Desirudin

Desirudin is an anticoagulant agent belonging to Direct thrombin Inhibitor.

Desirudin is a direct inhibitor of human thrombin. Desirudin is mainly indicated for the prevention of deep vein thrombosis in hip replacement surgery patients.

The absorption of Desirudin is complete when subcutaneously administered at doses of 0.3 mg/kg or 0.5 mg/kg. Following subcutaneous administration of single doses of 0.1 to 0.75 mg/kg, plasma concentrations of Desirudin increased to a maximum level (Cmax) between 1 and 3 hours. Desirudin is distributed in the extracellular space with a volume of distribution at steady state of 0.25 L/kg, independent of the dose. Desirudin binds specifically and directly to thrombin. The pharmacological effect of desirudin is not modified when co-administered with highly protein bound drugs (>99%). Human and animal data suggest that desirudin is primarily eliminated and metabolized by the kidney. The total urinary excretion of unchanged desirudin amounts to 40 to 50% of the administered dose. Plasma concentrations of Desirudin then decline with a mean terminal elimination half-life of 2 to 3 hours. After subcutaneous administration, the mean terminal elimination half-life is also approximately 2 hours.

Desirudin shows common side effects like bleeding gums, collection of blood under the skin, coughing up blood, deep, dark purple bruise, difficulty with breathing or swallowing, dizziness, headache, increased menstrual flow or vaginal bleeding, itching, pain, redness, or swelling, nosebleeds, paralysis, prolonged bleeding from cuts, red or black, tarry stools, red or dark brown urine, shortness of breath.

Desirudin is available in the form of Powder for injection.

Desirudin is available in India, UK, Germany, France, New Zealand, Spain, China, and Australia.

Desirudin belonging to the Direct thrombin Inhibitor, acts as an anticoagulant agent.

Desirudin is a direct, highly selective thrombin inhibitor. Reversibly binds to the active thrombin site of free and clot-associated thrombin. Inhibits fibrin formation, activation of coagulation factors V, VII, and XIII, and thrombin-induced platelet aggregation resulting in a dose-dependent prolongation of the activated partial thromboplastin time (aPTT).

The Data of onset of action od Desirudin is not available.

The Tmax of Desirudin is found to be 1-3 hours.

The Data of duration of Action of Desirudin is not available.

Desirudin is available in the form of Powder for Injection.

Desirudin Powder for injection is given subcutaneously. Do not administer intramuscularly.

Desirudin is a direct inhibitor of human thrombin. Desirudin is mainly indicated for the prevention of deep vein thrombosis in hip replacement surgery patients. It is mainly indicated for the prevention of deep vein thrombosis in hip replacement surgery patients. Common side effects include bleeding gums, collection of blood under the skin, coughing up blood, deep, dark purple bruise and difficulty with breathing or swallowing.

Desirudin is an anticoagulant agent belonging to a Direct thrombin inhibitor.

Desirudin inhibits the activation of thrombin-induced platelet aggregation, and coagulation factors V, VII, and XIII, which in turn results in the prolongation of the activated partial thromboplastin time.

Desirudin is approved for use in the following clinical indications

• Deep Vein Thrombosis (DVT) prophylaxis

It is mainly indicated for the prevention of deep vein thrombosis in hip replacement surgery patients.

• Deep Vein Thrombosis (DVT) prophylaxis

Subcutaneously: 15 mg every 12 hours; interrupt therapy if aPTT exceeds 2 times control; resume at a reduced dose (based on the degree of aPTT abnormality) when aPTT is <2 times control.

Desirudin is available in various strengths as 15mg.

Desirudin is available in the form of Powder for Injection.

Dosage Adjustment in Kidney Patient

• Moderate impairment (CrCl ≥31 to 60 mL/minute/1.73 m²)

Initial dose: 5 mg every 12 hours. Interrupt therapy if aPTT exceeds 2 times control; resume at a reduced dose (based on the degree of aPTT abnormality) when aPTT is <2 times control.

• Severe impairment (CrCl <31 mL/minute/1.73 m²)

Initial dose: 1.7 mg every 12 hours. Interrupt therapy if aPTT exceeds 2 times control; resume at a reduced dose (based on the degree of aPTT abnormality) when aPTT is <2 times control.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

• Desirudin is contraindicated in patients with known hypersensitivity to natural or recombinant hirudins due to risk of anaphylaxis, and in patients with active bleeding and/or irreversible coagulation disorders due to risk of hemorrhage.

• Spinal/Epidural Hematoma

There is a risk of neuraxial hematoma formation with the concurrent use of desirudin and spinal/epidural anesthesia, which has the potential to result in long term or permanent paralysis. The risk may be greater with the use of post-operative indwelling catheters or the concomitant use of additional drugs affecting hemostasis such as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), platelet inhibitors or other anticoagulants. The risk may also be increased by traumatic or repeated neuraxial puncture. To reduce the potential risk of bleeding associated with the concurrent use of desirudin and epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug should be considered. when scheduling or using epidural or spinal anesthesia in proximity to desirudin administration. The physician should consider placement of the catheter prior to initiating desirudin and removal of the catheter when the anticoagulant effect of desirudin is low. Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated. The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis Desirudin cannot be used interchangeably with other hirudins as they differ in manufacturing process and specific biological activity (ATUs). Each of these medicines has its own instructions for use.

