INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo VINOREL 10 (Injection)
VINOREL 50 (Injection)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form)

VINOREL 10 (Injection)
VINOREL 50 (Injection)

COMPOSITION
VINOREL 10: Each vial contains vinorelbine tartrate equivalent to 10.0 mg
vinorelbine.
VINOREL 50: Each vial contains vinorelbine tartrate equivalent to 50.0 mg vinorelbine.

PHARMACOLOGICAL CLASSIFICATION
A.26 Cytostatic agents

PHARMACOLOGICAL ACTION
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.
Pharmacokinetics
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 in urine.
The initial rapid decline in plasma concentration represents distribution of vinorelbine in peripheral compartments and its metabolism.
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.

INDICATIONS
VINOREL 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 than monotherapy.
VINOREL 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.

CONTRAINDICATIONS
VINOREL 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 thrombocytopenia.

WARNINGS
VINOREL IS FOR INTRAVENOUS USE ONLY.
VINOREL (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).
VINOREL 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 VINOREL is injected. If leakage into surrounding tissue occurs during intravenous administration of VINOREL, 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 VINOREL. 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 VINOREL (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 VINOREL.
VINOREL should be administered with caution to patients with hepatic insufficiency. The dose should be adjusted in patients who develop hyperbilirubinaemia during treatment with VINOREL.

INTERACTIONS
Concurrent use of VINOREL with other bone marrow depressants may increase the bone marrow depressant effect of VINOREL and radio therapy.
Acute pulmonary reaction has been reported with VINOREL use in conjunction with mitomycin.
Cautious administration of VINOREL is advised.
Concomitant or sequential use of paclitaxel and VINOREL may result in neuropathy and routine monitoring for neuropathy symptoms is recommended.
Due to the suppression of normal defence mechanisms by VINOREL, concurrent use of VINOREL 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 VINOREL therapy.

PREGNANCY AND LACTATION
VINOREL is contraindicated in pregnancy and lactating women (see CONTRAINDICATIONS).

DOSAGE AND DIRECTIONS FOR USE
Dosage
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.
Administration precautions
Patients receiving VINOREL 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.
VINOREL 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 VINOREL is injected. Leakage into surrounding tissue during intravenous administration of VINOREL 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. VINOREL 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 a guide:
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 encountered.
After VINOREL 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 VINOREL. Skin reactions may occur with accidental exposure. The use of gloves is recommended. If the solution of VINOREL 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 VINOREL, the eye should be washed with water immediately and thoroughly.
Preparation for the intravenous administration
VINOREL injection must be diluted in either a syringe or IV bag using one of the recommended solutions. The diluted VINOREL 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 products” below.
Parenteral products
Syringe:
The calculated dose of VINOREL should be diluted to a concentration between 1.5 and 3.0 mg/mL. VINOREL 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 VINOREL should be diluted to a concentration between 0.5 and 2 mg/mL. VINOREL 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 dilution:
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 with VINOREL.
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.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Blood and lymphatic system disorders
Frequent: Anaemia; granulocytopenia or leucopoenia.
Less frequent: Thrombocytopenia.
Nervous system disorders
Frequent: Asthenia.
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.
Cardiac disorders
Less frequent: Chest pain.
Respiratory disorders
Less frequent: Bronchopulmonary toxicity. VINOREL is 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.
Endocrine disorders
Less frequent: Pancreatitis.
Metabolic and nutritional disorders
Frequent: Anorexia.
Gastro-intestinal disorders
Frequent: Constipation; nausea and vomiting.
Less frequent: Diarrhoea.
Musculoskeletal disorders
Less frequent: Joint or muscle pain.
Skin disorders
Frequent: Alopecia.
Less frequent: Skin rash.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In case of overdose, the patient must be closely monitored for the appearance of severe granulocytopenia with an increased risk of serious secondary infections. There is no known antidote for the treatment of VINOREL overdosage. Therefore, treatment of overdose is supportive and may include appropriate blood transfusions and antibiotics.

IDENTIFICATION
Clear, transparent, colourless solution, essentially free from particulate matter.

PRESENTATION
VINOREL 10 is packed in transparent glass type I vials of 3.4 mL with a 13 mm bromobutyl stopper and yellow aluminium safety flip-off cap. VINOREL 50 is packed in transparent glass type I vials of 5 mL with a 13 mm bromobutyl stopper and yellow aluminium safety flip-off cap.

STORAGE INSTRUCTIONS
Store VINOREL between 2 and 8ºC in the original package to protect from light. Do not freeze. Discard unused portion.
Syringe: VINOREL 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.
IV Bags: VINOREL diluted 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.
VINOREL Injection 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, VINOREL should not be administered.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
VINOREL 10: 41/26/0834
VINOREL 50: 42/26/0005

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Pharmaplan (Pty) Ltd
106 16th Road
Midrand

DATE OF PUBLICATION OF THE PACKAGE INSERT
4 December 2008

Version: Jan 2009

Updated on this site: May 2014
Source: Pharmaceutical Industry

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