Vinorelbine tartrate Soft Capsules 80mg Taj Pharma

1. Name of the medicinal product
a) Vinorelbine tartrate Soft Capsules 20mg Taj Pharma
b) Vinorelbine tartrate Soft Capsules 30mg Taj Pharma
c) Vinorelbine tartrate Soft Capsules 80mg Taj Pharma

2. Qualitative and quantitative composition
a) Each Soft Capsule Contains:
Vinorelbine tartrate 20mg
Excipients    q.s.

b) Each Soft Capsule Contains:
Vinorelbine tartrate 30mg
Excipients     q.s.

c) Each Soft Capsule Contains:
Vinorelbine tartrate 80mg
Excipients        q.s.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form
Soft capsule.
Pink soft capsule

4. Clinical particulars

4.1 Therapeutic indications
As a single agent or in combination for:

  • The first line treatment of stage 3 or 4 non small cell lung cancer.
  • The treatment of advanced breast cancer stage 3 and 4 relapsing after or refractory to an anthracycline containing regimen.

4.2 Posology and method of administration
In adult patients

As a single agent, the recommended regimen is:

First three administrations
60mg/m² of body surface area, administered once weekly

Subsequent administrations
Beyond the third administration, it is recommended to increase the dose of Vinorelbine to 80mg/m² once weekly except in those patients for whom the neutrophil count dropped once below 500/mm3 or more than once between 500 and 1000/mm3 during the first three administrations at 60mg/m².

Neutrophil count during the first 3 administrations of 60 mg/m2/week Neutrophils

> 1000

Neutrophils

≥ 500 and < 1000

(1 episode)

Neutrophils

≥ 500 and < 1000

(2 episodes)

Neutrophils

< 500

Recommended dose starting with the 4th administration 80 80 60 60

Dose modification
For any administration planned to be given at 80mg/m², if the neutrophil count is below 500/mm3 or more than once between 500 and 1000 / mm3 the administration should be delayed until recovery and the dose reduced from 80 to 60mg/m2 per week during the 3 following administrations.

If the neutrophil count is below 1500 /mm3 and/or the platelet count below 100000/mm3, then the treatment should be delayed until recovery.

Neutrophil count beyond the 4th administration of 80 mg/m2/week Neutrophils

> 1000

Neutrophils

≥ 500 and < 1000

(1 episode)

Neutrophils

≥ 500 and < 1000

(2 episodes)

Neutrophils

< 500

Recommended dose starting with the next administration 80 60

It is possible to re-escalate the dose from 60 to 80 mg/m2 per week if the neutrophil count did not drop below 500/mm3 or more than once between 500 and 1000/mm3 during 3 administrations given at 60 mg/m2 according to the rules previously defined for the first 3 administrations.

For combination regimens, the dose and schedule will be adapted to the treatment protocol.
Based on clinical studies, the oral dose of 80 mg/m2 was demonstrated to correspond to 30 mg/m2 of the iv form and 60 mg/m2 to 25 mg/m2.

This has been the base for combination regimens alternating iv and oral forms improving patient convenience.

Capsules of different strengths (20, 30, 80 mg) are available in order to choose the adequate combination for the right dosage.

The following table gives the dose required for appropriate ranges of body surface area (BSA).

60 mg/m2 80 mg/m2
BSA (m2) Dose (mg) Dose (mg)
0.95 to 1.04

1.05 to 1.14

1.15 to 1.24

1.25 to 1.34

1.35 to 1.44

1.45 to 1.54

1.55 to 1.64

1.65 to 1.74

1.75 to 1.84

1.85 to 1.94

≥ 1.95

60

70

70

80

80

90

100

100

110

110

120

80

90

100

100

110

120

130

140

140

150

160

Even for patients with BSA≥ 2 m2 the total dose should never exceed 120 mg per week at 60 mg /m2 and 160 mg per week at 80 mg/m2.

Administration
Vinorelbine must be given strictly by the oral route.
Vinorelbine must be swallowed whole with water, without chewing, sucking or dissolving the capsule.
It is recommended to administer the capsule with some food.

Administration in the 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 vinorelbine: see section 5.2.

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

Administration in patients with liver insufficiency
Vinorelbine can be administered at the standard dose of 60 mg/m²/week in patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN). In patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT), Vinorelbine should be administered at a dose of 50 mg/m²/week. The administration of Vinorelbine in patients with severe hepatic impairment is contra-indicated: see sections 4.3, 4.4, 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 serious renal insufficiency: see sections 4.4, 5.2.