• Hemorrhagic Events

Avoid intramuscular injection of Desirudin as bleeding and local hematoma formation can occur. Desirudin increases the risks of hemorrhage in patients with recent major surgery, organ biopsy or puncture of a non-compressible vessel within the last month; a history of hemorrhagic stroke, intracranial or intraocular bleeding including diabetic (hemorrhagic) retinopathy; recent ischemic stroke, severe uncontrolled hypertension, bacterial endocarditis, a known hemostatic disorder (congenital or acquired, e.g. hemophilia, liver disease) or a history of gastrointestinal or pulmonary bleeding within the past 3 months. Bleeding can occur at any site during therapy with Desirudin. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site. In post marketing experience reports of fatal and serious bleeding events have occurred in patients treated with Desirudin. Sources of hemorrhage included bleeding from the brain, gastrointestinal tract, spleen, rectum, and vagina. Avoid use with other drugs that inhibit or modify platelet function or affect blood clotting (e.g., anticoagulants, antiplatelet agents, NSAIDs, SSRIs) as coadministration with Desirudin may potentiate bleeding. If these concomitant medications cannot be avoided, patients should be monitored for bleeding.

• Increased Risk of Bleeding with Renal Impairment

Desirudin must be used with caution in patients with renal impairment due to an increased risk for bleeding, particularly in those with moderate and severe renal impairment (creatinine clearance ≤60 mL/min). Reduce dose and monitor daily aPTT and serum creatinine in patients with moderate and severe renal impairment.

• Antibodies/Re-exposure

Antibodies have been reported in patients treated with hirudins. Potential for cross-sensitivity to hirudin products cannot be excluded. Irritative skin reactions were observed in 9/322 volunteers exposed to Desirudin by subcutaneous injection or intravenous bolus or infusion in single or multiple administrations of the drug. The allergic reaction in volunteers consisted of arthralgia, erythema, pruritus, or uticaria. Allergic events were reported in 1% of patients receiving unfractionated heparin and 1% of patients receiving enoxaparin. Hirudin-specific IgE evaluations may not be indicative of sensitivity to Desirudin as this test was not always positive in the presence of symptoms., Anti-hirudin antibodies have been detected upon re-exposure to desirudin. Fatal anaphylactic reactions have been reported during hirudin therapy.

It is not known whether desirudin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Desirudin, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

• Common Adverse effects

Deep vein thrombophlebitis, wound secretion, Nausea, Hematoma, anemia, hemophthalmias, intracranial hemorrhage, intraspinal hemorrhage, prosthetic joint hemorrhage, or retroperitoneal hemorrhage, and residual mass at injection site.

• Rare Adverse effects

Anaphylactoid reaction, anaphylaxis, cerebrovascular disease, decreased hemoglobin, dizziness, epistaxis, fever, hematemesis, hematuria, hemorrhage (fatal), hypersensitivity reaction, hypotension, leg pain, lower extremity edema, thrombosis, vomiting, wound healing impairment.

• Drugs that Increase Bleeding Risk

Discontinue any agent which may enhance the risk of hemorrhage prior to initiation of Desirudin therapy. These agents include medications such as Dextran 40, systemic glucocorticoids, thrombolytics, and anticoagulants. If co-administration cannot be avoided, close clinical and laboratory monitoring should be conducted. During prophylaxis of venous thromboembolism, concomitant treatment with heparins (unfractionated and low-molecular weight heparins) or dextrans is not recommended. The effects of desirudin and unfractionated heparins on prolongation of aPTT are additive. As with other anticoagulants, desirudin should be used with caution in conjunction with drugs which affect platelet function. These medications include systemic salicylates, NSAIDS including ketorolac, acetylsalicylic acid, ticlopidine, dipyridamole, sulfinpyrazone, clopidogrel, abciximab and other glycoprotein IIb/IIIa antagonists.

• Coadministration with Warfarin

The concomitant administration of warfarin did not significantly affect the pharmacokinetic effects of desirudin. When warfarin and desirudin were coadministered, greater inhibition of hemostasis measured by activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR) was observed.

The common side effects of Desirudin include the following

• Common

Bleeding gums, collection of blood under the skin, coughing up blood, deep, dark purple bruise, difficulty with breathing or swallowing, dizziness, headache, increased menstrual flow or vaginal bleeding, itching, pain, redness, or swelling, nosebleeds, paralysis, prolonged bleeding from cuts, red or black, tarry stools, red or dark brown urine, shortness of breath.

• Rare
  

Blood in the urine, blurred vision, confusion, dizziness, faintness, or light-headedness when getting up suddenly from a lying or sitting position, Fever, severe or sudden headache, sudden loss of coordination, sudden slurring of speech, sweating, tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over affected area, trouble healing, vomiting of blood or material that looks like coffee grounds.

• Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies in pregnant women. Desirudin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Desirudin was teratogenic in rats and rabbits when given in doses 0.3 to 4 times the human dose. Teratology studies have been performed in rats at subcutaneous doses in a range of 1 to 15 mg/kg/day (about 0.3 to 4 times the recommended human dose based on body surface area) and in rabbits at intravenous doses in a range of 0.6 to 6 mg/kg/day (about 0.3 to 3 times the recommended human dose based on body surface area) and have revealed desirudin to be teratogenic. Observed teratogenic findings included: omphalocele, asymmetric and fused sternebrae, edema, and shortened hind limbs in rats; and spina bifida, malrotated hind limb, hydrocephaly, and gastroschisis in rabbits.

• Nursing Mothers

It is not known whether desirudin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Desirudin, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

• Pediatric Use

As per FDA, safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

In three clinical studies of Desirudin, the percentage of patients greater than 65 years of age treated with 15 mg of Desirudin subcutaneously every 12 hours was 58.5%, while 20.8% were 75 years of age or older. Elderly patients treated with Desirudin had a reduction in the incidence of VTE like that observed in the younger patients. Regarding safety, in the clinical studies the incidence of hemorrhage (major or otherwise) in patients 65 years of age or older was like that in patients less than 65 years of age. In addition, the elderly had a similar incidence of total, treatment-related, or serious adverse events compared to those patients less than 65 years of age. Serious adverse events occurred more frequently in patients 75 years of age or older as compared to those less than 65 years of age.

• In case of overdose, most likely reflected in hemorrhagic complications or suggested by excessively high aPTT values, Desirudin therapy should be discontinued. Emergency procedures should be instituted as appropriate (for example, determination of aPTT and other coagulation levels, hemoglobin, the use of blood transfusion or plasma expanders).
• No specific antidote for Desirudin is available; however, the anticoagulant effect of desirudin may be partially reversible using thrombin-rich plasma concentrates while aPTT levels can be reduced by the intravenous administration of 0.3 µg/kg DDAVP (desmopressin). The clinical effectiveness of DDAVP in treating bleeding due to desirudin overdose has not been studied. In an open, pilot, dose-ascending study to assess safety, the highest dose of desirudin (40 mg every 12 hours) caused excessive hemorrhage.

Pharmacodynamic

The pharmacodynamic effect of Desirudin on proteolytic activity of thrombin was assessed as an increase in aPTT. A mean peak aPTT prolongation of about 1.38 times baseline value (range 0.58 to 3.41) was observed following subcutaneous twice a daily injections of 15 mg desirudin. Thrombin time (TT) frequently exceeds 200 seconds even at low plasma concentrations of desirudin, which renders this test unsuitable for routine monitoring of Desirudin therapy. At therapeutic serum concentrations, desirudin has no effect on other enzymes of the hemostatic system such as factors IXa, Xa, kallikrein, plasmin, tissue plasminogen activator, or activated protein C. In addition, it does not display any effect on other serine proteases, such as the digestive enzymes trypsin, chymotrypsin, or on complement activation by the classical or alternative pathways.

Pharmacokinetics

• Absorption

The absorption of Desirudin is complete when subcutaneously administered at doses of 0.3 mg/kg or 0.5 mg/kg. Following subcutaneous administration of single doses of 0.1 to 0.75 mg/kg, plasma concentrations of Desirudin increased to a maximum level (Cmax) between 1 and 3 hours. Both C max and area-under-the-curve (AUC) values are dose proportional.

• Distribution

The pharmacokinetic properties of Desirudin following intravenous administration are well described by a two- or three- compartment disposition model. Desirudin is distributed in the extracellular space with a volume of distribution at steady state of 0.25 L/kg, independent of the dose. Desirudin binds specifically and directly to thrombin, forming an extremely tight, non-covalent complex with an inhibition constant of approximately 2.6 x 10-13 M. Thus, free or protein bound Desirudin immediately binds circulating thrombin. The pharmacological effect of desirudin is not modified when co-administered with highly protein bound drugs (>99%).

• Metabolism

Human and animal data suggest that desirudin is primarily eliminated and metabolized by the kidney. The total urinary excretion of unchanged desirudin amounts to 40 to 50% of the administered dose. Metabolites lacking one or two C-terminal amino acids constitute a minor proportion of the material recovered from urine (< 7%). There is no evidence for the presence of other metabolites. This indicates that desirudin is metabolized by stepwise degradation from the C-terminus probably catalyzed by carboxypeptidase(s) such as carboxypeptidase A, originating from the pancreas. Total clearance of Desirudin is approximately 1.5 to 2.7 mL/min/kg following either subcutaneous or intravenous administration and is independent of dose. This clearance value is close to the glomerular filtration rate.

• Excretion
  

The elimination of desirudin from plasma is rapid after intravenous administration, with approximately 90% of the dose disappearing from the plasma within 2 hours of the injection. Plasma concentrations of Desirudin then decline with a mean terminal elimination half-life of 2 to 3 hours. After subcutaneous administration, the mean terminal elimination half-life is also approximately 2 hours.

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