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VIPRINEX«
Knoll
Ancrod
Anticoagulant
 
Action And Clinical Pharmacology: Ancrod, a thrombin-like enzyme obtained from the venom of the Malayan Pit Viper (Agkistrodon rhodostoma), is highly specific for fibrinogen, producing anticoagulation by defibrinogenation.

Enzymatically, Ancrod cleaves fibrinogen to split off the A-fibrinopeptides (A, AY and AP), but not the B-fibrinopeptide. The resulting fibrin polymers are imperfectly formed and much smaller in size (1 to 2 Ám long) than the fibrin polymers produced by the action of thrombin. These ancrod-induced microthrombi are friable, unstable, urea-soluble and have significantly degraded a-chains. They do not cross-link to form thrombi. They are markedly susceptible to digestion by plasmin and are rapidly removed from circulation by either reticuloendothelial phagocytosis or normal fibrinolysis, or both.

Anticoagulant Effects: Anticoagulation through the removal of fibrinogen from the blood is rapid, occurring within hours following ancrod administration.

The blood viscosity in patients receiving ancrod is progressively reduced by 30 to 40% of the pretreatment levels. The decreased viscosity is directly attributable to lowered fibrinogen levels and leads to important improvements in blood flow and perfusion of the microcirculation. Erythrocyte flexibility is not affected by normal doses of ancrod. The rheological changes are readily maintained and the viscosity approaches pretreatment values very slowly (within about 10 days) after stopping ancrod.

Fibrinolytic Effects: Ancrod does not activate plagminogen and does not degrade preformed, fully cross-linked thrombin fibrin. Consequently, unlike fibrinolytic agents, ancrod can be used postoperatively.

However, ancrod has been reported to reduce the level of plasminogen activator inhibitor (PAI) and may stimulate the release of tissue plasminogen activator (TPA) from the endothelium. The profibrinolytic effect of these 2 actions appears to be limited to local microthrombus degradation. However, the extent and clinical significance of these effects are uncertain.

Effects on Other Clotting Factors: Unlike thrombin, ancrod does not directly activate Factor XIII, nor does it produce platelet aggregation nor cause the release of ADP, ATP, potassium, nor serotonin from platelets.

Platelet counts and survival time remain normal during ancord therapy.

Although ancrod has no direct effect on platelet aggregation, the fibrinogen degradation products (FDP) do inhibit platelet aggregation. For this reason the initial (Induction) dose of ancrod must be administered sufficiently slowly to prevent undue accumulation of FDP and thus minimize platelet aggregation inhibition.

Clinical Pharmacokinetics: When the fate of ancrod labelled with 25 is followed, half the label disappears from the plasma in 3 to 5 hours, and at about 4 days 10% remains.

Ancrod is partially bound to the a2 macroglobulin. Once the state of hypofibrinogenaemia is achieved by the induction dose it can be maintained by i.v. injections at 12-hour intervals or by continuous i.v. infusions, or s.c. injections.

Indications And Clinical Uses: For the treatment of established deep vein thrombosis; central retinal and branch vein thrombosis; priapism; pulmonary hypertension of embolic origin; embolism after insertion of prosthetic cardiac valves; rethrombosis after thrombolytic therapy and rethrombosis after vascular surgery. It is also indicated for the prevention of deep venous thrombosis after repair of the fractured neck of a femur.

For the treatment of moderate and severe chronic circulatory disorders of peripheral arteries (e.g., arteriosclerosis obliterans, thromboangiitis obliterans, diabetic microangiopathy and Raynaud's phenomenon).

Ancrod has been shown to be useful for maintaining anticoagulation in the presence of heparin-induced thrombocytopenia and thrombosis (HIT).

Contra-Indications: There is some evidence that the ancrod effect may be dangerous in septicemic states with or without evidence of diffuse intravascular coagulation.

Plasma expanders: Artificial plasma expanders (e.g. dextran) may cause severe bleeding in defibrinated patients and should not be administered during or within 10 days of ancrod therapy.

Pregnancy: It was not found to be teratogenic in animal studies, but some fetal deaths occurred as a result of placental hemorrhages in animals given high doses; therefore, it should not be used during pregnancy as the defibrinogenation mechanism of ancrod might be expected to interfere with the normal implantation of the fertilized egg.

Gastrointestinal pathology: The presence of lesions liable to bleed, such as peptic ulcer, ulcerative colitis contraindicates its administration.

Ulcerogenic drugs: Similarly, patients on drug regimes known to cause gastrointestinal bleeding should not be given ancrod.