Specific instructions must be observed for handling Vinorelbine: see section 6.6

4.3 Contraindications
– Known hypersensitivity to vinorelbine or other vinca-alkaloids or to any of the constituents.
– Disease significantly affecting absorption
– Previous significant surgical resection of stomach or small bowel.
– Neutrophil count < 1500/mm3 or severe infection current or recent (within 2 weeks).
– Platelet count < 100000/mm3
– Severe hepatic insufficiency
– Pregnancy: see section 4.6
– Lactation: see section 4.6
– Patients requiring long-term oxygen therapy
– In combination with yellow fever vaccine: see section 4.5

4.4 Special warnings and precautions for use
Special warnings
Vinorelbine should be prescribed by a physician who is experienced in the use of chemotherapy with facilities for monitoring cytotoxic drugs.

If the patient chews or sucks the capsule by error, the liquid is an irritant. Proceed to mouth rinses with water or preferably a normal saline solution.

In the event of the capsule being cut or damaged, the liquid content is an irritant, and so may cause damage if in contact with skin, mucosa or eyes. Damaged capsules should not be swallowed and should be returned to the pharmacy or to the doctor in order to be properly destroyed. If any contact occurs, immediate thorough washing with water or preferably with normal saline solution should be undertaken.

In the case of vomiting within a few hours after drug intake, do not re-administer. Supportive treatment such as metoclopramide or 5HT3 antagonists (e.g. ondansetron, granisetron) may reduce the occurrence of this: see section 4.5. Vinorelbine soft capsule is associated with a higher incidence of nausea/vomiting than the intravenous formulation. Primary prophylaxis with antiemetics and administration of the capsules with some food is recommended as this has also been shown to reduce the incidence of nausea and vomiting: see section 4.2.

Patients receiving concomitant morphine or opioid analgesics: laxatives and careful monitoring of bowel mobility are recommended. Prescription of laxatives may be appropriate in patients with prior history of constipation.

Due to sorbitol content, patients with rare hereditary problems with fructose intolerance should not take the capsules.

Close haematological monitoring must be undertaken during treatment (determination of haemoglobin level and the leucocyte, neutrophil and platelet counts on the day of each new administration).

Dosing should be determined by haematological status:

– If the neutrophil count is below 1500 /mm3 and/or the platelet count is below 100000/mm3, then the treatment should be delayed until recovery.

– For dose escalation from 60 to 80 mg/m2 per week, after the third administration: see section 4.2.

– For the administrations given at 80mg/m², if the neutrophil count is below 500/mmor more than once between 500 and 1000 /mm3, then the treatment should be delayed until recovery. The administration should not only be delayed but also reduced to 60mg/m² per week. It is possible to reescalate the dose from 60 to 80 mg/m2 per week: see section 4.2.

During clinical trials where treatments were initiated at 80 mg/m2, a few patients developed excessive neutropenic complications including those with a poor performance status. Therefore it is recommended that the starting dose should be 60 mg/mescalating to 80 mg/m2 if the dose is tolerated as described in section 4.2.

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: see section 4.8

– poor performance status

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: see section 4.3.

Caution must be exercised when combining Vinorelbine and strong inhibitors or inducers of CYP3A4 (see section 4.5), and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca alkaloids) is not recommended.

Oral Vinorelbine was studied in patients with liver impairment at the following doses:

– 60 mg/m² in 7 patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN);

– 50 mg/m² in 6 patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT).

Total clearance of vinorelbine was neither modified between mild and moderate liver impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function.

Oral Vinorelbine was not studied in patients with severe hepatic impairment therefore its use is contra-indicated in these patients: see sections 4.2, 4.3, 5.2.

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: see sections 4.2, 5.2.

4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use contraindicated
Yellow fever vaccine: as with all cytotoxics, risk of fatal generalised vaccine disease: see section 4.3.

Concomitant use not recommended
Live attenuated vaccines: (for yellow fever vaccine, see concomitant use contraindicated) as with all cytotoxics, risk of generalised vaccine disease, possibly fatal. This risk is increased in patients already immunodepressed by their underlying disease. It is recommended to use an inactivated vaccine when one exists (e.g. poliomyelitis): see section 4.4

Phenytoin: as with all cytotoxics, 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.

Itraconazole: as with all vinca-alkaloids, increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.

Concomitant use to take into consideration
Cisplatin: 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.

Mitomycin C: risk of bronchospasm and dyspnoea are increased, in rare case an interstitial pneumonitis was observed.

