Cases of accidental acute overdose have been reported in humans: Such cases can result in bone marrow hypoplasia and are sometimes associated with infection, fever and paralytic ileus. Supporting treatment such as blood transfusion, growth factors or broad-spectrum antibiotic treatment is normally initiated at the doctor's discretion. There is no known antidote.
As there is no specific antidote for the overdose of Vinorrelbina Hikma given intravenously, symptomatic measures are necessary in case of an overdose, e.g.:
- Continuous control of vital signs and careful monitoring of the patient.
- Daily control of blood count to observe the need of blood transfusions, of growth factors and to detect the need of intensive care and to minimise the risk of infections.
- Measures for prevention or for therapy of paralytic ileus
- Control of circulation system and of liver function
- Broad spectrum antibiotic therapy may be necessary in case of complications due to infections. In case of a paralytic ileus, decompression by a probe may be necessary.
- Neutrophil count < 1,500/mm³ or severe current or recent infection (within the last 2 weeks)
- Thrombocyte count below 100,000/mm³
- Severe hepatic impairment not related to the tumoural process
- In combination with yellow fever vaccine
- Pregnancy
- Lactation
- Vinorrelbina Hikma 10 mg/ml concentrate for solution for infusion should not be diluted with alkaline solutions (risk for precipitation).
The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, anaemia, neurologic disorders and gastrointestinal toxicity with nausea, vomiting, stomatitis and constipation, transient elevations of liver function tests, alopecia and local phlebitis.
In combined chemotherapy of Vinorrelbina Hikma with other antineoplastic medicinal products it has to be considered, that the listed undesirable effects can occur more frequently and more severe than those undesirable effects observed during and after monotherapy. Moreover, the additional specific undesirable effects of the other medicinal products have to be considered.
Adverse reactions reported as more than isolated cases are listed below, by system organ class and by frequency. Frequencies are defined as:
Very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000).
Additional adverse reactions from post marketing experience have been added according to the MedDRA classification with the frequency Not known (cannot be estimated from the available data).
Detailed adverse reactions information: Reactions were described using the W.H.O classification (grade 1 = G1; grade 2 = G2; grade 3 = G3; grade 4 = G4; grade 1-4 = G1-4); grade 1-2 = G1-2; grade 3-4 = G3-4).
| Infections and infestations | Common Infection bacterial, viral or fungal at different localisation (respiratory, urinary, GI tract) mild to moderate and usually reversible with an appropriate treatment. Uncommon Severe sepsis with other visceral failure, septicaemia. Very rare Septicaemia complicated; septicaemia fatal. Not known Neutropenic sepsis (with potential fatal outcome in 1.2 % of cases). |
| Blood and lymphatic system disorders | Very common Bone marrow depression resulting mainly in neutropenia (G3: 24.3 % and G4: 27.8 % in monotherapy) reversible within 5 to 7 days and non-cumulative over time, anaemia (G3-4: 7.4 % in monotherapy). Common Thrombocytopenia (G3-4: 2.5 %) may occur but is seldom severe. Not known Febrile neutropenia, pancytopenia. |
| Immune system disorders | Common Allergic reactions (skin reactions, respiratory reactions). Not known Systemic allergic reactions (anaphylactic reaction or shock, anaphylactoid reaction, angioedema). |
| Endocrine disorders | Not known Inappropriate antidiuretic hormone secretion (SIADH). |
| Metabolism and nutrition disorders | Rare Severe hyponatraemia. Not known Anorexia. |
| Nervous system disorders | Very common Neurological disorders (G3: 2.6 %; G4: 0.1 %) including loss of deep tendon reflexes. Weakness of the lower extremities has been reported after a prolonged chemotherapy. Uncommon Severe paraesthesia with sensory and motor symptoms. These effects are generally reversible. Very rare Guillain Barré syndrome |
| Cardiac disorders | Rare Ischaemic heart diseases like angina pectoris, transitory electrocardiogram changes, myocardial infarction, sometimes fatal. Very rare Tachycardia, palpitation and heart rhythm disorders. |
| Vascular disorders | Uncommon Hypotension, hypertension, flushing and peripheral coldness Rare Severe hypotension, collapse. |
| Respiratory, thoracic and mediastinal disorders | Uncommon Dyspnoea and bronchospasm may occur in association with Vinorrelbina Hikma treatment as with other vinca alkaloids. Rare Interstitial lung disease, sometimes fatal has been reported. Very rare Respiratory insufficiency. |