Hematological defects: Underlying defects interfering with hemostasis, such as a platelet count less than 100 000/mm are also contraindications, unless the defect is drug-induced and reversible (as is the case in patients with HIT).

Reticulo-endothelial and lytic systems: Drugs that block the reticuloendothelial system (e.g. dextran), or block the physiological lytic system (e.g. aminocaproic acid), should not be administered concurrently with or within 10 days of ancrod therapy.

Manufacturers' Warnings In Clinical States: Medical Support Level: To-date, clinical experience with ancrod has been gained in situations where high medical support levels exist (i.e., within the hospital environment). Until more extensive experience has been gained, this practice should be continued (see Dosage).

Before initiating therapy with ancrod, a supply of fibrinogen-rich cryoprecipitate should be secured and available to the physician (see Overdose).

Cardiovascular disease: The following cardiovascular conditions may be complicated by defibrinogenation: malignant hypertension; acute pericarditis; sub-acute bacterial endocarditis; retinopathy, grade 3 or worse; diabetic retinopathy; resting diastolic pressure >120 mm Hg.

Other conditions: Similarly, defibrinogenation may cause bleeding in uremia >100 mg% (>35.7 mM/L), renal colic with calculus; cerebrovascular accidents; history of neurosurgery.

Coronary thrombosis: In view of some evidence of delay in wound healing in experimental animals, it is considered at the present time that ancord should not be used in coronary thrombosis, until further data on safety are available.

Antibody Formation/Resistance: I.M. use is not recommended as an alternative to i.v. administration, owing to the possibility of inducing antibody formation.

The s.c. regime recommended under Dosage should not be continued beyond a period of 1 month owing to risk of inducing resistance.

ESR: During treatment with ancrod, the erythrocyte sedimentation rate falls to about 1 mm/hour and cannot be used as an index of pathological activity.

Major Surgery: I.V. administration of ancrod is not recommended before, during or within 48 hours of major surgery. An exception is to prevent rethrombosis after vascular surgery when the risk of bleeding does exist, in which case, ancrod can be administered immediately postoperatively.

Induction Dose Duration: The first dose of ancrod must be given slowly so that the physiological methods of dealing with the fibrinogen degradation products are not overloaded.

When using the intravenous regime, the first dose is termed the Induction Dose and should be given by i.v. drip over a period of a minimum of 12 hours for maximum benefit at minimum risk.

The Induction Dose must not be given faster than over a period of 8 hours (see Dosage).

Although faster rates have been employed, usually in emergency situations, the risks are considered to outweigh the benefits.

Where there is circulatory insufficiency, the period of administration must be at least 12 hours.

Precautions: Pretreatment investigations: It is recommended that a blood film, platelet count and fibrinogen estimation should be made before treatment.

Daily Control: The fibrinogen concentration should be measured at six hours into, and at the end of the infusion of the Induction Dose.

Fibrinogen should also be measured at regular intervals, at the same time of the day, during the maintenance dose infusions.

Migraine: A few patients with a history of migraine have experienced headaches after ancrod injections. Maintenance doses should be administered very slowly to these individuals.

Minor surgery: It is possible to carry out minor surgery (e.g., opening an abscess) while the patient is undergoing ancrod therapy, but each case must be judged carefully for risk of bleeding.

Transfusion: Whole blood, plasma or albumin may be given as needed, but artificial plasma expanders must not be used until fibrinogen levels have returned to normal.

Adverse Reactions: Bleeding: Since ancrod has a highly specific effect upon fibrinogen, the risk of bleeding is low. Nevertheless, patients should be selected carefully in the light of the advice given under Warnings and Precautions.

Hemorrhaging may occur. If necessary, the effects of ancrod may be rapidly reversed by specific procedures described under Overdose.

Minor bleeding and oozing may occur and these are dealt with by pressure.

Skin reactions: Reactions such as skin rash are rare and have responded to antihistamine.

Local injection site reactions to s.c. injections are not common and may be cleared with an antihistamine.

Other: Transient chills and elevated temperatures have been infrequently reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of severe hemorrhage, or if major surgery becomes necessary during the course of ancrod therapy cryoprecipitate can be administered to rapidly raise the plasma fibrinogen concentrations to safe levels.

The need for specific emergency procedures has been very rare. Following discontinuation of ancrod, fibrinogen levels rise slowly, reaching normal levels within a few days to 1 week. An infusion of human plasma will accelerate this process.

Nevertheless, it is recommended that cryoprecipitate is always available when ancrod is used.

Use of Cryoprecipitate: Cryoprecipitate can be administered to rapidly raise the plasma fibrinogen concentrations to safe levels.