Ciclosporin, tacrolimus: excessive immunodepression with risk of lymphoproliferation.

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.

The combination of VINORELBINE with other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.

No clinically significant pharmacokinetic interaction was observed when combining Vinorelbine with several other chemotherapeutic agents (paclitaxel, docetaxel, capecitabine and oral cyclophosphamide).

As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong inhibitors of this isoenzyme (e.g. azole antifungals such as ketoconazole and 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.

Anti-emetic drugs such as 5HT3 antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of Vinorelbine soft capsules (see section 4.4).

Anticoagulant treatment: as with all cytotoxics, the frequency of INR (International Normalised Ratio) monitoring should be increased due to the potential interaction with oral anticoagulants and increased variability of coagulation in patients with cancer.

Food does not modify the pharmacokinetics of vinorelbine.

4.6 Fertility, pregnancy and lactation
Pregnancy
Vinorelbine is suspected to cause serious birth effects when administered during pregnancy: see section 5.3.

Vinorelbine is contra-indicated in pregnancy: see section 4.3.

In case of a vital indication for treatment with Vinorelbine during pregnancy a medical consultation concerning the risk of harmful effects for the child should be conducted. If pregnancy occurs during treatment genetic counseling should be offered.

Women of child-bearing potential
Women of child-bearing potential must use effective contraception during treatment and up to 3 months after treatment: see section 4.3

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 child cannot be excluded therefore breast feeding must be discontinued before starting treatment with Vinorelbine: see section 4.3.

Fertility
Men being treated with Vinorelbine are advised not to father a child during and minimally up to 3 months after treatment: see section 4.3.

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 patients treated with vinorelbine considering some adverse effects of the drug: see section 4.8.

4.8 Undesirable effects
The overall reported frequency of undesirable effects was determined from clinical studies in 316 patients (132 patients with non small cell lung cancer and 184 patients with breast cancer) who received the recommended regimen of Vinorelbine (first three administrations at 60mg/m²/week followed by 80mg/m²/week).

Adverse reactions reported are listed below, by system organ and by frequency.

Additional Adverse reactions from Post Marketing experience has been added according to the MedDRA classification with the frequency Not known.

The reactions were described using the NCI common toxicity criteria

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
Not known Post marketing reports

Undesirable effects reported with Vinorelbine soft capsule:

Pre-marketing experience:
The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, anaemia and thrombocytopenia, gastrointestinal toxicity with nausea, vomiting, diarrhoea, stomatitis and constipation. Fatigue and fever were also reported very commonly.

Post-marketing experience:
Vinorelbine soft capsule is used as single agent or in combination with other chemotherapeutic agents or targeted therapy agents such as cisplatin, capecitabine, carboplatin, epirubicin, trastuzumab, erlotinib, sorafenib.

The most commonly system organ classes involved during post-marketing experience are: ‘Blood and lymphatic system disorders’, ‘Gastrointestinal disorders’, ‘Infections and infestations’ and ‘General disorders and administration site conditions’. This information is consistent with the pre-marketing experience.

Infections and infestations
Very common: Bacterial, viral or fungal infections without neutropenia at different sites: G1-4: 12.7%; G3-4: 4.4%,
Common: Bacterial, viral or fungal infections resulting from bone marrow depression and/or immune system compromise (neutropenic infections) are usually reversible with an appropriate treatment.

Neutropenic infection: G3-4: 3.5%.

Not known: Neutropenic sepsis.
Blood and lymphatic disorders
Very common: Bone marrow depression resulting mainly in neutropenia G1-4: 71.5%; G3: 21.8%; G4: 25.9%, is reversible and is the dose limiting toxicity.

Leucopenia: G1-4: 70.6 %; G3: 24.7 %; G4: 6%.

Anaemia: G1-4: 67.4 %; G3-4: 3.8%.

Thrombocytopenia: G1-2: 10.8%.

Common: G4 Neutropenia associated with fever over 38°C including febrile neutropenia 2.8%.
Metabolism and nutrition disorders
Not known: Severe hyponatraemia.
Psychiatric disorders
Common: Insomnia : G1-2: 2.8%.
Nervous system disorders
Very common: Neurosensory disorders: G1-2: 11.1%, generally limited to loss of tendon reflexes and infrequently severe.
Common: Neuromotor disorders: G1-4: 9.2%; G3-4:1.3%.

Headache: G1-4: 4.1%, G3-4: 0.6%.