| Gastrointestinal disorders | Very common Constipation is the main symptom (G 3-4: 2.7 %) which rarely progresses to paralytic ileus with Vinorrelbina Hikma as single agent (G3-4: 4.1 %) and with the combination of Vinorrelbina Hikma and other chemotherapeutic agents. Nausea and vomiting (G1-2: 30.4 %, G3-4: 2.2 % in monotherapy; antiemetic therapy may reduce their occurrence), stomatitis (G1-4: 15 % in monotherapy), oesophagitis. Common Diarrhoea (usually mild to moderate). Rare Paralytic ileus; treatment may be resumed after recovery of normal bowel mobility, pancreatitis |
| Hepatobiliary disorders | Very common Transient elevations of liver function tests (G1-2) without clinical symptoms were reported (total bilirubin increased, alkaline phosphatase increased, aspartate aminotransferase increased in 27.6 %, alanine aminotransferase increased in 29.3 %). |
| Skin and subcutaneous tissue disorders | Very common Alopecia usually mild in nature (G3-4: 4.1 % in monotherapy). Rare Generalised cutaneous reactions. Not known: Palmar-plantar erythrodysesthesia syndrome. |
| Musculoskeletal and connective tissue disorders | Common Myalgia, arthralgia, jaw pain. |
| Renal and urinary disorders | Common Creatinine increased. |
| General disorders and administration site conditions | Very common Asthenia, fatigue, fever, pain in different locations including chest pain and pain at the tumour site. Reactions at the injection site may include erythema, burning pain, vein discolouration and local phlebitis (G3-4: 3.7 % with Vinorrelbina Hikma as single chemotherapeutic agent). Rare Injection site necrosis (proper positioning of the intravenous needle or catheter and bolus injection followed by liberal flushing of the vein can limit these effects). |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
The limiting toxicity in animals is bone marrow depression. In animal studies, Vinorrelbina Hikma induced aneuploidy and polyploidy.
It can be assumed that Vinorrelbina Hikma can also cause genotoxic effects in humans (induction of aneuploidy and polyploidy).
The results of studies for carcinogenic potential in mice and rats were negative but only low doses have been tested.
In animal reproductive studies, effects were observed at subtherapeutic doses. Embryo- and fetotoxicity were seen, such as intra-uterine growth retardation and delayed ossification. Teratogenicity (fusion of the vertebrae, missing ribs) was observed at maternally toxic doses. In addition, spermatogenesis and secretion of prostate and seminal vesicles were reduced, but fertility in rats was not diminished.
- As a single agent or in combination for the first line treatment of stage 3 or 4 non-small cell lung cancer.
- Treatment of advanced breast cancer stage 3 and 4 relapsing after or refractory to an anthracycline containing regimen.
Pharmacotherapeutic group: Antineoplastic and immunmodulating agents, vinca alkaloids
ATC code: L 01 CA 04
Vinorrelbina Hikma is an antineoplastic active substance of the vinca alkaloid family, but in contrast to all other vinca alkaloids the catharanthine portion of Vinorrelbina Hikma has undergone a structural modification. On the molecular level it affects the dynamic equilibrium of tubulin in the microtubular system of the cell.
Mechanism of action
Vinorrelbina Hikma inhibits tubulin polymerisation and binds preferentially to mitotic microtubules, only affecting axonal microtubules at high concentrations. Spiralisation of the tubulin is induced to a lesser degree than with vincristine. Vinorrelbina Hikma blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.
Paediatric population
The safety and efficacy of Vinorrelbina Hikma in paediatric patients have not been established. Clinical data from two single arm Phase II studies using intravenous Vinorrelbina Hikma in 33 and 46 paediatric patients with recurrent solid tumours, including rhabdomyosarcoma, other soft tissue sarcoma, Ewing sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, central nervous system cancer, osteosarcoma, neuroblastoma at doses of 30 to 33.75 mg/m² D1 and D8 every 3 weeks or once weekly for 6 weeks every 8 weeks, showed no meaningful clinical activity. The toxicity profile was similar to that reported in adult patients.
Distribution
The active ingredient is widely distributed in the body with a volume of distribution ranging from 25.4-40.1 l/kg. Penetration of Vinorrelbina Hikma into pulmonary tissue is significant with tissue/plasma concentration ratios of greater than 300 in a study involving surgical biopsy. There is moderate binding to plasma proteins (13.5 %) but strong binding to platelets (78 %). Linear pharmacokinetics has been shown for intravenously administered Vinorrelbina Hikma up to a dose of 45 mg/m².
