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PACKAGE LEAFLET: INFORMATION FOR THE USER-

Velbe Injection 10mg *

(Vinblastine Sulphate)

Read all of this leaflet carefully before you start taking this medicine.

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. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

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

In this leaflet:

1.    What Velbe is and what it is used for

2.    Before you use Velbe

3.    How to use Velbe 1. WHAT VELBE IS AND WHAT IT IS USED FOR

Velbe contains vinblastine sulphate. Velbe is a cytotoxic drug. Cytotoxic drugs kill cells which are dividing, including cancer cells. It is used to treat patients who have a cancer such as Hodgkin’s Disease or a lymphoma, or a cancer of the breast, placenta, kidney, testicle or blood. If your doctor gives you this medicine for anything lse, ask him or her if you have any questions.

^____________________________________________________________________________________

2. BEFORE YOU USE VELBE-

Do not use Velbe if you are:

•    allergic (hypersensitive) to vinblastine sulphate or any of the other ingredients in Velbe (see section 6 - Further information for details)

•    taking antibiotics, or you think you have an infection.

Take special care with Velbe if you:

are having radiotherapy in the liver area

suffer from constipation have suffered from a peptic ulcer

Using other medicines

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

Take care if you are taking any of the following medicines:

•    phenytoin for treating epilepsy

•    cytotoxic drugs called mitomycin, cisplatin or carboplatin. Pregnancy and breast-feeding

If you are pregnant, planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before taking any medicine.

3. HOW TO USE VELBE

Your doctor will only inject Velbe into a vein. It must never be injected intrathecally (into your back with the needle going into your spine). If you have a bacterial infection, your doctor will probably treat the infection, before starting treatment with Velbe.

Velbe and most other cytotoxic drugs may affect the cells in your bone marrow. These cells divide quickly to make new blood cells Your doctor or nurse will take samples of your blood when you are treated with Velbe. The hospital’s laboratory will then count the numbers of different types of blood cells (platelets, white cells and rec cells). Your doctor may decide to change the dose or put off treating you if your blood cell counts are too low. Your blood cell counts soon improve as the bone marrow makes new cells.

A lot of injections (more than one a week) may cause more side-effects.

Velbe works by sticking to certain molecules in dividing cells to stop the cells dividing. It also sticks to the same sort of molecule in nerves and causes side-effects to your nervous system (please see section 4 - Possible side-effects.) You may not notice the start of these side-effects until you have had several injections. Your doctor may also decide to change the dose or put off treating you if these side-effects are severe. The effects on your nervous system usually get better when you stop being treated with Velbe.

Your doctor or nurse will take great care that the Velbe solution does not leak out of your vein when it is being injected. Please tell them immediately if you have pain or swelling during the injection or later. If this is not treated quickly, Velbe can cause your tissue to be inflamed where the solution leaked out. They will also be very careful that Velbe does not get into anyone’s eyes.

Information for the Health Care Professional SUMMARY OF PRODUCT CHARACTERISTICS

VELBE⁴

WARNING

FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY.

1    Name of the Medicinal Product Velbe injection 10 mg.

2    Qualitative and Quantitative Composition Vinblastine Sulphate Ph. Eur. 10 mg as the base.

3    Pharmaceutical Form Powder for solution for intravenous injection.

4    Clinical Particulars

4.1    Therapeutic Indications Velbe is an anti-neoplastic drug for intravenous use. Information available at present suggests that Velbe may be useful, either alone or in combination with other oncolytic drugs for the treatment of: Hodgkin’s disease; non-Hodgkin’s lymphoma; carcinoma of the breast; methotrexate-resistant choriocarcinoma; renal cell carcinoma; testicular teratoma and seminoma; histiocytosis X. Other neoplasms occasionally show a marked response to Velbe, but less frequently than the more susceptible conditions listed above.

4.2    Posology and method of administration This preparation is for intravenous use only. It should be administered only by individuals experienced in vinblastine administration.

FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY.

In case of mistaken administration by the intrathecal route, see section 4.4.

