Argatroban parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Parenteral formulations of argatroban monohydrate.
Drugs List
Therapeutic Indications
Uses
Anticoagulation in heparin-induced thrombocytopenia (HIT) type II
Dosage
Discontinue all parenteral anticoagulants prior to initiating argatroban and obtain a baseline aPTT value. When using argatroban after cessation of heparin therapy, allow sufficient time (approximately 1-2 hours) for the effect of heparin on aPTT to decrease before starting argatroban.
Maximum recommended duration of treatment is 14 days.
Adults
Standard dosing schedule
Initial: 2microgram/kg/minute continuous IV infusion. Check aPTT after 2 hours and adjust infusion rate as required (see Dosage; Additional).
Maintenance: Adjust infusion rate as required to achieve a target aPTT of 1.5 to 3 times baseline value (see Dosage; Additional). Maximum dose 10microgram/kg/minute.
Following cardiac surgery or critically ill patients
Initial: 0.5microgram/kg/minute continuous IV infusion.
Maintenance: Adjust infusion rate as required to achieve a target aPTT of 1.5 to 3 times baseline value (see Dosage; Additional). Maximum dose 10microgram/kg/minute.
Patients undergoing percutaneous coronary intervention (PCI)
Data is limited. Safety and efficacy of use in combination with GPIIb/IIIa inhibitors has not been established. Where there is no alternative, the following schedule is recommended:
Initial: 350microgram/kg IV bolus followed by 25microgram/kg/minute continuous IV infusion. Check ACT 5 to 10 minutes after completion of the initial bolus and adjust infusion rate as required (see Dosage; Additional).
Maintenance: Adjust infusion rate to achieve a target ACT of 300 and 450 seconds (see Dosage; Additional).
Patients with Renal Impairment
Patients receiving haemodialysis:
Initial: 250microgram/kg IV bolus followed by 2microgram/kg/minute continuous IV infusion. Patients already treated with argatroban do not require an initial bolus dose.
Maintenance: Adjust infusion rate as required to achieve a target ACT of 170-230 seconds. Stop the infusion 1 hour before the end of the procedure.
Patients with Hepatic Impairment
Moderate hepatic impairment (Child-Pugh Class B):
Initial: 0.5microgram/kg/minute.
Monitor aPTT closely and adjust infusion rate as required to achieve a target aPTT of 1.5 to 3 times baseline value (see Dosage; Additional).
Severe hepatic impairment:
Contraindicated.
Hepatic impairment undergoing percutaneous coronary intervention:
Specific dosing unavailable. Not recommended.
Additional Dosage Information
Dose modifications to achieve target aPTT for standard dosing schedule
aPTT less than 1.5 times baseline:
Increase infusion rate by 0.5micrograms/kg/minute. Repeat aPTT in 2 hours.
aPTT 1.5 to 3 times baseline and 100 seconds or less:
Continue current infusion rate. Repeat aPTT in 2 hours. Following 2 consecutive aPTTs within target range, reduce aPTT monitoring to at least once per day.
aPTT greater than 3 times baseline or greater than 100 seconds:
Stop the infusion until aPTT is 1.5 to 3 times baseline. Resume at half the previous infusion rate. Repeat aPTT in 2 hours.
Dose modifications to achieve target aPTT for critically ill patients or patients with moderate hepatic impairment
aPTT less than 1.5 times baseline:
Increase infusion rate by 0.1micrograms/kg/minute. Repeat aPTT in 4 hours.
aPTT 1.5 to 3 times baseline and 100 seconds or less:
Continue current infusion rate. Repeat aPTT in 4 hours. Following 2 consecutive aPTTs within target range, reduce aPTT monitoring to at least once per day.
aPTT greater than 3 times baseline or greater than 100 seconds:
Stop the infusion until aPTT is 1.5 to 3 times baseline. Resume at half the previous infusion rate. Repeat aPTT in 4 hours.
Dose modifications to achieve target ACT in patients undergoing percutaneous coronary intervention (PCI)
ACT less than 300 seconds:
Administer an additional 150microgram/kg IV bolus and increase infusion rate to 30micrograms/kg/minute. Check ACT after 5 to 10 minutes.
ACT between 300 and 450 seconds:
Continue current infusion rate for the duration of the procedure.
ACT greater than 450 seconds:
Decrease infusion rate to 15microgram/kg/minute. Check ACT after 5 to 10 minutes.
Conversion from argatroban to oral anticoagulation (coumarin type)
Delay conversion until substantial resolution of thrombocytopenia.
Initiate the oral anticoagulant at the intended maintenance dose (no loading dose required).
Continue argatroban and the oral anticoagulant for a minimum of 5 days, measuring INR daily. Once the target INR has been achieved for at least 2 days, argatroban can be discontinued.
Target INRs vary according to the assay used. For quick type PT assay, a target INR of 4 is recommended. For Owren type assay, the usual target INR for the oral anticoagulant alone (i.e. 2 to 3) is recommended.
