Interaction between Waran and Venoruton forte?/nCase record: A man, 68 years of age, has been trea

Fråga: "Interaction between Waran and Venoruton forte?

Case record: A man, 68 years of age, has been treated for a time with Waran and, recently, the licensed drug Venoruton forte has been added to this basic treatment, by a colleague.

Venoruton (ortho-rutoside, monoxerutin) forte is given in fixed doses 500 mg 2x3 daily. The drug is not registered in Sweden but is available on license from Zyma, Switzerland.

Clinically, the patient´s PK values go up and down like a "temperature curve" from one occasion to another."

Sammanfattning: Hydroxyethylrutosides are made up of a standardised mixture of semi-synthetic flavonoids and are available as registered drugs in certain European countries. In Sweden they can be obtained on license. The main pharmacological action seems to be to influence microvascular permeability, thereby reducing oedema formation. The best clinical documentation is obtained from studies on patients with chronic venous insufficiency mainly in post-thrombotic syndromes and primary venous insufficiency. Side-effects in general are mild. Drug interactions have been only partly studied. However, a metabolic interaction with warfarin seems unlikely and has also been found negative in a couple of studies.

In the present case an absorption interaction would fit in with the clinical picture and therefore the following measures are recommended: 1) The time for administration of warfarin and the drug should be separated by at least 3 to 4 hours. 2) The clinical benefit for the patient seems questionable, which is why cancellation of the drug should be considered, at least temporarily combined with a close follow-up of the PK values. 3) A laboratory interference is not known (see above) but has been reported and could be excluded following these steps.

Depending on the outcome of these measures a report to the Swedish Adverse Drug Reactions Advisory Committee could be considered.

Svar: Hydroxyethylrutosides (oxerutins) make up a standardised mixture of semi-synthetic flavonoids isolated from plants. The compounds have been used for about 20-30 years and marketed mainly in middle Europe as certain standard preparations, eg Venoruton and Paroven. In Sweden, the drug is available on license (Zyma/Ciba-Geigy). A number of papers of varying quality have accumulated over the years (1) concerning its pharmacology and clinical effects.

The mechanism of action is not completely known, but the primary pharmacological action seems to be on the microvascular endothelium, to reduce hyperpermeability and oedema. Both animal and clinical models in humans have been used to study this. There seems to be no effect on central haemodynamics.

Limited data are available on the pharmacokinetic properties of hydroxyethylrutosides. Less than 10 per cent of an orally administered dose is absorbed and peak plasma concentrations are reached within 1-6 hours. The plasma elimination half-life following oral administration to humans ranges from 10 to 25 hours. Primarily, the components of hydroxyethylrutosides are eliminated via metabolism to aglucones by the intestinal flora. After absorption the metabolites are eliminated mainly via the bile. The plasma protein binding is given as 27-29 per cent. Oral doses of 1-3 g/daily have improved parameters of microvascular perfusion. Hydroxyethylrutosides are very hydrophilic.

A number of clinical trials of varying quality have been performed and published. Hydroxyethylrutosides have been tried in a number of clinical conditions such as haemorrhoids, diabetic circulatory disturbances such as retinopathy, lymphoedema, venous disorders in pregnancy etc (1,3). The best results in controlled trials have been obtained on symptoms and signs of chronic venous insufficiency. Doses of 0.6-1.2 g/day for up to six months significantly improve objective and subjective measures of lower limb venous insufficiency (1,2). A Swedish controlled clinical trial has also been performed in 149 patients with chronic venous insufficiency, showing a favourable effect of the drug in a daily dose of 1.5 gram compared with the effect of a placebo (4). The recommended daily dose is 0.2-1.2 g/day orally. This patient is on the highest recommended dosage and has been prescribed the drug by a Swiss doctor. It is recommended that the drug be taken in conjunction with meals.

In clinical trials hydroxyethylrutosides have generally been well tolerated and the incidence of adverse events reported are similar to those of placebo recipients. Most commonly reported side-effects are diarrhoea, vomiting or sleep disorders. No serious ADR have been reported during long-term treatment. In one study, abnormal laboratory data were observed in two per cent of patients treated with either hydroxyethylrutosides or placeboes but this was attributed to the treatment given (3).

DRUG INTERACTION. There are only scanty data concerning drug interactions. In two studies (5,3) hydroxyethylrutosides do not appear to interact with warfarin (due to the low protein binding?). An oral dose of one gram per day as an adjuvant to warfarin therapy in 12 patients with deep venous thrombosis had no effect on activated partial thromboplastin time (5). However, since drug interactions are in general dose-related, this matter is not fully elucidated and an interaction in the patient involved should perhaps not be ruled out due to the high dose given. Also, the clinical picture rather points to the possibility of an absorption interaction. 1 Wadworth AN, Faulds D: Hydroxyethylrutosides. A review of its pharmacology and therapeutic efficacy in venous insufficiency and related disorders. Drugs 1992; 44: 1013-1032 2 Cheatle TR, Scurr JH, Smith PD: Drug treatment of chronic venous insufficiency and venous ulceration: a review. J R Soc Med 1991; 84: 354-358 3 Pharmacy file, Danderyd Hospital (Ciba-Geigy license), 1993 4 Bergqvist D, Hallböök T, Lindblad B, Lindhagen A: A double-blind trial of 0-beta-hydroxethyl)rutoside in patients with chronic venous insufficiency. VASA - J Vasc Dis 1981; 10: 253-260 5 Eastham RD, Perham TGM, Pocock PV: Warfarin and hdyroxyethylrutosides in deep vein thrombosis. Br Med J 1971; 4: 491