The amount of cryoprecipitate required is dependent upon the level of ancrod circulating in the patient. It can be titrated against the circulating fibrinogen concentration, which should be measured within 1 hour of cryoprecipitate administration.

A single administration of 10 to 20 units is usually sufficient. (One bag enables the fibrinogen level to be raised by 0.2 g/L.)

Where cryoprecipitate is not available, plasma can be used.

Dosage And Administration: Medical Support Levels: ancrod can be injected s.c. or by i.v. infusion.

S.C. treatment should be carried out in a hospital; if there are adequate facilitites for the regular control of fibrinogen concentration it may also be undertaken in the Out-patient's Clinic.

Most frequently, ancrod is given i.v. The infusion should be done under close observation in a hospital.

I.M. use is not recommended owing to the possibility of inducing antibody formation.

S.C. Regimen: Peripheral Arterial Insufficiency: The dose of Arvin should be determined individually depending on the concentration of fibrinogen. This should be slowly reduced to 0.2 to 0.7 g/L of plasma. It should be kept within this range during the whole course of treatment. Under these conditions the rheological properties of the blood are sufficiently improved. The duration of therapy is generally 3 to 4 weeks, and may be prolonged if necessary.

The following alternative schemes will produce the desired fibrinogen concentration within 3 to 6 days: 70 units (1 ampul) daily for the first 4 days, followed by 70 to 140 units (1 to 2 ampuls) daily from the 5th day onwards depending on the fibrinogen concentration; or 140 units (2 ampuls) per day in the initial stage of treatment. When the fibrinogen concentration has fallen to a level within the therapeutic range, 210 to 280 units (3 to 4 ampuls) are given in one injection 2 to 3 times per week.

Prophylaxis of Deep Vein Thrombosis in patients undergoing surgery for the fractured neck of a femur: The dose should be determined individually. The concentration of fibrinogen should be slowly reduced to 0.5 g/L of plasma or lower and should be maintained within this range during treatment. This may be achieved by giving 4 units/kg body weight (e.g., 4 ampuls for 70 kg weight) as a single s.c. injection immediately after surgery, then 1 ampul (1 unit/kg body weight) daily for the next 4 days.

S.C. regimes should not be continued beyond a period of one month owing to the risk of inducing resistance.

I.V. regimen: Induction Dose Administration: The first dose of ancrod must be given slowly so that the physiological methods of dealing with the fibrinogen degradation products are not overloaded.

The first dose is termed the Induction Dose and should be given by i.v. drip over a period of at least 12 hours.

The Induction Dose must not be given faster than over a period of 8 hours. Although faster rates have been employed, usually in emergency situations, the risks are considered to outweigh the benefits (see Warnings).

Induction Doses: 1 to 2 units/kg body weight in sodium chloride injection or dextrose 5% injection, the volume being varied from 250 to 500 mL according to the patient's condition. The target endpoint is to lower fibrinogen levels to between 0.2 and 0.7 g/L.

Dextran must not be used.

Maintenance Dose Administration: Subsequent (maintenance) doses of ancrod may be administered by i.v. infusion over 24 hours, to maintain a fibrinogen level of between 0.2 and 0.7 g/L.

Maintenance Doses: 0.5 to 1.0 units/kg body weight in 250 to 500 mL sodium chloride injection, or dextrose 5% injection, the volume being varied according to the patient's condition.

It is considered that the ideal period of treatment in patients with conditions such as deep vein thrombosis, central retinal vein thrombosis, is of the order of 7 days. Some patients have been successfully treated for periods up to 28 days.

The margin of safety with overdosage in the maintenance period, e.g. in the defibrinogenated state, is very wide, by a factor of at least 10. The regime for the Induction Dose, however, must be adhered to, so that the rate of production of fibrin degradation products does not overload the system.

Control methods: The fibrinogen concentration should be measured at 6 hours into, and at the end of the infusion of the Induction Dose. Fibrinogen should also be measured at regular intervals at the same time of day, during Maintenance Dose infusions.

A target fibrinogen level of between 0.2 and 0.7 g/L should be maintained, in order to provide adequate anticoagulation.

Copies of the methods for estimating the effect of ancrod on the plasma fibrinogen are available on application to Knoll Pharma Inc.

Availability And Storage: Each mL of sterile, clean, colorless, aqueous solution contains: 70 IU ancrod in isotonic saline. pH 6.8 containing approximately 0.0025 M phosphate. Ampuls of 1 mL, boxes of 5. Store between 2 and 8░C. Do not freeze. Protect from light.