Donovit-vc®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DO NOVIT-VS® (DONOVIT-VS)

Composition:

Active substance: liquid extract of aconite root;

One 10 mcg tablet contains 0.02 ml of liquid extract of aconite root (Aconiti radices extractum fluidum) (1:4) (extracting agent: 40% ethanol) (containing acetylbensoylaconine in the amount of not less than 480 mcg/ml and not more than 520 mcg/ml);

Excipients: lactose monohydrate; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: biconvex tablets of grayish-white or yellowish-white color. Dark specks are permissible.

Pharmacotherapeutic group

Plant-derived alkaloids and other natural origin drugs.

ATC code: L01CX.

Pharmacological Properties

Pharmacodynamics

DONOVIT-VC® is a medicinal product of plant origin containing liquid extract of aconite root. Aconite is a perennial herbaceous plant of the buttercup family (Ranunculaceae Juss), the root of which (Aconiti radix) contains diterpenoid alkaloids. The main active component of DONOVIT-VC® is the alkaloid aconitine (acetylbenzoylaconine), which exhibits antitumor and antimetastatic activity against solid tumors with angiogenesis-dependent growth.

DONOVIT-VC® demonstrates antitumor activity, which has been observed in solid non-metastatic experimental models: Lewis lung carcinoma LLC/R9, Ehrlich carcinoma, and sarcoma S180. Antitumor activity was manifested as more than 65% inhibition (p < 0.05) of primary tumor growth (Ehrlich carcinoma, sarcoma S180), with the effect persisting for at least 8 days after discontinuation of the drug. Antimetastatic activity of the drug against Lewis lung carcinoma LLC/R9 was evident in significant inhibition of both the number and volume of metastases: a 92.2% reduction in the average number of lung metastases (p < 0.01) and a 78.0% reduction in metastatic burden (p < 0.05). The antitumor activity of DONOVIT-VC® is completely absent against ascitic forms of experimental tumors.

Preclinical studies have demonstrated that antitumor and antimetastatic effects are mediated by two mechanisms: antiangiogenic and antivascular.

Research findings indicate that DONOVIT-VC® significantly affects the vascular system. Microscopic examination of tumors (LLC, LLC/R9, glioma 101-8) and internal organs (lungs, liver, kidneys, and heart) in intact mice and rats after single administration of the drug at lethal and sublethal doses revealed a pronounced damaging effect of the extract on blood vessels, manifested as vessel dilation, increased permeability, or in some cases, vessel wall rupture. Ruptures of blood vessel walls, particularly in tumor tissue, were accompanied by erythrocyte extravasation into the perivascular space. In control groups of animals, no vascular damage was observed either in tumor tissue or in normal organs.

The antivascular and antiangiogenic effects of DONOVIT-VC® were further confirmed by studies assessing its impact on vascularization of the chorioallantoic membrane (CAM), evaluated in chicken embryos.

Inhibition of CAM vascularization by the aconitine-containing extract was dose-dependent. The proportion of vessels with a diameter exceeding 0.6 mm progressively decreased with increasing drug dose, and at a dose of 0.4 µg per embryo, such vessels were completely absent.

A significant effect of DONOVIT-VC® on the electrophoretic characteristics of endothelial and tumor cells was observed. The drug's effect on the electrophoretic properties of endothelial cells MAEK (modeling angiogenesis in vitro using 3D cultures of endothelial cells) differed significantly from its effect on tumor cells. Increasing concentrations of DONOVIT-VC® caused a 30% reduction (p < 0.05) in surface charge density of LLC/R9 cells without altering its sign. A 50% reduction in surface charge density while preserving its sign was observed when the drug acted on endothelial cells at a concentration of IC50/10. However, at lower concentrations (IC50/20), DONOVIT-VC® induced a significant negative surface charge in most endothelial cells. Since a positive surface charge of endothelial cells plays a crucial role in vascular morphogenesis, the drug-induced shift to a negative charge may lead to inhibition of new vessel formation (antiangiogenic effect) and disruption of vascular structure, increasing vascular permeability (direct antivascular effect).

Chemotherapeutic agents, such as cisplatin, demonstrated higher efficacy when used in combination with DONOVIT-VC®.

In clinical studies, DONOVIT-VC® was administered to patients with colorectal cancer, breast cancer, and glioblastoma as an adjunctive treatment during chemotherapy. In patients with colorectal cancer and breast cancer receiving DONOVIT-VC®, in addition to antimetastatic and antitumor effects, a reduction in the severity of chemotherapy-related complications such as leukopenia, anemia, neutropenia, and thrombocytopenia was observed, compared to patients receiving chemotherapy alone. Additionally, a reduction in the severity and frequency of nausea and vomiting was noted.

Pharmacokinetics

Not studied.

Clinical characteristics

Indications

For the prevention of adverse reactions during adjuvant chemotherapy in patients with colorectal cancer and breast cancer after radical surgery; to be used in patients with glioblastoma as a supportive drug during chemotherapy.

Contraindications

Hypersensitivity to the active substance or to any other component of the medicinal product.

Severe hepatic insufficiency, severe renal insufficiency, hypotension, typhoid fever, asystole.

Interaction with other medicinal products and other forms of interaction

Should not be used concurrently with glucocorticoids, antihistamines, or caffeine-containing agents.

Special precautions for use

DONOVIT-BC® contains lactose; therefore, if a patient has been diagnosed with an intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

DONOVIT-BC® should be used with caution in patients with mild renal impairment, as it is predominantly excreted by the kidneys.

Use during pregnancy or breastfeeding

The medicinal product is not to be used during pregnancy and breastfeeding; studies have not been conducted.

Effect on ability to drive or operate machinery

Studies on the effect of the drug on the ability to drive or operate machinery have not been conducted.

Dosage and Administration

The dosage must be individually adjusted depending on the patient's clinical condition. The maximum single dose is 1 tablet. The maximum daily dose is 3 tablets (in 3 divided doses).

Administer 1 tablet three times a day for 3 months.

Tablets should preferably be taken 15–20 minutes before a meal or 1.5–2 hours after a meal, swallowed with ½ glass of warm boiled water.

The duration of treatment depends on the severity and course of the disease and is determined by the physician based on CT, MRI, and PET scan findings.

Patients with impaired renal function

For patients with mild to moderate renal impairment, cautious dose titration is recommended, especially at the beginning of therapy. Treatment should be initiated at 1 tablet per day. The dose may be increased up to a maximum of 2 tablets per day in patients with moderate renal insufficiency (glomerular filtration rate (GFR) > 30 mL/min but < 60 mL/min), if clinically indicated.

Children

The medicinal product is not intended for use in children.

Overdose

Symptoms: nausea, dyspnea, headache, facial hyperemia, numbness of the tip of the tongue and lips, and occasionally numbness of the skin of the head.

Treatment: In case of overdose, discontinue the medicinal product and seek medical advice.

Side effects

When using the medicinal product Donovit-VC®, allergic reactions to the active substance or any other component of the product are possible.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the use of this medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging

30 tablets in a blister pack, 3 blisters per carton.

Prescription status

Prescription only.

Manufacturer

LLC "ASTRAFARM", Ukraine.

Manufacturer's address and location of its business activities

6, Kyivska Street, Vyshneve, Buchanskyi district, Kyiv region, 08132, Ukraine.

Marketing Authorization Holder

LLC "NVP AKSOMED LTD", Ukraine.

Address of the Marketing Authorization Holder

18, Ozerne Street, apt. 75, Kyiv, 04209, Ukraine