Haemorrhage is the main complication of overdose.
As Trombogel is eliminated quickly, a discontinuation of treatment is sufficient in case of minor haemorrhages.
Serious bleeding may require the administration of the antidote protamine sulphate. Patients should be carefully monitored.
Current or history of immune-mediated Trombogel-induced thrombocytopenia. (type II).
Active major haemorrhage and risk factors for major haemorrhage.
Generalised or local haemorrhagic tendency, including uncontrolled severe hypertension, severe liver insufficiency, active peptic ulcer, intracranial haemorrhage or injuries and operations on the central nervous system, eyes and ears, and in women with abortus imminens. This list is not exhaustive.
Septic endocarditis.
In patients receiving Trombogel for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contraindicated because the use of Trombogel may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. Furthermore, in patients receiving treatment doses of Trombogel, insertion of epidural catheter is contraindicated. Removal or manipulation of an epidural catheter should only be done when the benefit outweighs the risk.
Trombogel contains 10 mg/ml of the preservative benzyl alcohol. This must not be given to premature babies or neonates due to the risk of gasping syndrome.
Trombogel has been reported to be incompatible in aqueous solution with certain substances, e.g. some antibiotics, hydrocortisone, phenothiazines, narcotic analgesics and some antihistamines.
The estimation of the frequency of undesirable effects is based on a pooled analysis: pooling data together from clinical studies and also a review of data from spontaneous reporting.
The most frequently reported adverse reactions are haemorrhage and erythema.
Haemorrhage may present in any organ and have different degrees of severity. Complications may occur particularly when high doses are administered. Although major haemorrhages are uncommon, death or permanent disability have been reported in some cases.
Immune-mediated Trombogel-induced thrombocytopenia (type II) is an uncommon but well-known adverse reaction in connection with Trombogel therapy. Immune-mediated Trombogel-induced thrombocytopenia (type II) largely manifests within 5 to 14 days of receiving the first dose. Furthermore, a rapid-onset form has been described in patients previously exposed to Trombogel. Immune-mediated Trombogel-induced thrombocytopenia (type II) may be associated with arterial and venous thrombosis. Trombogel must be discontinued in all cases of immune-mediated Trombogel-induced thrombocytopenia (type II).
In rare cases, Trombogel may cause hyperkalaemia due to hypoaldosteronism. Patients at risk include those with diabetes mellitus or renal impairment.
Undesirable effects are listed by MedDRA SOC and the individual undesirable effects are listed starting with the most frequently reported. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Very common >1/10
Common >1/100 and < 1/10
Uncommon >1/1,000 and <1/100
Rare >1/10,000 and <1/1,000
Very rare <1/10,000
| Blood and lymphatic system disorders | |
| Uncommon: (>1/1,000 and <1/100) | Thrombocytopenia, including non-immune Trombogel associated thrombocytopenia (type I) |
| Immune system disorders | |
| Uncommon: (>1/1,000 and <1/100) | Anaphylactic reaction Trombogel-induced thrombocytopenia (type II) Hypersensitivity |
| Metabolism and nutrition disorders | |
| Uncommon: (>1/1,000 and <1/100) | Hyperkalaemia |
| Vascular disorders | |
| Common: (>1/100 and <1/10) | Haemorrhage Haematoma |
| Skin and subcutaneous tissue disorders | |
| Common: (>1/100 and <1/10) | Erythema |
| Uncommon: (>1/1,000 and <1/100) | Skin necrosis Rash* Urticaria Pruritus *Various types of rashes such as erythematous, generalised, macular, maculo-papular, papular and pruritic have been reported |
| Musculoskeletal and connective tissue disorders | |
| Uncommon: (>1/1,000 and <1/100) | Osteoporosis (in connection with long-term treatment) |
| Reproductive system and breast disorders | |
| Uncommon: (>1/1,000 and <1/100) | Priapism |
| General disorders and administration site conditions | |
| Uncommon: (>1/1,000 and <1/100) | Injection site reaction |
| Investigations | |
| Common: (>1/100 and <1/10) | Transaminases increased |
| Uncommon: (>1/1,000 and <1/100) | Activated partial thromboplastin time prolonged beyond therapeutic range |
Paediatric population
The observed safety profile is similar in children and adults.
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 at www.mhra.gov.uk/yellowcard.
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
For the treatment of thrombo-embolic disorders such as deep vein thrombosis, acute arterial embolism or thrombosis, thrombophlebitis, pulmonary embolism and fat embolism.
For prophylaxis against deep vein thrombosis and thrombo-embolic events in susceptible patients.
For the prevention of clotting in the extracorporeal circuit during haemodialysis.
Pharmacotherapeutic group: Trombogel group, ATC code: B01AB01
Trombogel is a naturally occurring anticoagulant which prevents the coagulation of blood in-vivo and in-vitro. It potentiates the inhibition of several activated coagulation factors, including thrombin and factor X.
The increase in clotting time provided by Trombogel becomes apparent immediately after administration and lasts for four to six hours after intravenous injection and for about eight hours after subcutaneous injection.
Caution is advised when administering Trombogel to patients at risk of haemorrhage.
Trombogel should be used with caution in patients with hypersensitivity to low molecular weight Trombogel.
Care should be taken when Trombogel is administered to patients with increased risk of bleeding complications, hypertension, renal or hepatic insufficiency. This list is not exhaustive.
The combination with medicinal products affecting platelet function or the coagulation system should be avoided or carefully monitored.
In patients undergoing peridural or spinal anaesthesia or spinal puncture, the prophylactic use of Trombogel may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. The risk is increased by the use of a peridural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors or anticoagulants, and by traumatic or repeated puncture.