INR must be re-checked 4 to 6 hours after stopping argatroban. If the repeat INR falls below the desired therapeutic range, resume argatroban and repeat the procedure daily until the desired therapeutic range on oral anticoagulants alone is reached.
For doses greater than 2microgram/kg/minute, INR is less predictable. With such higher doses, the dose of argatroban should be temporarily reduced to 2microgram/kg/minute in order to improve the prediction of INR on oral anticoagulants alone. The INR on argatroban and oral anticoagulants should be measured 4 to 6 hours after reduction of the argatroban dose.
Administration
For intravenous infusion only.
Therapeutic Drug Monitoring
During therapy, monitor using the activated partial thromboplastin time (aPTT), adjusting the dose to achieve a target of 1.5 to 3 times the baseline aPTT value (not exceeding 100 seconds).
When switching therapy to an oral anticoagulant (coumarin type), use the international normalised ratio (INR). Target INR varies according to the assay type used (see Dosage; Additional).
Contraindications
Children under 18 years
Haemorrhage
Breastfeeding
Hereditary fructose intolerance
Severe hepatic impairment
Precautions and Warnings
Acute critical illness
Lumbar puncture
Major surgery
Percutaneous coronary intervention
Spinal/epidural anaesthesia
Coagulopathy
Diabetic retinopathy
Gastrointestinal ulcer
Haemodialysis
Hepatic impairment
Pregnancy
Severe hypertension
Treatment to be initiated by specialist
Contains alcohol
Presentations with sorbitol unsuitable in hereditary fructose intolerance
Measure parameters of haemostasis (APTT, PT, platelets) during infusion
Heparin-induced thrombocytopenia type II should be confirmed using the heparin induced platelet activation assay (or equivalent), however confirmation must not delay the start of the treatment.
Consider a haemorrhagic event following an unexplained fall in haematocrit, fall in blood pressure, or any other unexplained symptoms.
When discontinuing argatroban monohydrate in patients with hepatic impairment,, full reversal of anticoagulant effects may take longer than 4 hours due to decreased clearance of argatroban.
Pregnancy and Lactation
Pregnancy
Use argatroban monohydrate with caution in pregnancy.
At the time of writing there is limited published data (including animal studies), regarding the use of argatroban during pregnancy. Transfer across the human placenta is unknown. Briggs (2015) suggests that due to the drugs molecular weight, low metabolism and moderate serum protein binding, embryo-foetal exposure is likely. The potential risk is unknown.
Argatroban infusion also contains sufficient ethanol that a 70kg patient (prescribed the maximum daily dose) would receive 4g ethanol per day.
The manufacturer states that argatroban should only be used during pregnancy if treatment is clearly necessary.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Argatroban monohydrate is contraindicated during breastfeeding.
Animal studies have demonstrated excretion of argatroban in breast milk. At the time of writing, there is no published information regarding use in humans. Briggs (2015) suggests that due to the drug's molecular weight, low metabolism and moderate serum protein binding, excretion in human breast milk is likely. Lactmed (2018) states that if argatroban is required, breastfeeding does not need to be discontinued but, alternative drugs are preferred.
The manufacturer advises either discontinuing breastfeeding or abstaining from argatroban treatment.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Side Effects
Alanine aminotransferase increased
Alopecia
Anorexia
Application site reaction
Aspartate aminotransferase increased
Atrial fibrillation
Bullous dermatoses
Cardiac arrest
Cerebrovascular accident
Changes in hepatic function
Coagulation disorders
Constipation
Deafness
Diarrhoea
Dizziness
Dysphagia
Dyspnoea
Embolism
Fatigue
Gastritis
Gastro-intestinal haemorrhage
Haematuria
Headache
Hepatic failure
Hepatomegaly
Hiccups
Hyperbilirubinaemia
Hypertension
Hypoglycaemia
Hyponatraemia
Hypotension
Hypotonia
Hypoxia
Increase in alkaline phosphatase
Increase in lactate dehydrogenase
Increased coagulation time
Increased sweating
Infections
Injection site reactions
Jaundice
Leukopenia
Melaena
Muscle weakness
Myalgia
Myocardial infarction
Pain
Pericardial effusion
Peripheral ischaemia
Peripheral oedema
Phlebitis
Pleural effusion
Pulmonary embolism
Pulmonary haemorrhage
Pyrexia
Rash
Renal impairment
Reversible confusional states
Shock
Skin disorder
Speech disturbances
Supraventricular arrhythmias
Syncope
Tachycardia
Thrombocytopenia
Thrombophlebitis
Thrombosis
Tongue disorder
Urinary tract infections
Urticaria
Ventricular tachycardia
Visual disturbances
Vomiting
Wound secretion
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: July 2018
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Summary of Product Characteristics: Exembol 1 mg/ml Solution for Infusion-Ready to Use. Mitsubishi Tanabe Pharma Europe Ltd. Revised September 2017.
Summary of Product Characteristics: Exembol Multidose 100 mg/ml concentrate for solution for infusion. Mitsubishi Tanabe Pharma Europe Ltd. Revised October 2014.
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Argatroban Last revised: 01 March 2018
Last accessed: 30 July 2018
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