Dizziness: G1-4: 6%; G3-4: 0.6%.

Taste disorders: G1-2:3.8%.

Uncommon: Ataxia grade 3: 0.3%.
Eye disorders
Common: Visual disorders: G1-2: 1.3%.
Cardiac disorders
Not known: Myocardial infarction in patients with cardiac medical history or cardiac risk factors.
Vascular disorders
Common: Hypertension: G1-4: 2.5%; G3-4: 0.3%.

Hypotension: G1-4: 2.2%; G3-4: 0.6%.

Respiratory system, thoracic and mediastinal disorders
Common: Dyspnoea: G1-4: 2.8%; G3-4: 0.3%.

Cough: G1-2: 2.8%.

Gastrointestinal disorders
Very Common: Nausea: G1-4: 74.7% ; G3-4: 7.3%;

Vomiting: G1-4: 54.7%; G 3-4: 6.3%, Supportive treatment such as 5HT3 antagonists (ondansetron) may reduce the occurrence of nausea and vomiting: see section 4.4.

Diarrhoea: G1-4: 49.7%; G3-4: 5.7%,

Anorexia: G 1-4: 38.6%; G 3-4: 4.1%,

Stomatitis: G1-4:10.4%; G3-4: 0.9%,

Abdominal pain: G1-4: 14.2%,

Constipation: G1-4: 19%; G3-4: 0.9%, Prescription of laxatives may be appropriate in patients with prior history of constipation and/or who receive concomitant treatment with opioid analgesics: see section 4.4.

Gastric disorders: G1-4: 11.7%.

Common: Oesophagitis: G1-3: 3.8%; G3: 0.3%,

Dysphagia: G1-2: 2.3%.

Uncommon: Paralytic ileus: G3-4: 0.9% [rarely fatal], treatment may be resumed after recovery of normal bowel mobility.
Not known: Gastro-intestinal bleeding.
Hepatobiliary disorders
Common: Hepatic disorders: G1-2: 1.3%.
Skin and subcutaneous tissue disorders
Very common: Alopecia usually mild in nature G1-2: 29.4%, may occur.
Common: Skin reactions: G1-2: 5.7%.
Musculoskeletal and connective tissue disorders
Common: Arthralgia including jaw pain, Myalgia: G1-4: 7 %, G3-4: 0.3%.
Renal and urinary disorders
Common: Dysuria: G1-2: 1.6%.

Other genitourinary disorders: G1-2: 1.9%.

General disorders and administration site conditions
Very common: Fatigue/malaise: G1-4: 36.7%; G3-4: 8.5%.

Fever: G1-4: 13.0%, G3-4: 12.1%.

Common: Pain including pain at the tumour site: G1-4: 3.8%, G3-4: 0.6%.

Chills: G1-2: 3.8%.

Investigations
Very common: Weight loss: G1-4: 25%, G3-4: 0.3%.
Common: Weight gain: G1-2: 1.3%.

Undesirable effects with Vinorelbine, concentrate for infusion:
Some undesirable effects were observed with Vinorelbine, concentrate for solution for infusion during pre- and post-marketing experience which were not reported with Vinorelbine soft capsule.

In order to provide the complete information and to further the safety of use of Vinorelbine soft capsule, these effects are presented below:

Infections and infestations
Uncommon: Septicaemia [very rarely fatal]
Immune system disorders
Not known: Systemic allergic reactions were reported as anaphylaxis, anaphylactic shock or anaphylactoïd type reaction.
Endocrine disorders
Not known: Inappropriate antidiuretic hormone secretion (SIADH).
Vascular disorders
Uncommon: Flushing and peripheral coldness
Rare : Severe hypotension, collapse.
Respiratory system, thoracic and mediastinal disorders
Uncommon: Bronchospasm may occur as with other vinca alkaloids.
Rare: Interstitial pneumonopathy has been reported in particular in patients treated with Vinorelbine in combination with mitomycin.
Gastrointestinal disorders
Rare: Pancreatitis.


4.9 Overdose
Symptoms
Overdosage with Vinorelbine soft capsules could produce bone marrow hypoplasia sometimes associated with infection, fever, paralytic ileus and hepatic disorders.

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. A close monitoring of hepatic function recommended.

Antidote
There is no known antidote for overdosage of Vinorelbine.

5. Pharmacological properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Vinca alkaloïds and analogues

Vinorelbine is a 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 paediatric 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 tumours, including rhabdomyosarcoma, other soft tissue sarcoma, Ewing sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, central nervous system cancer, osteosarcoma, neuroblastoma at doses of 30 to 33.75mg/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.

