VINORELBIN EBEWE 10 MGML

VIN API May 2020

1.

NAME OF THE MEDICINAL PRODUCT

Vinorelbin "Ebewe" 10mg/ml, concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Vinorelbine 10 mg/ml (as tartrate)

Each 1 ml concentrate for solution for infusion contains 10 mg vinorelbine (as tartrate)

Each 5 ml concentrate for solution for infusion contains 50 mg vinorelbine (as tartrate)

For a full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless to pale yellow solution.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

For the treatment of non small cell lung cancer.

For the treatment of advanced breast cancer.

Hormone-refractory prostate cancer, especially in combination with low dose oral corticoid

therapy or Estramustin.

4.2.

Posology and method of administration

Strictly intravenous administration after appropriate dilution.

Intra-thecal administration of vinorelbin

may be fatal.

Instructions for use and handling: refer to paragraph 6.6.

It is recommended to infuse vinorelbine

over 6-10 minutes after dilution in 20-50 ml of sodium

chloride 9 mg/ml (0.9%) solution for injection or in glucose solution for injection 5%.

Administration should always be followed with at least 250 ml of an isotonic solution infusion

to flush the vein.

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Non-small cell lung cancer and advanced breast cancer

In monotherapy the usual dose given is 25-30 mg/m² once weekly.

In combination chemotherapy the usual dose (25-30 mg/m²) is usually maintained, while

the frequency of administration is reduced e.g. day 1 and 5 every 3 weeks or day 1 and 8 every

3 weeks according to treatment protocol.

Hormone-resistant prostate cancer

The usual dose given is 30 mg/m

on days 1 and 8 every 3 weeks with low doses of

corticosteroids everyday (i.e. hydrocortisone 40 mg/day).

Administration in the elderly

Clinical experience has not identified relevant 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 vinorelbine.

Administration in patients with liver insufficiency

The pharmacokinetics of vinorelbine is not modified in patients presenting moderate or severe

liver impairment. Nevertheless as a precautionary measure a reduced dose of 20mg/m

close monitoring of haematological parameters is recommended in patient with severe liver

impairment (refer to sections 4.4 and 5.2).

Administration in patients with renal insufficiency

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose

of vinorelbine in patients with renal insufficiency.

Administration in children

Safety and efficacy in children have not been established and administration is therefore not

recommended (

see section 5.1

4.3.

Contraindications

Known hypersensitivity to the active substance or other vinca alkaloids, or to any of the

excipients listed in section 6.1.

Neutrophil count < 1500/mm

or severe infection current or recent (within 2 weeks).

Platelet count <100,000/mm

In combination with yellow fever vaccine (refer to section 4.5).

Pregnancy (refer to section 4.6).

Lactation (refer to section 4.6).

4.4.

Special warnings and special precautions for use

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Special warnings

Vinorelbine

should be administered under the supervision of a physician experienced in the use

of chemotherapy.

Since inhibition of the hematopoietic system is the main risk associated with vinorelbine, close

haematological

monitoring

should

undertaken

during

treatment

(determination

hemoglobin level and the leukocyte, neutrophil and platelet counts on the day of each new

administration).

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 below 1500/mm

and/or the platelet count is below 100000/mm

then the treatment should be delayed until recovery.

If patients present signs or symptoms suggestive of infection, a prompt investigation should be

carried out.

Special precautions for use

Special care should be taken when prescribing for patients with history of ischemic heart disease

(refer to section 4.8).

The pharmacokinetics of vinorelbine

is not modified in patients presenting moderate or severe

liver impairment. For dosage adjustment in this specific patient group, refer to section 4.2.

As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing the

dose of vinorelbine in patients with impaired kidney function (Refer to section 4.2).

Vinorelbine

should not be given concomitantly with radiotherapy if the treatment field includes

the liver.

This product is specifically contra-indicated with yellow fever vaccine and its concomitant use

with other live attenuated vaccines is not recommended.