The recommended dose for adults, the elderly and children is 6 mg/m² usually administered no more frequently than once every seven days. For testicular tumours, the dosage may be increased to 0.2 mg/kg administered on each of two consecutive days every three weeks. As vinblastine is excreted principally by the liver, toxicity may be increased when there is hepatic insufficiency and it may be necessary to reduce initial doses in the presence of significantly impaired hepatic or biliary function. A reduction of 50% in the dose is recommended for patients having a direct serum bilirubin value above 3 mg/100 ml. Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.

The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes. (See ‘Interaction with other medicinal products and other forms of interaction’).

To prepare a solution containing 1 mg/ml, add 10 ml of sterile 0.9% sodium chloride intravenous infusion to the 10 mg vial. The drug dissolves rapidly to give a clear solution.

The dose of Velbe solution may be injected either into the tubing of a running intravenous infusion of sodium chloride 0.9% or directly into a vein. In either case, the injection should be completed in about 1 minute. If care is taken to ensure that the needle is securely within the vein and that no solution containing vinblastine is spilled extravascularly, cellulitis and/or phlebitis will not occur. To minimise further the possibility of extravascular spillage, it is suggested that the syringe and needle be rinsed with venous blood before withdrawal. The dose should not be diluted in large volumes of diluent (ie, 100 to 250 ml) or given intravenously for prolonged periods (ranging from 30 to 60 minutes or more), since this frequently results in irritation of the vein and increases the chance of extravasation. Because of the enhanced possibility of thrombosis, it is considered inadvisable to inject a solution of Velbe into an extremity in which the circulation is impaired, or potentially impaired, by such conditions as compressing or invading neoplasm, phlebitis or varicosity.

Caution: If leakage into surrounding tissue should occur during intravenous administration of vinblastine, it may cause considerable irritation. 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 help disperse the drug and are thought to minimise discomfort and the possibility of cellulitis.

4.3    Contra-indications

FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY.

In case of mistaken administration by the intrathecal route, see section 4.4.

Vinblastine is contra-indicated in patients who are leucopenic unless this is the result of the disease

The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dl.

The following measures have also been used in addition but may not be essential:

Glutamic acid has been given IV 10 gm over 24 hours, followed by 500 mg tds by mouth for 1 month Folinic acid has been administered intravenously as a 100 mg bolus and then infused at a rate of 25 mg/h for 24 hours, then bolus doses of 25 mg 6-hourly for 1 week. Pyridoxine has been given at a dose of 50 mg 8-hourly by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.

Aspermia has been reported in men. Animal studies show metaphase arrest and degenerative changes in germ cells. Amenorrhoea has occurred in some patients treated with vinblastine in combination with other drugs.

Recovery of menses was frequent.

Stomatitis and neurological toxicity, although not common or permanent, can be disabling. Precautions: Care must be taken to avoid contamination of the eye with concentrations of Velbe used clinically. If accidental contamination occurs, severe irritation (or, if the drug was delivered under pressure, even corneal ulceration) may result. The eye should be washed with water immediately and thoroughly. Sperm abnormalities have been noticed in mice. Additional studies in mice demonstrated no reduction in fertility in males.

Myelosuppression: The dose-limiting factor is myelosuppression. Effective therapy with vinblastine is more likely to be followed by leucopenia than is the case with Oncovin (vincristine sulphate).

In general, the larger the dose employed, the more profound and longer lasting the leucopenia will be The fact that the granulocyte count returns to normal levels after drug-induced leucopenia is an indication that the granulocyte producing mechanism is not permanently depressed. Following therapy with vinblastine, the nadir in the granulocyte count may be expected to occur five to ten days after the last day of drug administration.