Absorption
After oral administration, vinorelbine is rapidly absorbed and the Tmax is reached between 1.5 to 3 h with a blood concentration peak (Cmax) of approximately 130 ng/ml after a dose of 80 mg/m².

Absolute bioavailability is approximately 40% and a simultaneous intake of food does not alter the exposure to vinorelbine.

Oral vinorelbine at 60 and 80 mg/m2 leads to blood exposure comparable to that achieved with intravenous vinorelbine at 25 and 30 mg/m2, respectively.

The blood exposure to vinorelbine increases proportionally with the dose up to 100mg/m2. Interindividual variability of the exposure is similar after administration by intravenous and oral routes.

Distribution
The steady-state volume of distribution is large, on average 21.2 l.kg-1(range: 7.5 – 39.7 l.kg-1), which indicates extensive tissue distribution.

Binding to plasma proteins is weak (13.5%), vinorelbine binds strongly to blood cells and especially to platelets (78%).

There is a significant uptake of vinorelbine in lungs, as assessed by pulmonary surgical biopsies which showed concentration up to a 300- fold higher concentration 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, and is 0.72 l.h-1.kg-1 (range: 0.32-1.26 l.h-1.kg-1).

Renal elimination is low (<5 % of the 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 patients groups

Renal and liver impairment:
The effects of renal dysfunction on the pharmacokinetics of vinorelbine have not been studied. However, dose reduction in case of reduced renal function is not indicated with vinorelbine due to the low level of renal elimination.

Pharmacokinetics of orally administered vinorelbine were not modified after administration of 60 mg/m² in 7 patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN) and of 50 mg/m² in 6 patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT). Total clearance of vinorelbine was neither modified between mild and moderate impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function.

No data is available for patients with severe liver impairment therefore Vinorelbine is contra-indicated in these patients: see sections 4.2, 4.3 and 4.4.

Elderly patients
A study with oral vinorelbine in elderly patients (≥ 70 years) with NSCLC demonstrated that pharmacokinetics of vinorelbine were not influenced by age. However, since elderly patients are frail, caution should be exercised when increasing the dose of Vinorelbine soft capsule: see section 4.2.

Pharmacokinetics/Pharmacodynamic relationships
A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.

5.3 Preclinical safety data
Pre-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

Vinorelbine induced chromosome changes but was not mutagenic in Ames test. It is assumed that vinorelbine can cause mutagenic effects (induction of aneuploidy of polyploidy) in man.

In animal reproductive studies, vinorelbine was embryo-feto-lethal and teratogenic.

No haemodynamic effects were found in dogs receiving vinorelbine at maximal tolerated dose; only some minor, non significant disturbances of repolarisation were observed as with other vinca alkaloids tested.

No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine over 39 weeks.

6. Pharmaceutical particulars

6.1 List of excipients
Fill solution:
Ethanol, anhydrous
Water, purified
Glycerol
Macrogol

Shell capsule:
Gelatin
Glycerol 85%
Sorbitol/Sorbitan Anidrisorb
Red iron oxide
Titanium dioxide
Triglycerides, medium chain
Phosal 53 MCT (Phosphatidylcholine; Glycerides; Ethanol, anhydrous)

Edible printing ink:
Cochineal extract
Hypromellose
Propylene glycol

6.2 Incompatibilities
Not applicable

6.3 Shelf life
3 years.

6.4 Special precautions for storage
Store at 2°C – 8°C (in a refrigerator). Store in the original container.

6.5 Nature and contents of container
Peel-push PVC/PVDC/ aluminium blister.
Pack size: 1 capsule

6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.

Instructions for use/handling

To open the packaging:

1.Cut the blister along the black dotted line
2. Peel the soft plastic foil off
3. Push the capsule through the aluminium foil.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Vinorelbine tartrate Soft Capsules 80mg Taj Pharma

Package leaflet: Information for the patient

a) Vinorelbine tartrate Soft Capsules 20mg Taj Pharma
b) Vinorelbine tartrate Soft Capsules 30mg Taj Pharma
c) Vinorelbine tartrate Soft Capsules 80mg Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

What is in this leaflet

1. What  Vinorelbine soft capsules is and what it is used for
2. Before you are given Vinorelbine soft capsules
3. How you will be given Vinorelbine soft capsules
4. Possible side effects
5. How Vinorelbine soft capsules is stored
6. Further Information

1. What Vinorelbine soft capsules is and what it is used for
Vinorelbine belongs to a family of medicines used to treat cancer called the vinca-alkaloid family.
Vinorelbine is used to treat:

  • Non-small cell lung cancer
  • Advanced breast cancer that has not responded to other medicines.

