Vinorelbine Ditartrate injection 10mg/ml Anticancer medicine
Each vial contains vinorelbine tartrate equivalent to 10.0 mg vinorelbine.
Vinorelbine is a semi-synthetic vinca alkaloid, derived from
vinblastine. Vinca alkaloids appear to exert its antitumor activity
by binding to tubulin with high affinity, blocking the ability of
the protein to polymerise into microtubules. The antitumor activity
of vinorelbine is primarily due to inhibition of mitosis at
metaphase through its interaction with tubulin, where it inhibits
the polymerisation of tubulin.
Vinorelbine may also interfere with amino acid, cyclic AMP, and
glutathione metabolism; cellular respiration; calmodulin-dependent
Ca2+ transport ATPase activity and nucleic acid and lipid biosynthesis.
Vinorelbine exhibits triphasic pharmacokinetics after intravenous
administration. It has a terminal half-life of between 28 and 44
hours and is metabolised in the liver. Vinorelbine and its
metabolites are excreted primarily in faeces via the bile but also
The initial rapid decline in plasma concentration represents
distribution of vinorelbine in peripheral compartments and its
Mean plasma clearances ranges from 0.97 to 1.26 L/hr/kg and steady
state volume distribution (Vss) values ranges from 25.4 to 40.1 L/kg.
The disposition of radiolabelled vinorelbine has been studied in a
limited number of patients.
Approximately 18% of the administered dose was recovered in the
urine and 46% in the faeces.
A study on the urinary excretion of vinorelbine indicated that
10.9% + 0.7% of a 30 mg/m2 intravenous dose was excreted unchanged in the urine.
Deacetylvinorelbine, a metabolite of vinorelbine, has been shown to
possess antitumor activity. This metabolite has not been quantified
in human plasma. The effects of renal of hepatic impairment on the
disposition of vinorelbine have not been assessed.
The concurrent administration of cisplatin with vinorelbine does
not influence the pharmacokinetics of vinorelbine.
Vinorelbine is indicated in the palliative treatment of advanced
inoperable Non-Small Cell Lung Cancer (NSCLC) as a single agent or
in combination. Combination therapy proves to be more effective
Vinorelbine is also indicated for the treatment of patients with
metastatic breast cancer who have failed anthracycline first-line
monotherapy for metastatic disease, or who have relapsed within 6
months of anthracycline-based adjuvant therapy.
VINORELBINE IS FOR INTRAVENOUS USE ONLY.
Vinorelbine(vinorelbine tartrate) is a cytotoxic drug and should be
administered only by physicians experienced with cancer
chemotherapeutic drugs. Blood counts should be taken prior to each
dose. The dosage should be discontinued or reduced on evidence of
abnormal depression of the bone marrow (see table).
Vinorelbine is a moderate vesicant and can cause phlebitis or
extravasation injury. The possibility of phlebitis may be increased
by inadequate flushing of the vein after peripheral administration.
It is extremely important that the needle be properly positioned in
the vein before Vinorelbineis injected. If leakage into surrounding
tissue occurs during intravenous administration of Vinorelbine, it
may cause severe irritation. The injection should be discontinued
immediately and any of the remaining portion of the dose should
then be introduced into another vein.
A low incidence of death (1%) due to neutropenic sepsis has been
reported (see SIDE EFFECTS AND SPECIAL PRECAUTIONS). Bone marrow
toxicity, specifically granulocytopenia, is dose-limiting. Complete
blood counts with differentials should be performed and results
reviewed prior to each dose of Vinorelbine. VINOREL should not be
administered to patients with granulocyte counts <1 000 cells/mm3. Patients developing severe granulocytopenia should be monitored
carefully for evidence of infection and/or fever (see DOSAGE AND
DIRECTIONS FOR USE –Administration precautions).
|Granulocytes cells/mm3(cubic millimetres) on days of treatment||Dose of Vinorelbine(mg/m2)|
|+ 1 500||30|
|1 000 to 1 499||15|
|<1 000||Do not administer. Repeat granulocyte count in one week. If
granulocyte count is <1 000 cells/mm3 for three weeks discontinue Vinorelbine.|
Vinorelbine should be administered with caution to patients with
hepatic insufficiency. The dose should be adjusted in patients who
develop hyperbilirubinaemia during treatment with Vinorelbine.
Concurrent use of Vinorelbine with other bone marrow depressants
may increase the bone marrow depressant effect of Vinorelbine and
Acute pulmonary reaction has been reported with Vinorelbine use in
conjunction with mitomycin.
Cautious administration of Vinorelbine is advised.
Concomitant or sequential use of paclitaxel and Vinorelbine may
result in neuropathy and routine monitoring for neuropathy symptoms
Due to the suppression of normal defence mechanisms by Vinorelbine,
concurrent use of Vinorelbine with live virus vaccine may
potentiate the replication of the vaccine virus, may increase the
side effects of the vaccine virus, and/or may decrease the
patient’s antibody response to the vaccine. Immunisation of these
patients should be undertaken only with extreme caution after
careful review of the patient’s haematological status and only with
the knowledge and consent of the physician managing the Vinorelbine
DOSAGE AND DIRECTIONS FOR USE
In single-agent therapy, the usual dose is 25 to 30 mg/m2 administered weekly. The dosage schedule for metastatic disease is
30 mg/m2 per week. In polychemotherapy, the dose and the frequency depend
on the protocol.
Patients receiving Vinorelbine should be under the supervision of a
physician experienced in cancer chemotherapy. Patients and/or
family members should be instructed to report any side effects.