Biotransformation
Vinorrelbina Hikma is primarily metabolised by CYP3A4 of cytochrome P450. All metabolites have been identified and none are active with the exception of 4-O-deacetylVinorrelbina Hikma, which is the principal metabolite in the blood.
Elimination
After intravenous bolus injection or infusion in patients, the plasma concentration of Vinorrelbina Hikma is characterised by a three exponential elimination curve. The terminal elimination phase reflects a long half-life greater than 40 hours. Total clearance of Vinorrelbina Hikma is high (0.97-1.26 l/h/kg).
Renal elimination is low (< 20 % of the dose). Small concentrations of deacetyl Vinorrelbina Hikma have been recovered in humans, but Vinorrelbina Hikma is principally detected as the unchanged compound in urine. Elimination of the active substance is mainly via the bile duct and consists of the metabolites and mainly of unchanged Vinorrelbina Hikma.
The effect of kidney dysfunction on the disposition of Vinorrelbina Hikma has not been studied, but dose reduction is not indicated because of the low degree of renal excretion. In patients with liver metastases changes only occurred in the mean clearance of Vinorrelbina Hikma when over 75 % of the liver was affected. In 6 cancer patients with moderate liver dysfunction (bilirubin ≤ 2 x ULN and aminotransferases ≤ 5 x ULN) treated with up to 25 mg/m² and 8 cancer patients with severe liver dysfunction (bilirubin > 2 x ULN and/or aminotransferases > 5 x ULN) treated with up to 20 mg/m², mean total clearance in the two groups were similar to that in patients with normal liver function. These data may however not be representative for patients with reduced capacity to eliminate the active substance via the liver and therefore caution is recommended in patients with severe hepatic impairment and careful monitoring of haematological parameters required.
Elderly
A study, conducted by the innovator, with Vinorrelbina Hikma in elderly patients (> 70 years) with NSCLC demonstrated that pharmacokinetics of Vinorrelbina Hikma were not influenced by age. However, since elderly patients are frail, caution should be exercised when increasing the dose of Vinorrelbina Hikma.
Special warnings
- Vinorrelbina Hikma should be administered under the supervision of a physician experienced in the use of chemotherapy.
- Vinorrelbina Hikma must only be administered by the intravenous route. The use of intrathecal route is contra-indicated. Administration should always be followed by a sodium chloride 9 mg/ml (0.9 %) infusion to flush the vein.
- Vinorrelbina Hikma must be administered intravenously with great precision: It is very important to make sure that the cannula has been accurately placed into the vein before starting to infuse Vinorrelbina Hikma. If Vinorrelbina Hikma extravasates during intravenous administration, this can cause considerable local irritation. In this case, the infusion must be stopped immediately, the vein flushed through with sodium chloride 9 mg/ml (0.9 %) solution and the rest of the dose should be administered in another vein. In the event of extravasation glucosteroids can be given intravenously in order to reduce the risk of phlebitis.
- Treatment should be undertaken with close haematological monitoring (determination of haemoglobin level and number of leukocytes, granulocytes and thrombocytes before each new injection). The dose-limiting adverse reaction is mainly neutropenia. This effect is non-cumulative, having its nadir between 7 and 14 days after the administration and is rapidly reversible within 5 to 7 days. If the neutrophil count is <1,500/mm³ and/or thrombocyte count is below 100,000/mm³, treatment should be delayed until recovery and the patient should be observed. Administration of the medicinal product is expected to be delayed by 1 week in about 35 % of treatment courses.
- If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.
- Interstitial lung disease has been reported more frequently in the Japanese population. Special attention should be exercised for this specific population.
Special precautions for use
- If there is significant hepatic impairment the dose should be reduced: caution is recommended and careful monitoring of haematological parameters required.
- In case of renal impairment, because of the low level of renal excretion, no dose modification is necessary.
- Vinorrelbina Hikma should not be given concomitantly with radiotherapy if the treatment field includes the liver.
- Strong CYP3A4- inhibitors or inducers should be administered with caution because of the risk of affecting the Vinorrelbina Hikma concentration.
- This product is generally not recommended in combination with itraconazole (like all vinca-alkaloids) and phenytoin (like all cytotoxics).
- This product is specifically contraindicated with yellow fever vaccine and its concomitant use with other live attenuated vaccines is not recommended.