It is not recommended for use by children under 18 years old.

2. Before you are given Vinorelbine soft capsules
Do not take Vinorelbine soft capsule

  • If you are allergic (hypersensitive) to the active ingredient, vinorelbine, or any of the related family of cancer drugs called the vinca alkaloids.
  • If you are allergic to any of the other ingredients in Vinorelbine capsules (refer to section 6 of this leaflet).
  • If you are pregnant or think that you might be pregnant.
  • If you are breast feeding.
  • If you have a severe liver disease.
  • If you have had an operation on your stomach or small bowel, or if you have gut disorder which affects how you absorb food. These may affect how your body absorbs Vinorelbine.
  • If you have a low white blood cell count (neutrophils, leucocytes) or a severe infection current or recent within two weeks.
  • If you have a low blood platelet cell count (thrombocytopenia).
  • If you plan to have a yellow fever vaccination or have just had one.
  • If you require long-term oxygen therapy

If in doubt, ask your doctor or pharmacist.

Take special care with Vinorelbine soft capsule
Please inform your doctor if:

  • You have a history of heart attack or severe chest pain.
  • Your ability to carry out activities of daily living is strongly reduced.
  • You have problems with your liver or you have received radiotherapy where the treatment field included the liver.
  • If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
  • You have symptoms of infection (such as fever, chills, joint pain, cough).
  • You take, or have recently taken, any other medicines including medicines obtained without a prescription.
  • You plan to have a vaccination or have just had one

Before and during your treatment with Vinorelbine blood cell counts are performed to check that it is safe for you to receive treatment. If the results of this analysis are not satisfactory, your treatment may be delayed and further checks made until these values return to normal.

Taking other medicines
Please inform your doctor or pharmacist if you are taking, or have recently taken, any other medicines, including medicines obtained without a prescription.

If you are given Vinorelbine as well as medicines that affect your bone marrow it may make some of the side effects worse.

Your doctor should take special attention if you are taking the following medicines:

  • medicines used to thin your blood (anticoagulants),
  • an anti-epileptic medicine called phenytoin,
  • antifungal medicines such as itraconazole and ketoconazole,
  • an anti-cancer medicine called mitomycin C,
  • medicines that impair your immune system such as ciclosporin and tacrolimus

Many vaccines (live attenuated vaccines) are not recommended during treatment. Please inform your doctor if you require any vaccinations.

Taking Vinorelbine soft capsule with food and drink
The soft capsule of Vinorelbine should be swallowed whole with water without chewing or sucking the capsule.

It is preferable to take Vinorelbine with a light meal.

Vinorelbine should not be taken with a hot drink as it will dissolve the capsule too quickly.

Male fertility
Men being treated with Vinorelbine are advised not to father a child during and up to 3 months after the last capsule. You should discuss sperm banking with your doctor before starting treatment with Vinorelbine.

Women of child bearing age
Women of child-bearing age must use effective contraception (birth control) during treatment and up to 3 months after treatment.

Pregnancy
Do not take Vinorelbine if you are pregnant, or think that you might be pregnant. If you have to start treatment with Vinorelbine and you are pregnant, or if pregnancy occurs during your treatment with Vinorelbine, do not stop taking Vinorelbine. Immediately ask your doctor about the potential risks for the unborn child.

Breast-feeding
Do not take Vinorelbine if you are breast feeding.
Breast feeding must be discontinued if treatment with Vinorelbine is necessary.
Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
It is unlikely that Vinorelbine will affect your ability to drive or operate machinery.

However, some of the possible side effects of Vinorelbine could affect your ability to drive or perform skilled tasks: see section 4; Possible side effects below for details. Therefore, it is recommended that you should not drive if you feel unwell or if your doctor has advised you not to drive.

Important information about some of the ingredients
This medicine contains sorbitol. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

This medicinal product contains small amounts of ethanol (alcohol), less than 100mg per dose, you will not be affected by this small quantity.

3. How you will be given Vinorelbine soft capsules
Vinorelbine should be given under the supervision of a qualified doctor who is experienced in the use of cancer treatments.

Vinorelbine must be taken by mouth.

Vinorelbine is used in patients over 18 years old.