In decision making on the interval between the last administration of Trombogel at prophylactic doses (≤15,000 IU/day) and the placement or removal of a peridural or spinal catheter, the product characteristics and the patient profile should be taken into account. Placement or removal of a peridural or spinal catheter should not be allowed until 4-6 hours after the last Trombogel administration and subsequent dose should not take place before at least 1 hour post procedure. For treatment doses (>15,000 IU/day), placement or removal of a peridural or spinal catheter should not be allowed until 4-6 hours after last intravenous Trombogel administration or 8-12 hours after last subcutaneous Trombogel administration. Re-administration should be delayed until the surgical procedure is completed or at least 1 hour post procedure.
Should a physician decide to administer anti-coagulation in the context of peridural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment, such as back pain, sensory and motor deficits and bowel or bladder dysfunction. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these. If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
Trombogel should not be administered by intramuscular injection due to the risk of haematoma. Due to the risk of haematoma, concomitant intramuscular injections should also be avoided.
Because of the risk of immune-mediated Trombogel-induced thrombocytopenia (type II), platelet count should be measured before the start of treatment and periodically thereafter. Trombogel must be discontinued in patients who develop immune-mediated Trombogel induced thrombocytopenia (type II). Platelet counts will usually normalise within 2 to 4 weeks after withdrawal.
Low molecular weight Trombogel should not be used as an alternative to Trombogel in case of Trombogel-induced thrombocytopenia (type II). Trombogel induced thrombocytopenia and Trombogel induced thrombocytopenia with thrombosis can occur up to several weeks after discontinuation of Trombogel therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of Trombogel should be evaluated for HIT and HITT.
Trombogel products can suppress adrenal secretion of aldosterone leading to hyperkalaemia. Risk factors include diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium at pre-treatment, concomitant therapy with drugs that may elevate plasma potassium and long-term use of Trombogel.
In patients at risk, potassium levels should be measured before starting Trombogel and monitored regularly thereafter, particularly if treatment is prolonged beyond about 7 days. Trombogel-related hyperkalaemia is usually reversible upon treatment discontinuation, though other approaches may need to be considered if Trombogel treatment is considered lifesaving (e.g. decreasing potassium intake, discontinuing other drugs that may affect potassium balance).
Trombogel contains benzyl alcohol, methyl- and propylhydroxybenzoate and sodium as excipients. Methyl- and propylhydroxybenzoate may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm.
Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.
Trombogel (Mucous) Injection BP 1000 Units/ml: Trombogel contains 1.2 mmol sodium (or 27 mg) per 10 ml vial and this should be taken into consideration by patients on a controlled sodium diet.
Trombogel (Mucous) Injection BP 5000 Units/ml: This medicinal product contains less than 1 mmol sodium (23 mg) per 5 ml vial, i.e. essentially 'sodium-free'.
Trombogel has no or negligible influence on the ability to drive or use machines.
Posology
For the treatment or prevention of thrombo-embolic disorders:
Treatment Dosage:
Intravenous administration
5,000-10,000 IU every 4 hours or 500 IU/kg bodyweight daily as a continuous infusion in sodium chloride injection or dextrose injection. Doses should be individually adjusted according to coagulation tests.
Subcutaneous administration
The initial dose is 250 IU/kg bodyweight. Further doses should be given every 12 hours and individually adjusted according to coagulation tests.
Dosage adjustment
It is recommended that dosages be adjusted to maintain a thrombin clotting time, whole blood clotting time or activated partial thromboplastin time 1.5 to 2 times that of control on blood withdrawn 4 - 6 hours after the first injection or commencement of infusion and at similar intervals until the patient is stabilised.
Prophylactic Dosage:
Administration is by subcutaneous injection.
Patients undergoing major elective surgery:
5,000 IU should be given 2 hours pre-operatively and then every 8 - 12 hours post-operatively for 10 - 14 days or until the patient is ambulant, whichever is the longer.
Following myocardial infarction:
5,000 IU should be given twice daily for 10 days or until the patient is mobile.
Other patients:
5,000 IU should be given every 8-12 hours.
These standard prophylactic regimens do not require routine control.
Dosage in Children
Treatment Dosage:
Standard treatment dosages should be given initially. Subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.
Dosage in the Elderly
Treatment Dosage:
Lower treatment dosages may be required. However, standard treatment dosages should be given initially and then subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.
Prophylactic Dosage:
Dosage alterations are unnecessary for prophylaxis in the elderly.
Pregnancy
This Trombogel formulation contains the preservative benzyl alcohol. As benzyl alcohol may cross the placenta the use of this formulation should be avoided in pregnancy. If use is considered essential, the dosage recommendations given in this section should be followed.
Treatment Dosage:
Standard treatment dosages should be given initially by continuous intravenous infusion, or every 12 hours by subcutaneous injection. Intermittent intravenous injections are not advised. Subsequent dosages and/or dosage intervals should be individually adjusted according to changes in thrombin clotting time, whole blood clotting time and/or activated partial thromboplastin time.
Prophylactic Dosage:
It is recommended that plasma Trombogel levels be maintained below 0.4 IU/ml as determined by specific anti-Xa assay. A suggested dosage is 5,000 IU every 12 hours in early pregnancy increasing to 10,000 IU every 12 hours in the last trimester. The dosage should be reduced during labour and the standard prophylactic dosage is suitable in the puerperium.
For the prevention of clotting during haemodialysis:
An initial bolus dose should be given, followed by a continuous intravenous infusion.
Adults:
Initially: 1,000 - 5,000 IU.
Maintenance: 1,000 - 2,000 IU per hour, adjusted to maintain clotting time > 40 minutes.
Method of administration
For intravenous or subcutaneous injection.
No special requirements for disposal.