Caution must be exercised when combining vinorelbine and strong inhibitors or inducers of

CYP3A4 (refer to Section 4.5 – Interactions specific to vinorelbine), and its combination with

phenytoin (like all cytotoxics) and with itraconazole (like all vinca-alkaloids) is not

recommended.

All contact with the eyes should be strictly avoided: there is a risk of severe irritation and even

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corneal ulceration if the drug is sprayed under pressure. Immediate washing of the eye with

sodium chloride 9mg/ml (0.9%) solution for injection should be undertaken if any contact

occurs.

4.5.

Interaction with other medicinal products and other forms of interaction

Interactions common to all cytotoxics:

Due to the increase of thrombotic risk in case of tumoral diseases, the use of anticoagulative

treatment is frequent. The high intra-individual variability of the coagulability during diseases,

and the eventuality of interaction between oral anticoagulants and anticancer chemotherapy

required, if it is decided to treat the patient with oral anticoagulants, to increase frequency of the

INR (International Normalised Ratio) monitoring.

Concomitant use contraindicated:

Yellow fever vaccine: risk of fatal generalised vaccine disease (refer to section 4.3).

Concomitant use not recommended:

Live attenuated vaccines (for yellow fever vaccine, see concomitant use contraindicated): risk of

generalised

vaccine

disease,

possibly

fatal.

This

risk

increased

patients

already

immunodepressed by their underlying disease. It is recommended to use an inactivated when

exists (poliomyelitis) (refer to section 4.4).

Phenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive

absorption by cytotoxic drug or risk of toxicity enhancement or loss of efficacy of the cytotoxic

drug due to increased hepatic metabolism by phenytoin.

Concomitant use to take into consideration:

Ciclosporine, tacrolimus: excessive immunodepression with risk of lymphoproliferation.

Interactions specific to vinca-alkaloids:

Concomitant use not recommended:

Itraconazole: increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic

metabolism.

Concomitant use to take into consideration:

Mitomycin C: risk of bronchospams and dyspnoea are increased, in rare case an interstitial

pneumonitis was observed.

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As vinca-alkaloids are known as substrates for P-glycoprotein, and in the absence of specific

study, caution should be exercised when combining vinorelbine with strong modulators of this

membrane transporter.

Interactions specific to vinorelbinee:

The combination of vinorelbine with other drugs with known bone marrow toxicity is likely to

exacerbate the myelosuppressive adverse effects.

As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong

inhibitors

this

isoenzyme

(e.g.

ketoconazole,

itraconazole)

could

increase

blood

concentrations of vinorelbine and combination with strong inducers of this isoenzyme (e.g.

rifampicin, phenytoin) could decrease blood concentrations of vinorelbine.

There is no mutual pharmacokinetic interaction when combining vinorelbine with cisplatin over

several cycles of treatment. However, the incidence of granulocytopenia associated with

vinorelbine use in combination with cisplatin is higher than associated with vinorelbine single

agent.

4.6.

Pregnancy and lactation

Pregnancy

Vinorelbine is suspected to cause serious birth effects when administered during pregnancy (refer

to section 5.3).

Vinorelbine is contraindicated in pregnancy (refer to section 4.3).

In case of a vital indication a medical consultation concerning the risk of harmful effects for the

child should be performed for the therapy of a pregnant patient. If pregnancy occurs anyhow

during treatment, genetic counselling should be offered.

Women of childbearing potential

Women of child-bearing potential must use effective contraception during treatment and up to

3 months after treatment.

Lactation

It is unknown whether vinorelbine

is excreted in human breast milk. The excretion of

vinorelbine in milk has not been studied in animal studies. A risk to the suckling can not be

excluded therefore breast feeding must be discontinued before starting treatment with

vinorelbine (refer to section 4.3).

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Fertility:

Men being treated with vinorelbine are advised not to father a child during and up to 3 months

after treatment. Prior to treatment advice should be sought for conserving sperm due to the

chance of irreversible infertility as a consequence of treatment with vinorelbine.

