Octim Injection

OCTIM Injection is indicated as follows:

1. To increase Factor VIII:C and Factor VIII:Ag in patients with mild to moderate haemophilia or von Willebrand's disease undergoing surgery or following trauma.

2. To test for fibrinolytic response

Mild to Moderate Haemophilia and von Willebrand's Disease:

By subcutaneous or intravenous administration.

The dose for adults, children and infants is 0.3 micrograms per kilogram body weight, administered by subcutaneous injection or intravenous infusion. Further doses may be administered at 12 hourly intervals so long as cover is required. As some patients have shown a diminishing response to successive doses, it is recommended that monitoring of Factor VIII levels should continue (See Section 4.4).

For intravenous infusion, the dose should be diluted in 50ml of 0.9% sodium chloride for injection and given over 20 minutes. This dose should be given immediately prior to surgery or following trauma. During administration of intravenous desmopressin, vasodilation may occur resulting in decreased blood pressure and tachycardia with facial flushing in some patients.

Increase of Factor VIII levels are dependent on basal levels and are normally between 2 and 5 times the pre-treatment levels. If results from a previous administration of desmopressin are not available then blood should be taken pre-dose and 20 minutes post-dose for assay of Factor VIII levels in order to monitor response.

Unless contraindicated, when surgery is undertaken tranexamic acid may be given orally at the recommended dose from 24 hours beforehand until healing is complete.

Fibrinolytic Response Testing:

By subcutaneous or intravenous administration.

The dose for adults and children is 0.3 micrograms per kilogram body weight, administered by subcutaneous injection or intravenous infusion.

For intravenous infusion, the dose should be diluted in 50ml of 0.9% sodium chloride for injection and given over 20 minutes. A sample of venous blood should be taken 20 minutes after the administration. In patients with a normal response the sample should show fibrinolytic activity of euglobulin clot precipitate on fibrin plates of at least 240mm².

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Habitual or psychogenic polydipsia (resulting in a urine production exceeding 40 ml/kg/24 hours)
• A history of unstable angina and/or known or suspected cardiac insufficiency and other conditions requiring treatment with diuretics
• Known hyponatraemia
• Syndrome of inappropriate ADH secretion (SIADH)
• Von Willebrand's disease type II B

When OCTIM injection is prescribed, it is recommended to maintain fluid and electrolyte balance. Treatment without concomitant reduction of fluid intake may lead to fluid retention and/or hyponatremia with or without accompanying warning signs and symptoms (see section 4.8).

Desmopressin should not be administered for haemostatic support beyond 2 days of ongoing bleeding, as prolonged use is associated with the development of tachyphylaxis and diminished therapeutic efficacy.

Measures to prevent fluid overload must be taken in patients requiring treatment with diuretic agents.

Special attention must be paid to the risk of fluid retention/hyponatraemia (see section 4.8). The fluid intake should be restricted to the least possible and the body weight should be checked regularly. If there is a gradual increase of the body weight, 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 OCTIM Injection interrupted.

OCTIM Injection does not reduce prolonged bleeding time in thrombocytopenia.

Due to post-marketing reports of both venous and arterial thromboembolic events, such as deep vein thrombosis, cerebral thrombosis, acute myocardial infarction and ischaemic stroke in relation to desmopressin injections used for the haematological indications, considerations should be taken before using OCTIM injection in patients with risk factors for, or a history of, thrombosis, atherosclerotic cardiovascular disease, atherosclerotic cerebrovascular disease or angioplasty.

Precautions must be taken in patients at risk for increased intracranial pressure.

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

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

Special attention should be given when desmopressin is co-administered with other drugs affecting water and/or sodium homeostasis (see section 4.5). In patients with chronic therapy with drug(s) affecting water and/or sodium homeostasis, OCTIM injection should be administered after confirmation of normal baseline sodium.

Precautions must be taken in patients with moderate and severe renal insufficiency (creatinine clearance below 50 ml/min), as the antidiuretic effect could be prolonged. Prolonged antidiuretic effect could increase the risk of hyponatraemia if the guidelines on fluid restriction is not strictly adhered to.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

Special attention should be given when desmopressin is co-administered with other drugs affecting water and/or sodium homeostasis, e.g. opioids, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), nonsteroidal anti-inflammatory drugs (NSAIDs), chlorpromazine, carbamazepine and some antidiabetics of the sulfonylurea group since concurrent use can lead to an increased risk of fluid retention/hyponatraemia (see section 4.4).

Desmopressin is unlikely to interact with medicinal products that affect the metabolism of the liver, as desmopressin does not show significant hepatic metabolism in in vitro studies with human microsomes. However, formal in vivo interaction studies have not been performed.

Pregnancy

Data on a limited number (n=53) of exposed pregnancies in women with diabetes insipidus indicate rare cases of malformations in children treated during pregnancy. 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. Blood pressure monitoring is recommended due to the increased risk of pre-eclampsia.

Lactation

Results from analyses of milk from nursing mothers receiving 300 micrograms desmopressin intranasally indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis or haemostasis.