- To avoid bronchospasm - especially if used concomitantly with mitomycin C-appropriate precautionary measures should be considered. Patients treated on an outpatient basis should be informed that they should contact the physician in case of dyspnoea.
- It is recommended that special caution should be shown towards patients with ischaemic heart disease in the medical history.
- All contact with the eyes should be strictly avoided: risk of severe irritation and even corneal ulceration if the medicinal product is sprayed under pressure. Immediate liberal washing of the eye with sodium chloride 9 mg/ml (0.9 %) solution should be undertaken if any contact occurs.
No studies of the effects on the ability to drive and use machines have been performed but on the basis of the pharmacodynamic profile Vinorrelbina Hikma has no or negligible influence on the ability to drive and use machines. However, caution is necessary in patients treated with Vinorrelbina Hikma considering some adverse effects of the medicinal product.
Posology
- Vinorrelbina Hikma is usually given at 25-30 mg/m² once weekly.
In combination with other cytostatic agents the exact dose should be taken from the treatment protocol.
Vinorrelbina Hikma may be administered by slow bolus (6-10 minutes) after dilution in 20-50 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % (w/v) glucose solution for injection or by a short infusion (20-30 minutes) after dilution in 125 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % (w/v) glucose solution for injection. Administration should always be followed by a sodium chloride 9 mg/ml (0.9 %) infusion with at least 250 ml to flush the vein.
The maximum tolerated dose per administration: 35.4 mg/m² body surface area
The maximum total dose per administration: 60 mg
Dose modifications
Vinorrelbina Hikma metabolism and clearance are mostly hepatic: only 18.5 % is excreted unchanged in the urine. No prospective study relating altered metabolism of the active substance to its pharmacodynamic effects is available in order to establish guidelines for Vinorrelbina Hikma dose reduction in patients with impaired liver or kidney function.
Hepatic impairment
The pharmacokinetics of Vinorrelbina Hikma is not modified in patients presenting moderate or severe liver impairment.
Nevertheless as a precautionary measure a reduced dose of 20 mg/m² and close monitoring of haematological parameters is recommended in patients with severe liver impairment.
Renal impairment
Given the minor renal excretion, there is no pharmacokinetic rationale for reducing Vinorrelbina Hikma dose in patients with impaired kidney function.
Elderly
Clinical experience has not detected any significant differences among elderly patients with regard to the response rate, although greater sensitivity in some of these patients cannot be excluded. Age does not modify the pharmacokinetics of Vinorrelbina Hikma.
Paediatric population
The safety and efficacy in children have not been established and administration is therefore not recommended.
Method of administration
Strictly intravenous administration after appropriate dilution.
Intrathecal administration of Vinorrelbina Hikma may be fatal.
Precautions to be taken before handling or administering the medicinal product
The preparation and administration of Vinorrelbina Hikma should be carried out only by trained personnel. Suitable protective goggles, disposable gloves, face mask and disposable clothing must be worn. Spills and leakages must be wiped up.
Any contact with the eyes must be strictly avoided. If the solution does come into contact with the eyes they must be rinsed immediately with plenty of sodium chloride 9 mg/ml (0.9 %) solution.
After preparation, any exposed surface must be thoroughly cleaned and hands and face washed.
There is no incompatibility between the contents and container for Vinorrelbina Hikma 10 mg/ml concentrate for solution for infusion and a neutral glass bottle, PVC bag, vinylacetate bag or infusion set with PVC tubes.
It is recommended to administer Vinorrelbina Hikma as an infusion over the course of 6-10 minutes after dilution in 20-50 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % (w/v) glucose solution for injection or by a short infusion (20-30 minutes) after dilution in 125 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection or in 5 % (w/v) glucose solution for injection. After administration the vein must be flushed through thoroughly with at least 250 ml sodium chloride 9 mg/ml (0.9 %) solution.
Vinorrelbina Hikma must be given strictly intravenously: it is very important to make sure that the cannula is accurately placed in the vein before starting to infuse Vinorrelbina Hikma. If the medicinal product extravasates into the surrounding tissue during the administration considerable local irritation may occur. In this case, the administration should be stopped, the vein flushed with sodium chloride 9 mg/ml (0.9 %) solution and the remaining dose administered in another vein.
In case of extravasations, to reduce the risk of phlebitis IV glucocorticoids could be administered immediately.
Any unused medicinal product and waste material should be disposed of in accordance with local requirements.