4.7.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed but

on the basis of the pharmacodynamic profile vinorelbine does not affect the ability to drive and

use machines. However, caution is necessary in patient treated with vinorelbine considering

some adverse effects of the drug.

4.8.

Undesirable effects

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 <1/10),

uncommon (>1/1,000 <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000),

according

to the MedDRA frequency convention and system organ classification.

The most commonly reported adverse drug reactions are bone marrow depression with

neutropenia, anaemia, neurologic disorders, gastrointestinal toxicity with nausea, vomiting,

stomatitis and constipation, transient elevations of liver function tests, alopecia and local

phlebitis.

Additional Adverse reactions from Post Marketing experience has been added according to

the MedDRA classification with the frequency

Not known.

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 localization (respiratory, urinary, GI

tract…) mild to moderate and usually reversible with an appropriate treatment.

Uncommon: Severe sepsis with other visceral failure.

Septicaemia

Very rare: Complicated septicaemia and sometimes fatal.

Not known: Neutropenic sepsis.

Blood and lymphatic system disorders:

Very Common: Bone marrow depression resulting mainly in neutropenia (G3: 24.3%; G4:

VIN API May 2020

27.8%), reversible within 5 to 7 days and non-cumulative over time.

Anaemia (G3-4: 7.4%).

Common: Thrombocytopenia (G3-4: 2.5%) may occur but are seldom severe.

Not known: Febrile neutropenia.

Immune system disorders

Not known: Systemic allergic reactions as anaphylaxis, anaphylactic shock or

anaphylactoïd

type reaction.

Endocrine disorders

Not known: Inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders

Rare: Severe hyponatraemia

Not known: Anorexia.

Nervous system disorders

Very Common: Neurologic disorders (G 3-4: 2.7%) including loss of deep tendon reflexes.

Weakness of the lower extremities has been reported after a prolonged

chemotherapy.

Uncommon: Severe paresthesias with sensory and motor symptoms are infrequent.

These effects are generally reversible.

Cardiac disorders

Rare: Ischemic heart disease (angina pectoris, myocardial infarction)

Very rare: Tachycardia, palpitation and heart rhythm disorders.

Vascular disorders

Uncommon: Hypotension, hypertension, flushing and peripheral coldness

Rare:

Severe hypotension, collapse

Respiratory system, thoracic and mediastinal disorders

Uncommon: Dyspnoea and bronchospasm may occur in association with

vinorelbine

treatment as with other vinca alkaloids.

Rare: Interstitial pneumopathy have been reported in particular in patients

treated with

vinorelbine

in combination with mitomycin.

Gastrointestinal disorders

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Very Common: Stomatitis (G1-4: 15% with vinorelbine

as single agent)

Nausea and vomiting (G 1-2: 30.4% and G 3-4: 2.2%). Anti-emetic therapy

may reduce their occurrence.

Constipation is the main symptom (G 3-4: 2.7%) which rarely progresses to

paralytic ileus with vinorelbine as single agent and (G3-4: 4.1%) with the

combination of vinorelbine and other chemotherapeutic agents.

Common:

Diarrhoea usually mild to moderate may occur.

Rare:

Paralytic ileus, treatment may be resumed after recovery of

normal bowel

mobility.

Pancreatitis have been reported.

Hepatobiliary disorders

Very common: Transient elevations of liver function tests (G 1-2) without clinical symptoms

were reported (SGOT in 27.6% and SGPT in 29.3%).

Skin and subcutaneous tissue disorders

Very Common: Alopecia, usually mild in nature, may occur (G3-4: 4.1% with

vinorelbine

single chemotherapeutic agent).

Rare: Generalized cutaneous reactions have been reported with

vinorelbine.

Not known : Erythema on hands and feet.

Musculoskeletal and connective tissue disorders

Common: Arthralgia including jaw pain and myalgia

General disorders and administration site conditions:

Very common: Reactions at the injection site may include erythema, burning pain, vein

discoloration and local phlebitis (G 3-4: 3.7% with vinorelbine as single

chemotherapeutic agent).