None

Summary of safety profile

The most frequently reported adverse reaction with desmopressin injection during post-marketing is hyponatraemia.

Serious hypersensitivity reactions including anaphylactic/anaphylactoid shock have been reported post-marketing (see section ‎4.4). Further details are described below under “Description of selected adverse reactions”.

Tabulated summary of adverse reactions

The below table is based on the frequency of adverse drug reactions reported in clinical trials with desmopressin injection 4 μg/mL conducted in adults for treatment of central diabetes insipidus and haematological indications (n=53) and desmopressin injections 15 μg/mL (n=76), combined with post marketing experience.

Reactions only seen in post marketing have been added in the 'Not known' frequency column. The table below shows the frequencies of adverse reactions reported. Adverse reactions are classified according to frequency and system organ class. Frequency categories are defined according to the following convention: Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000) and Not known (cannot be estimated from the available data).

Table 1 Frequency of adverse drug reactions reported (clinical trials, spontaneous reports including the literature)

^1. Only for the haematological indications (high dose) and only in patients with known history of, or risk factors for, thrombosis, atherosclerotic cardiovascular/cerebrovascular disease, or a history of angioplasty.

^2. For the haematological indications (high dose), transient fall in blood pressure with a reflex tachycardia and facial flushing at the time of administration.

^3. Reported mainly for the haematological indications (high dose).

Description of selected adverse reactions

Hyponatremia

During post-marketing the most frequently reported adverse reaction with desmopressin injection is hyponatraemia. Hyponatraemia may cause headache, nausea, vomiting, weight increase, malaise, abdominal pain, muscle cramps, dizziness, confusional state, decreased consciousness, generalized oedemas, and in severe cases brain oedema, hyponatraemic encephalopathy, convulsions, and coma. Nausea, headache and dizziness have been reported without registered hyponatraemia. The hyponatraemia is a result of the antidiuretic effect, arising from increased water reabsorption by the renal tubules and osmotic dilution of plasma. Special attention should be paid to the precautions addressed in section 4.4.

Hyponatraemia is reversible. Treatment should be individualised and rapid overcorrection should be avoided to reduce the risk of further complications (see sections 4.2 and 4.4).

Hypersensitivity reactions

Post-marketing hypersensitivity reactions including local allergic reactions such as dyspnoea, erythema, generalized or local oedemas (peripheral, face), pruritus, rash, 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. Hypersensitivity reactions usually occur rapidly after drug administration and may occur during first time usage or after repeated exposure of desmopressin injection.

Paediatric population

Adverse reaction data from clinical trials in children is very limited.

Other special populations

Elderly and patients with serum sodium levels in the lower range of normal may have an increased risk of developing hyponatraemia (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: https://yellowcard.mhra.gov.uk.

An overdose of OCTIM Injection leads to a prolonged duration of action with an increased risk of water retention and/or hyponatraemia.

Treatment

Although the treatment of hyponatraemia should be individualised, the following general recommendations can be given. Hyponatraemia is treated by discontinuing the desmopressin treatment, fluid restriction and symptomatic treatment if needed.

Desmopressin is a structural analogue of vasopressin, with two chemical changes namely desamination of the N-terminal and replacement of the 8-L-Arginine by 8-D-Arginine. These changes have increased the antidiuretic activity and prolonged the duration of action. The pressor activity is reduced to less than 0.01% of the natural peptide as a result of which side-effects are rarely seen.

Like vasopressin, desmopressin also increases concentrations of Factor VIII:C, Factor VIII:Ag (vWF) and Plasminogen Activator (t-PA).

Following intravenous injection, plasma concentrations of desmopressin follow a biexponential curve. The initial fast phase of a few minutes duration and with a half life of less than 10 minutes is thought mainly to represent the diffusion of desmopressin from plasma to its volume of distribution. The second phase with a half life of 51-158 minutes represents the elimination rate of desmopressin from the body.

As a comparison, the half life of vasopressin is less than 10 minutes.

Subcutaneous administration of desmopressin results in a later T_max and lower C_max values but comparable bioavailability.

In vitro, in human liver microsome preparations, it has been shown that no significant amount of desmopressin is metabolised in the liver and thus human liver metabolism in vivo is not likely to occur.

It is unlikely that desmopressin will interact with drugs affecting hepatic metabolism, since desmopressin has been shown not to undergo significant liver metabolism in in vitro studies with human microsomes. However, formal in vivo interaction studies have not been performed.

There are no pre-clinical data of relevance to the prescriber which are additional to those already included in other sections of the SPC.

Sodium chloride Ph. Eur.

Hydrochloric acid Ph. Eur.

Water for injection Ph. Eur.

None

48 months.

Store in a refrigerator at 2°C- 8°C and protect from light.

Clear glass ampoules.

The injection is administered by subcutaneous injection or intravenous infusion.

For intravenous infusion, the dose should be diluted in 50ml of 0.9% sodium chloride for injection and given over 20 minutes.