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Innohep - Scientific Information

Manufacture: LEO Pharma
Country: Canada
Condition: Deep Vein Thrombosis
Class: Heparins
Form: Liquid solution, Subcutaneous (SC)
Ingredients: tinzaparin sodium, sodium metabisulphite, benzyl alcohol

Pharmaceutical information

Drug Substance

Proper name: Tinzaparin Sodium
Chemical name: Polymers of alternating derivatives of D-glycosamine (N-sulphated or N-acetylated) and uronic acid (L-iduronic acid or D-glucuronic acid) joined by glycosidic linkages, the components being liberated in varying proportions on complete hydrolysis.

Structural formula:


Molecular mass: 4500 ± 1500 Daltons (Peak Maximum Molecular Mass)
Physicochemical properties: A white or yellowish powder, freely soluble in water, insoluble in organic solvents. pH of a 1% aqueous solution is between 5.5 and 8.0.
Origin: Porcine intestinal mucosa.

Detailed pharmacology

Animal Studies

The antithrombotic activity and anticoagulant activity of tinzaparin have been demonstrated in rats and rabbits in three different in vivo models and in rats and dogs in ex vivo model systems. These studies have shown that, as with unfractionated heparin, bleeding complications are the major side effect of tinzaparin. Tinzaparin is essentially devoid of significant secondary pharmacological effect. Tinzaparin had no effect on platelet aggregation in vitro. Although osteopenic effects of long-term treatment were not specifically determined, bone ash weights were lower in rats treated for 52 weeks with subcutaneous tinzaparin (25 mg/kg/day) or unfractionated heparin (12.5 mg/kg/day) compared to the vehicle control group.

Tinzaparin is well absorbed following subcutaneous administration. The bioavailability based on anti-Xa activity is 90%. The absorption half-life is over 3 hours. Dose-related increases in plasma anti-Xa and anti-IIa activity are observed with the peak activities of each seen 4 to 6 hours after administration. The anti-IIa activity is always less than the anti-Xa activity. The volume of distribution is approximately 4 L. Tinzaparin is not metabolized to any significant degree and is eliminated by a nonsaturable renal mechanism. The mean elimination half-lives of anti-Xa and anti-IIa activity are 82 minutes and 71 minutes, respectively.

Human Studies

The pharmacokinetic properties of tinzaparin are determined indirectly by plasma anti-Xa and anti-IIa activities. Following subcutaneous administration, dose related increases in peak activities have been observed 4 to 6 hours following subcutaneous administration. Anti-Xa activity is always greater than anti-IIa activity (see Table below). Both anti-Xa and anti-IIa plasma levels show correlation with body weight as well as with the administered dose.

Dose
(anti-Xa IU)
Peak Plasma Anti-Xa Activity
(Units/mL)
Peak Plasma Anti-IIa Activity
(Units/mL)
2,500 0.12 0.02
5,000 0.28 0.03
10,000 0.54 0.08

Plasma levels of anti-thrombin III, platelet counts and the activated partial thromboplastin time (APTT) remain essentially unaltered following subcutaneous tinzaparin administration.

Anti-Xa levels have been reported to be undetectable in plasma 24 hours following low doses of 50 anti-Xa IU/kg in both single and repeat dose studies. At higher doses, 150 anti-Xa IU/kg once daily, plasma anti-Xa activity of 0.15 units/mL have been reported. However, no clinically relevant accumulation effect was found after repeated once daily subcutaneous administration of up to 175 anti-Xa IU/kg.

A correlation between the antithrombotic effect and anti-Xa activity was seen in animal experiments where the effect of different doses was determined shortly after administration of the drug. However, this does not correspond to the increasing/decreasing plasma concentrations during 24 hours after subcutaneous administration in patients. Peak serum anti-Xa levels are recommended for monitoring serum tinzaparin levels.

Pregnancy

In two studies tinzaparin was given SC and IV to healthy women undergoing therapeutic abortions by two different methods. Tinzaparin at a dose of 35 anti-Xa IU/kg or 40 anti-Xa IU/kg was compared with unfractionated heparin (70 anti-Xa IU/kg) and a placebo control group. The anti-Xa activity in the mother's plasma rose accordingly and no anti-Xa activity was found in the blood of the fetus. Heparin-like activity was measured in a competitive binding assay and could be demonstrated in all fetal groups including the controls.