It is not recommended for use by children under 18 years old.

Always take Vinorelbine exactly as your doctor has told you.

You should check with your doctor or pharmacist if you are not sure

Dosage

Before and during your treatment with Vinorelbine your doctor will check your blood cell count to determine when you receive your treatment and which dose is suitable for you. Your doctor will tell you the number and strength of capsules which you should take. This will depend on your body weight and body height.

Your doctor will calculate your body surface area in square meters (m2). The usual weekly dose, taken in a single dose, is 60 mg/m2 of body surface area for the first 3 doses. After the third dose, your doctor will decide if the dose will be increased to 80mg/m2 of body surface area. In any case, your doctor may adjust the dose of Vinorelbine.

If you are receiving the capsules with another medicine to treat your cancer/condition, your doctor will decide on an appropriate dose for you.

The total dose should never exceed 160 mg per week.

You should never take Vinorelbine more than once a week

Frequency of administration

Normally Vinorelbine treatment is scheduled once a week. The frequency will be determined by your doctor.

Duration of treatment

The duration of your treatment is decided by your doctor.

If you take an anti-sickness medicine

Vomiting can occur with Vinorelbine: see section 4. Possible side effects. If your doctor has prescribed an anti-sickness medication, always take it exactly as the doctor has told you.

Take Vinorelbine during a light meal; this will help to reduce the feeling of sickness.

Method of administration

Before opening the blisters containing Vinorelbine, make sure that there are no damaged capsules because the liquid inside is an irritant and may be harmful if it comes into contact with your skin, eyes or mucosa. If it happens, wash the affected area immediately and thoroughly with water.

Do not swallow any damaged capsules; return them to your doctor or pharmacist.
Opening the “peel-push” blister:

1. Cut the blister along the black dotted line with a pair of scissors.
2. Peel the soft plastic foil off.
3. Push the capsule through the aluminium foil.

Taking Vinorelbine soft capsule:

  • Swallow Vinorelbine whole with water, preferably with a light meal. It should not be taken with a hot drink as it will dissolve the capsule too quickly.
  • Do notchew or suck the capsules.
  • If you chew or suck a capsule by mistake, rinse your mouth thoroughly with water and tell your doctor immediately.
  • If you vomit within a few hours after taking your Vinorelbine, contact your doctor; do not repeat the dose.

If you take more Vinorelbine soft capsule than you should:

If you may have taken more Vinorelbine than the prescribed dose, contact a doctor immediately.

Your dose of Vinorelbine is carefully monitored and checked by your doctor and pharmacist. However, although you will have received the correct amount of chemotherapy your body may sometimes react giving severe symptoms.

Some of these symptoms may develop as signs of an infection (such as fever, chills, cough, joint pain). You may also become severely constipated. You must immediately contact your doctor if any of these severe symptoms occur.

If you forget to take Vinorelbine soft capsule:

Do not take a double dose to make up a forgotten dose. Contact your doctor who will take the decision about rescheduling your dose.

If you stop using Vinorelbine soft capsule

Your doctor will decide when you should stop your treatment. However, if you want to stop your treatment earlier, you should discuss other options with your doctor.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. Possible Side Effects
Like all medicines, Vinorelbine can have side effects although not everybody gets them.

While taking Vinorelbine, if you develop any of the following symptoms you should contact your doctor immediately:

  • signs of a major infection such as cough, fever and chills
  • severe constipation with abdominal pain when your bowels have not been open for several days,
  • severe dizziness, light-headedness when you stand up
  • severe chest pain which is not normal for you
  • signs of allergy such as itching, shortness of breath

Very common side effects

(can occur in more than 1 in 10 patients treated)

What should you do?

  • Feeling sick (nausea)
  • Vomiting

Immediately contact your doctor if this becomes uncontrollable. These side effects may be controlled with standard therapy.

Do not repeat the dose if you vomit within a few hours after taking your Vinorelbine.

  • A fall in some white blood cells which makes you more vulnerable to infection. This can commonly cause bacterial, viral or fungal infections in your body (respiratory, urinary, gastro-intestinal systems and possibly others)

Immediately contact your doctor, especially if your temperature reaches 38°C or higher.

  • A fall in red blood cells (anaemia) which can make the skin pale and cause weakness or breathlessness
  • A fall in blood platelets (thrombocytopenia) which can increase the risk of bleeding or bruising
  • Loss of some reflex reactions, occasionally difference in the perception of touch

Immediately contact your doctor for treatment, should these symptoms become severe.