Common: Asthenia, fatigue, fever, pain at different locations including chest pain and

pain at the tumour site have been experienced by patients receiving vinorelbine

therapy.

Rare: Local necrosis has been observed. 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 authorization of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form via the following link:

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http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh

.gov.il

4.9.

Overdose

Symptoms

Overdosage with vinorelbine could produce bone marrow hypoplasia sometimes associated

with infection, fever and paralytic ileus.

Emergency procedure

General supportive measures together with blood transfusion, growth factors and broad spectrum

antibiotic therapy should be instituted as deemed necessary by the physician.

Antidote

There is no known antidote for overdosage of vinorelbine.

5.

PHARMACOLOGICAL PROPERTIES

ATC Code: L01C A04 (Vinca alkaloïds and analogues)

5.1.

Pharmacodynamic properties

Vinorelbine is an antineoplastic drug of the vinca alkaloid family but unlike all the other

vinca alkaloids, the catharantine moiety of vinorelbine has been structurally modified. At the

molecular level, it acts on the dynamic equilibrium of tubulin in the microtubular apparatus of

the cell. It inhibits tubulin polymerization and binds preferentially to mitotic microtubules,

affecting axonal microtubules at high concentrations only. The induction of tubulin spiralization

is less than that produced by vincristine.

Vinorelbine

blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.

Safety and efficacy of vinorelbine in pediatric patients have not been established. Clinical

data from two single arm phase II studies using intravenous vinorelbine in 33 and 46 paediatric

patients with recurrent solid tumors, 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 (see section 4.2).

5.2.

Pharmacokinetic properties

Pharmacokinetic parameters of vinorelbine were evaluated in blood.

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Distribution

The steady-state volume of distribution is large, on average 21.2 l.kg

(range: 7.5-39.7 l.kg

which indicates extensive tissue distribution.

Binding to plasma protein is low (13.5%). However, vinorelbine binds strongly to blood cells

and especially to platelets (78%).

There is significant uptake of vinorelbine in the lungs, as assessed by surgical lung biopsies,

which showed concentrations up to 300-fold higher than in serum. Vinorelbine is not found in

the central nervous system.

Biotransformation

All metabolites of vinorelbine are formed by CYP3A4 isoform of cytochromes P450, except 4-O-

deacetylvinorelbine likely to be formed by carboxylesterases.

4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood.

Neither sulfate nor glucuronide conjugates are found.

Elimination

The mean terminal half-life of vinorelbine is around 40 hours. Blood clearance is high,

approaching

hepatic

blood

flow,

0.72

average

(range:

0.32 – 1.26 l.h

Renal elimination is low (< 20% of the intravenous dose administered) and consists mostly in

parent compound. Biliary excretion is the predominant elimination route of both unchanged

vinorelbine, which is the main recovered compound, and its metabolites.

Special patient groups

Renal and liver impairment

The effects of renal dysfunction on vinorelbine disposition have not been studied. However, dose

reduction in case of reduced renal function is not indicated due to the low renal elimination.

A first study has reported the effects of liver impairment on vinorelbine pharmacokinetics. This

study was performed in patients with liver metastases due to breast cancer, and concluded that a

change in mean clearance of vinorelbine was only observed when more than 75% of the liver

is involved. A phase I pharmacokinetic dose-adjusted study was conducted in cancer patients

with liver dysfunction: 6 patients with moderate dysfunction (Bilirubin < 2 x UNL and

Transaminases < 5 x UNL) treated up to 25 mg/m² and 8 patients with severe dysfunction

(Bilirubin > 2 x UNL and/or Transaminases > 5 x UNL) treated up to 20 mg/m². Mean total

clearance in these two subsets of patients was similar to that in patients with normal hepatic

function. Therefore, the pharmacokinetics of vinorelbine is not modified in patients presenting

moderate or severe liver impairment. Nevertheless as a precautionary measure a reduced dose of

20mg/m

and close monitoring of haematological parameters is recommended in patient with