There is no evidence of any transplacental passage of tinzaparin.

INNOHEP in Renal Insufficiency Study (IRIS)

This was an international, multicentre, prospective, open, centrally randomised, parallel group study comparing treatment doses of INNOHEP (175 anti-Xa IU/kg once daily; N=269) and unfractionated heparin (UFH) (N=268) in the treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in elderly patients. All patients were aged 70 years or older (INNOHEP mean age 82.9 years, range 73- 101; UFH mean age 82.6 years, range 70-99) and had renal impairment (patients aged ≥75 years with a CrCl ≤60 ml/min; and patients aged ≥70 years with a CrCl ≤30 ml/min ). Oral anticoagulants were co-administered with study drug on Days 1 to 3 and treatment continued for at least five days and until the international normalized ratio (INR) was between 2 to 3, on two consecutive days. Patients then continued on oral anticoagulants alone and were followed until day 90 ± 5. Anti-Xa activity was assessed in a sub-set of IRIS patients under a prospective sub- study protocol. During a planned interim safety analysis, a difference in mortality was observed between the treatment groups and the study was stopped. The all cause mortality rates for patients at Day 90 ± 5 were 6.3% (17/268) in the UFH group and 11.5% (31/269) in the INNOHEP group. There was no clear explanation for this difference; however mortality was not due to recurrent VTE or bleeding. Since the study was stopped prematurely, no definitive conclusions could be drawn from this study.

Published Clinical Trials in Patients with Cancer:

Information for INNOHEP in support of extended treatment for patients with cancer comes from the published clinical trials of Hull (LITE) and Romera (see REFERENCES 6-8, 14). In these clinical trials, INNOHEP has been studied in patients with cancer associated thrombosis at 175 IU/kg daily for 3 and 6 months respectively.

Toxicology

From the toxicological studies performed, it has been shown that the major risk of treatment with tinzaparin is loss of blood, either internal or external, due to bleeding.

Acute Toxicity

NMRI mice and Wistar rats were used in single dose toxicity studies involving tinzaparin and USP Heparin by intravenous and subcutaneous administration. The deaths seen in these studies, together with a few other signs seen in all the single dose studies, were caused by the exaggerated pharmacological effect of tinzaparin, namely massive loss of blood from the circulatory system caused by the effect of tinzaparin on the coagulation system. No other toxic effects of tinzaparin were seen even at extremely high dosages given once. The LD50 has not been established after either subcutaneous or intravenous administration.

Long-Term Toxicity

Repeated dose studies were performed in rats and dogs; Two 4-week studies were performed by intravenous administration and two 52-week studies were performed by subcutaneous administration.

No signs of thrombocytopenia were seen in the repeated dose studies. In the one year dog study, only females showed increased plasma content of triglycerides, phospholipids and total cholesterol. Heparin and LMWH activate lipoprotein lipase and hepatic lipase, enhance plasma lipolytic activity and elevate plasma levels of free fatty acid in man. It is believed the effect seen in the female dogs may reflect these characteristics.

From the repeated dose studies, an increased spleen weight was found in connection with extra- medullar haematopoiesis. Further, increased liver and kidney weights were observed but no histopathological changes were found in these organs. It has been postulated that increased liver weight may be due to this organ containing the first binding sites of tinzaparin to the reticuloendothelial system. The kidneys are the main excreting organ for heparin and heparin- like substances and the increased kidney weight is thought to be an adaptive reaction to treatment.

From the repeated dose studies carried out in rats and dogs, it can be concluded that tinzaparin was well tolerated.

Mutagenicity

In four mutagenicity tests tinzaparin showed no evidence of chromosomal damage or mutagenic potential.

Carcinogenicity

An investigation into former use of heparin in humans or into research data from animal studies did not indicate any oncogenic or carcinogenic potential nor did the production of tinzaparin introduce any elements which should be taken into consideration. Furthermore, none of the above mentioned toxicological studies on tinzaparin indicate any carcinogenic risks. As a result, no animal carcinogenicity studies have been performed.

Reproduction and Teratology

The reproduction studies showed that tinzaparin had no effect on fertility in male and female rats or on their F1 generation progeny. Fetal development and teratogenicity studies produced no evidence of embryotoxic or teratogenic effects in rats and rabbits. Peri- and post-natal development studies indicated that tinzaparin had no toxic effects on the F1 or F2 generation.