be interrupted or carefully adjusted during acute intercurrent illnesses characterized by fluid and/or electrolyte imbalance (such as systemic infections, fever, gastroenteritis), and the fluid and electrolyte balance should be carefully monitored, especially in situations with excessive bleeding.

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.

OCTOSTIM must be used with caution in patients prone to vascular headaches, and patients with coronary insufficiency and hypertensive cardiovascular diseases because of possible changes in blood pressure and tachycardia.

Rapid infusion rates may result in severe hypotension; therefore, the speed of intravenous infusion of OCTOSTIM should not be shorter than 20-30 minutes. A maximum dose of 0.3 mcg/kg should not be exceeded.

Lack of therapeutic effect has been noted in patients who have been febrile or otherwise “stressed” for several days. Whenever possible, therapeutic efficacy (i.e., Factor VIII response in hemophilia and bleeding time correction in other disorders) should be established in individual patients prior to use and followed throughout the course of treatment. The coincident use of antifibrinolytic agents to counteract desmopressin-induced plasminogen activator release has been recommended, however, benefit has not been clearly established.

The benefits of desmopressin versus other hemostatic therapies should be carefully assessed in situations where prolonged haemostasis is required including active postoperative bleeding and variceal bleeding in patients with cirrhosis.

Desmopressin should not be used routinely in the bleeding trauma patient (grade 2C). Desmopressin (0.3 mcg/kg) can be administered in patients treated with platelet-inhibiting drugs or with von Willebrand disease (Grade 2C).

The addition of desmopressin does not improve and may worsen the efficacy of terlipressin in controlling acute variceal bleeding in cirrhotic patients.

Desmopressin use is not recommended in patients with cirrhosis undergoing elective surgery or at the time of variceal bleeding (B2). Desmopressin administration in patients with cirrhosis undergoing dental extraction may be considered (B2).

OCTOSTIM should not be used to treat patients with Type IIB von Willebrand’s disease since platelet aggregation may be induced (see CONTRAINDICATIONS).

OCTOSTIM should not be used in patients with Hemophilia B because it has no effect on Factor IX levels.

OCTOSTIM has no therapeutic effect in Glazmann’s thrombaesthenia.

OCTOSTIM does not reduce prolonged bleeding time in thrombocytopenia.

Tachyphylaxis may develop with repeated use.

There have been rare reports of thrombotic events (thrombosis, cerebral thrombosis, cerebrovascular accident and disorder (stroke), acute myocardial infarction, angina pectoris and chest pain,) following desmopressin acetate injection in patients predisposed to thrombus formation. No causality has been determined; however, the drug should be used with caution in elderly patients and in patients with risk factors and history of thrombosis, thrombophilia and known cardiovascular disease.

Persistently increased endogenous Factor VIII levels are a risk factor for venous thromboembolism (VTE). The evidence for elevated vWF levels as a risk factor for VTE is less strong, but some studies have demonstrated an association.

Severe allergic reactions have been reported rarely. Fatal anaphylaxis has been reported in one patient who received intravenous OCTOSTIM . It is not known whether antibodies to desmopressin acetate are produced after repeated administration.

OCTOSTIM has an antidiuretic effect. Patients receiving this drug should be cautioned to reduce their ingestion of fluids for at least 6 hours after receiving the drug. Patients receiving intravenous fluids must be placed on fluid input/output monitoring.

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 OCTOSTIM is administered to a nursing woman.

General

Precautions must be taken in patients with moderate and severe renal insufficiency (creatinine clearance below 50 ml/min).

Severe bladder dysfunction and outlet obstruction should be ruled out before starting treatment.

OCTOSTIM (desmopressin acetate) produces changes in blood pressure; either an elevation or a decrease and a compensatory tachycardia. Subcutaneous administration usually results in a slight change that is transient. Greater changes may occur with intravenous infusion, especially if administered rapidly. It should, therefore, be used with caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease.

OCTOSTIM should not be administered to dehydrated patients until water balance has been adequately restored.

OCTOSTIM should be used with caution in patients with cystic fibrosis because these patients are prone to hyponatremia. Children and geriatric patients should be closely observed for possible water retention due to over ingestion of fluids.

Special Populations

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. Published reports stress that, as opposed to preparations containing the natural hormone, desmopressin acetate in antidiuretic doses has no uterotonic action, but the physician will have to weigh the possible therapeutic advantage against potential danger in each case.

Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due desmopressin acetate. Subcutaneous doses up to 4 times the human dose for Factor VIII stimulation on a mg/m² basis (or 12.5 times the human dose on a mg/kg basis) and doses up to 4 times the human dose for diabetes insipidus on a mg/m² basis (or 12.5 times the human dose on a mg/kg basis) were studied. There are several publications of management of diabetes insipidus in pregnant women with no harm to the fetus reported.

Published data on a limited number (n = 53) of exposed pregnancies in women with diabetes insipidus indicate no adverse effects of desmopressin on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Caution should be exercised when prescribing to pregnant women.

Nursing Women

There have been no controlled studies in nursing mothers. A single study on a post-partum woman demonstrated a marked change in plasma desmopressin acetate level following an intranasal dose of 10 mcg, but little drug was detectable in breast milk (See WARNINGS AND PRECAUTIONS).

Results from analyses of milk from nursing mothers receiving a high dose of desmopressin (300 mcg intranasally), indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis.

Pediatrics

No controlled trials have been conducted in children with renal insufficiency.

Use in infants and children will require careful fluid intake restriction to prevent possible hyponatremia and water intoxication. The physician should weigh possible therapeutic advantages against potential risks in each case. No controlled trials have been conducted in infants under 3 months of age with von Willebrand’s disease or Hemophilia A thus OCTOSTIM should not be used in this patient population.