  • Inflammation or sores in the mouth or throat (stomatitis)
  • Diarrhoea
  • If you have abdominal pain or if you do not have a bowel movement for several days
  • Gastric disorders

Immediately contact your doctor.

  • Hair loss (alopecia),
  • Tiredness (fatigue)
  • Malaise
  • Fever
  • Weight loss
  • Loss of appetite (anorexia)

Ask your doctor for advice if the symptoms persist.
These are possible symptoms when receiving chemotherapy.

Common side effects
(can occur in less than 1 in 10 patients treated)

What should you do?

  • Difficulty in sleeping
  • Headache
  • Dizziness
  • A difference in your taste of the flavours
  • Inflammation of the throat and gullet (oesophagitis)
  • Difficulty when swallowing food or liquids
  • Skin reactions
  • Joint pain (arthralgia)
  • Jaw pain
  • Muscle pain (myalgia)
  • Pain at different sites in your body and pain where your tumour is
  • Chills
  • Weight gain

Ask your doctor for advice if the symptoms persist.

  • Neuromotor disorders
  • Differences in your eyesight
  • High blood pressure with symptoms such as a headache
  • Low blood pressure with symptoms such as dizziness or feeling faint
  • Shortness of breath
  • Cough
  • Abnormal liver test
  • Pain, burning and difficulty in passing urine

Immediately contact your doctor for treatment, should any of these symptoms become severe.

Uncommon side effects

(can occur in more than 1 in 100 patients treated)

What should you do?

Effects on your nervous system:

  • Balance disorders (ataxia)

Effects on your gastrointestinal system:

Severe constipation with abdominal pain when your bowels have not been open for several days (paralytic ileus)

Immediately contact your doctor

The list below specifies side effects also reported with Vinorelbine soft capsule, with frequency not known:

Side effects with frequency not known

What should you do?

Effects on your blood:

  • Low blood sodium (severe hyponatraemia) which can cause symptoms of tiredness, confusion, muscle twitching and coma.
    Generalised infection (sepsis) due to severe fall of white blood cells

Effects on your gastrointestinal system:

  • Gastrointestinal bleeding

Effects on your heart and blood vessels:

  • Heart attack (myocardial infarction in patients with cardiac medical history or cardiac risk factors)

Effects on your breathing:

  • Severe difficulties in breathing

Immediately contact your doctor

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

5. How Vinorelbine soft capsules is stored
Keep out of the reach and sight of children

Do not use Vinorelbine after the expiry date which is stated on the blister and box (after Exp). The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect from light.

Medicines should not be disposed of via wastewater or household waste. For safety reasons any unused capsules must be returned to your doctor or pharmacist for destruction. These measures will help to protect the environment.

6. Further information

What Vinorelbine soft capsules contains
The active substance is: Vinorelbine (as tartrate) 20, 30 or 80 mg.
a) Each Soft Capsule Contains: Vinorelbine tartrate 20mg
b) Each Soft Capsule Contains: Vinorelbine tartrate 30mg
c) Each Soft Capsule Contains: Vinorelbine tartrate 80mg
The other ingredients are:

  • The solution contains: ethanol anhydrous; purified water; glycerol; macrogol 400
  • The capsule shell contains: gelatin; glycerol 85 %; sorbitol/sorbitan (anidrisorb 85/70); triglycerides, medium chain and PHOSAL 53 MCT (phosphatidylcholine; glycerides; ethanol anhydrous) and colouring agents (E171-titanium dioxide and E172 red and/or yellow iron oxide depending on the strength).
  • The edible printing ink contains: cochineal extract (E120), hypromellose, propylene glycol.

 What Vinorelbine soft capsules looks like and contents of the pack
Vinorelbine 20mg soft capsules are light brown coloured.

Vinorelbine 30mg soft capsules are pink coloured.

Vinorelbine 80mg soft capsules are pale yellow coloured.

Soft capsules of 20, 30 and 80 mg are available as packs of 1 blister of 1 soft capsule.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

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Taj Generics (Taj Pharma) provides a wide range of products to the Indian market, including an extensive range of generics and specialty products; Our products cover a vast array of therapeutic categories, and we offer an extensive range of dosage forms and delivery systems including oral solids, controlled-release, steriles, injectables, topicals, liquids, transdermals, semi-solids and high-potency products. Our Generics portfolio offers over 1500 products in the major therapeutic areas of gastro-intestinal, cardiovascular, pain management, oncology, anti-infectives, paediatrics and dermatology.