Vinorelbine must be administered intravenously. Intrathecal
administration of other vinca alkaloids has resulted in death. It
is extremely important that the intravenous needle or catheter be
properly positioned before any Vinorelbine is injected. Leakage
into surrounding tissue during intravenous administration of
Vinorelbine may cause considerable irritation, local tissue
necrosis and/or thrombophlebitis (see WARNINGS).
If extravasation occurs, the injection should be discontinued
immediately and any remaining portion of the dose should then be
introduced into another vein. Local injection of hyaluronidase and
the application of moderate heat to the area of leakage have been
reported to help disperse drug and minimise discomfort associated
with the extravasation of other vinca alkaloids.
Although venous irritation is a problem associated with
peripherally administered vinorelbine, there is no need of central
line placement. Incidence of this problem can be reduced with a
shorter duration of administration. Vinorelbine should be diluted
in either a syringe or intravenous bag and administered by
intravenous injection, over a period of 6 to 10 minutes. However,
if a central line is to be considered, the following can be used as
|•||If the patient has poor venous access, early placement of the
central line should be considered.|
|•||If a patient has reasonable venous access, treatment should be
started with peripheral administration. Placement of a central line
should be considered only if difficulty in venous access is
|•||After Vinorelbine has been infused, flushing of the vein should be
continued with at least 100 mL of normal saline or 5% dextrose in
water to prevent injection site reactions. The catheter should not
be removed without flushing the vein.|
As with other toxic compounds, caution should be exercised in
handling and preparing the solution of Vinorelbine . Skin reactions
may occur with accidental exposure. The use of gloves is
recommended. If the solution of Vinorelbine contacts the skin or
mucosa, immediately wash the skin or mucosa thoroughly with soap
and water. Severe irritation of the eye has been reported with
accidental contamination of the eye with other vinca alkaloids. If
this happens with Vinorelbine , the eye should be washed with water
immediately and thoroughly.
Preparation for the intravenous administration
Vinorelbine injection must be diluted in either a syringe or IV bag
using one of the recommended solutions. The diluted Vinorelbine
should be administered over 6 to 10 minutes into the side port of a
free-flowing IV followed by flushing with at least 75 to 125 mL of
one of the solutions. For diluents that may be used see “Parenteral
Syringe: The calculated dose of Vinorelbine should be diluted to a
concentration between 1.5 and 3.0 mg/mL. Vinorelbine diluted to a
concentration between 1.5 and 3.0 mg/mL may be used for up to 24
hours when stored in polypropylene syringes between 5 and 30ºC. The
following solutions may be used for dilution:
|•||0.9% Sodium Chloride Injection, USP.|
|•||Preferably 5% Dextrose Injection, USP.|
IV Bag: The calculated dose of Vinorelbine should be diluted to a
concentration between 0.5 and 2 mg/mL. Vinorelbine diluted to a
concentration of 0.5 to 2 mg/mL may be stored for a period of up to
24 hours after preparation if stored in polyvinyl chloride bags
between 5 and 30ºC. The following solutions may be used for
|•||0.9% Sodium Chloride Injection, USP; preferably 0.45% Sodium
Chloride Injection, USP.|
|•||5% Dextrose Injection, USP.|
|•||5% Dextrose and 0.45% Sodium Chloride Injection, USP.|
|•||Ringer's Injection, USP.|
|•||Lactated Ringer's Injection, USP.|
|•||Potassium Chloride Injection solutions are found to be compatible
Intravenous mixtures should be inspected visually for clarity,
particulate matter, discolouration and leakage prior to
administration, whenever solution and container permit. Any unused
portion should be discarded.
Vinorelbine is contraindicated in:
|•||Patients who are hypersensitive (allergic) to vinorelbine.|
|•||Patients with severe hepatic insufficiency.|
|•||Pregnancy and lactation.|
|•||Patients who have drug-induced severe granulocytopenia or severe
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Blood and lymphatic system disorders
Frequent: Anaemia; granulocytopenia or leucopoenia.
Less frequent: Thrombocytopenia.
Nervous system disorders
Less frequent: Peripheral neuropathy (including paraesthesia and hypoaesthesia).
General disorders and administration site conditions
Frequent: Injection site reactions (redness, increased warmth, pain or
discolouration of vein at place of injection).
Less frequent: Stomatitis (sores in mouth and on lips); jaw pain.
Less frequent: Chest pain.
Less frequent: Bronchopulmonary toxicity. Vinorelbineis likely to cause
dyspnoeic states and bronchospasm. The reactions begin minutes
following the injection, but they may appear some hours later.
Renal and urinary disorders
Less frequent: Haemorrhagic cystitis.
Less frequent: Pancreatitis.
Metabolic and nutritional disorders
Frequent: Constipation; nausea and vomiting.
Less frequent: Diarrhoea.
Less frequent: Joint or muscle pain.
Less frequent: Skin rash.
Store Vinorelbinebetween 2 and 8ºC in the original package to
protect from light. Do not freeze. Discard unused portion.
Syringe: Vinorelbinediluted to a concentration between 1.5 and 3.0 mg/mL
may be used for up to 24 hours when stored in polypropylene
syringes between 5 and 30ºC.
IV Bags: Vinorelbinediluted to a concentration of 0.5 to 2.0 mg/mL may be
stored for a period of up to 24 hours after preparation if stored
in polyvinyl chloride bags between 5 and 30ºC.
VinorelbineInjection is initially clear and colourless to pale
yellow, but may develop a slightly darker yellow to light amber
colour in time. This does not indicate a change which should
preclude its use. Parenteral drug products should be visually
inspected for particulate matter and discolouration prior to
administration whenever solution and container permit. If
particulate matter is seen, Vinorelbineshould not be administered.