Monitoring and Laboratory Tests

Hemophilia A

Laboratory tests for assessing patient status include levels of Factor VIII coagulant, Factor VIII antigen and Factor VIII ristocetin cofactor (von Willebrand factor) as well as activated partial thromboplastin time. Factor VIII coagulant activity should be determined before giving OCTOSTIM for hemostasis. If Factor VIII coagulant activity is present at less than 5% of normal, OCTOSTIM should not be relied upon alone.

von Willebrand’s Disease

Laboratory tests for assessing patient status include levels of Factor VIII coagulant, Factor VIII antigen and Factor VIII ristocetin cofactor (von Willebrand factor). The skin bleeding time may be helpful in following these patients and should always be assessed pre-operatively.

Uremia

A test dose of OCTOSTIM should be administered at the time of diagnosis of the bleeding disorder, or at least 72 hours prior to an elective treatment. The skin bleeding times should be measured before and 1 hour after OCTOSTIM administration.

Adverse Drug Reaction Overview

The most serious adverse reaction with desmopressin is hyponatremia/water retention, which is associated with headache, nausea, vomiting, water intoxication, decreased serum sodium, weight increase, malaise, abdominal pain, muscle cramps/spasms, dizziness, decreased consciousness, confusion, generalized or local oedemas (peripheral, face), and in severe cases brain oedema, hyponatremic encephalopathy, convulsions and coma. Hyponatremia is reversible in two thirds of the adult cases reported during post-marketing. In the rest of the cases, 7% are reported as not recovered at the time when the events were reported and 21% had an unknown outcome. Treatment should be individualised and rapid overcorrection should be avoided to reduce the risk of further complications.

Post-marketing hypersensitivity reactions including local allergic reactions such as dyspnoea, erythema, generalized or local oedemas (peripheral, face), pruritus, rash, rash macular, rash maculopapular, rash erythematous, skin plaque and urticaria, have been reported in association with desmopressin injection. More serious hypersensitivity reactions including anaphylactic shock and reaction, and anaphylactoid shock and reaction have also been reported in association with desmopressin injection. Allergic reactions usually occur rapidly after drug administration and may occur during first time usage or after repeated exposure of desmopressin injection.

Rare post marketing cases of deep vein thrombosis, cerebrovascular accident/disorder (stroke), cerebral thrombosis, hypertension, pulmonary embolism, myocardial infarction, angina pectoris and chest pain have been reported in patients treated with desmopressin.

OCTOSTIM has produced transient headache, nausea, facial flushing, tachycardia, hypotension, oliguria, abdominal cramps and vulvar pain. The frequency varies with the dosage and the route of administration.

See WARNINGS AND PRECAUTIONS for the possibility of water intoxication and hyponatremia. Very occasionally, intravenous injection of OCTOSTIM has produced local erythema, swelling or burning pain along the course of the vein.

Side effects following intravenous administration to 297 patients included transient facial flushing (approximately 18%), fatigue (3%), headache (2%), and oliguria (1%). Other effects reported at a frequency of less than 1% included nausea, dizziness, syncope and abdominal cramping.

Side effects following subcutaneous administration to 190 subjects included transient facial flushing (7%). Other effects reported at a frequency of less than 1% included hypotension, transient headache, abdominal tension, nausea, tachycardia and discomfort at the injection site.

Side effects following intranasal administration to 78 patients included facial flushing and warmth (24%), dizziness or headache (13%), palpitations (9%), nausea (6%), fatigue (6%), red eyes (4%), decreased diuresis (3%), nasal congestion, rhinitis, tachycardia. Other effects reported at a frequency of less than 1% include abdominal cramps, allergic reactions both to desmopressin and to the preservative, somnolence.

Severe hypotension was observed in some patients who received OCTOSTIM intravenously during cardiac surgical procedures and this may have resulted from rapid infusion rates. A dosage of 0.3 mcg/kg should not be exceeded, and the infusion rate of 20 to 30 minutes should not be exceeded.

Additional Post-Marketing Adverse Reaction Reports

The following post-marketing events have been reported:

Respiratory, thoracic and mediastinal disorders: dyspnea

Gastrointestinal disorders: nausea, vomiting

Nervous system disorders: headache, dizziness

General disorders and administration site conditions: injection/infusion site reactions including swelling, pain, extravasation, erythema, bruising and nodules, generalized or local oedemas (peripheral, face), chills

Overview

Although the pressor activity of desmopressin acetate is very low, its use with other pressor agents should be done only with careful patient monitoring.

Desmopressin acetate injection has been used with epsilon aminocaproic acid without adverse events.

Precautions to avoid hyponatremia, including careful attention to fluid restriction and more frequent monitoring of serum sodium, must be taken in case of concomitant treatment with substances which affect water and/or sodium homeostasis, are known to release antidiuretic hormone and suspected to induce SIADH, e.g., opioids, tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine, carbamazepine, antidiabetics of the sulfonylurea group particularly chlorpropamide, urea, fludrocortisone and NSAIDs, as these may cause an additive antidiuretic effect and increase the risk of water retention/hyponatremia.

Desmopressin should be used cautiously in patients who are receiving lithium, large doses of epinephrine, demeclocycline, heparin or alcohol, because the antidiuretic response to desmopressin may be decreased.

Concurrent administration of clofibrate with desmopressin reportedly potentiates and prolongs the antidiuretic effect of desmopressin.

Indomethacin may augment the magnitude but not the duration of the response to desmopressin.