Recovery of the granulocyte count is fairly rapid thereafter and is usually complete within another seven to fourteen days. If granulocytopenia with less than 1,000 granulocytes/mm³ occurs following a dose of vinblastine, the patient should be watched carefully for evidence of infection until the granulocyte count has returned to a safe level. Any infection must be brought under control immediately. When cachexia or ulcerated areas of the skin surface are present, there may be a more profound granulocytopenic response to the drug; therefore, its use should be avoided in older persons suffering from either of these conditions. Although the thrombocyte count is not usually significantly lowered by therapy with vinblastine, patients whose bone marrow has been recently impaired by prior therapy with radiation or with other oncolytic drugs may show thrombocytopenia (less than 150,000 platelets/mm³). When other chemotherapy or radiation has not been employed previously, thrombocyte reduction below the level of 150,000/mm³ is rarely encountered, even when vinblastine may be causing significant granulocytopenia. Rapid recovery from thrombocytopenia within a few days is the rule.

The effect of vinblastine upon the red blood cell count and haemoglobin is usually insignificant when other treatment does not complicate the picture. In patients with malignant-cell infiltration of the bone marrow, the granulocyte and platelet counts have sometimes fallen drastically after moderate doses of vinblastine. Further use of the drug in such patients is inadvisable. Breaks and aberrations were not observed on chromosome analysis of marrow cells from patients treated with vinblastine although chromosomal changes have been noted in some hamster lung cell in vitro tests. There is no currently available evidence to indicate that vinblastine itself has been carcinogenic in humans although some patients have developed leukaemia following radiation therapy and the administration of vinblastine in combination with alkylating agents.

Pharmaceutical precautions Special dispensing information: When dispensing vinblastine in other than the original container, it is imperative that it be packed in an overwrap bearing the statement ‘DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY’. A syringe containing a specific dose must be labelled, using the auxiliary sticker provided in the pack with this warning.

Guidelines for the safe handling of antineoplastic agents: cytotoxic preparations should not be handled by pregnant staff. Trained personnel should reconstitute and administer the drug. This should be performed in a designated area. The work surface should be covered with disposable plastic-backed absorbent paper.

Adequate protective gloves, mask and clothing should be worn. Precautions should be taken to avoid

Adults and children

The usual dose is 6 milligrams for every square metre of your body surface. This dose may be increased for testicular cancers or reduced f you suffer from liver problems.

Your nurse will measure your height and weight and work out your body surface area from the measurements. Your doctor will use your body surface area to work out the right dose for you.

Your doctor or nurse will inject the correct amount of Velbe - usually bnce a week. Velbe must only go into a vein. You may have an injection every week and your doctor may treat you with other ytotoxic drugs at the same time.

f you are being treated as an out-patient it is important that you go to the clinic for all your appointments.

If you receive more Velbe Injection than you should As a doctor or nurse will usually give this medicine to you, it is unlikely that you will be given too much or that you will miss a dose. However, if you are worried tell the doctor or nurse.

4. POSSIBLE SIDE-EFFECTS

Like all medicines, Velbe can cause side-effects, although not everybody gets them.

Very rare side-effects include:

heart attack or a stroke when receiving Velbe with other cytotoxic drugs.

Rare side-effects include:

hearing difficulty - sometimes with dizziness or eyeball movements fits.

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Other side-effects that have been reported:

a low blood cell count causing

a fever, abnormal bleeding

or bruising

loss of reflexes

nerve, muscle, bone, jaw pain

or pain in the tumour

constipation, which may

be severe

abdominal pain

sore mouth

pain or swelling where you have the injection being short of breath feeling weak, confused or drowsy (due to lack of sodium in the blood)

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

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

By reporting side effects you can help provide more information on the safety of this medicine.

5.    HOW TO STORE VELBE-

Keep out of the sight and reach of children.

The hospital pharmacy should keep the bottles of Velbe in a fridge (2-8°C). When Velbe has been dissolved, the hospital should keep the Velbe solution in a fridge.

The bottle should not be used after the expiry date printed on the bottle label. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or householc waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment

6.    FURTHER INFORMATION The active substance in Velbe is vinblastine sulphate.

What Velbe looks like and the contents of the pack Velbe is a white crystalline powder, supplied as a lyophilised plug in a rubber stoppered 10ml glass vial.

PL 06831/0116    Velbe Injection 10mg

Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: Genus Pharmaceuticals, Linthwaite, Huddersfield, HD7 5QH, UK.

Manufacturer: Cellpharm GmbH, Feodor-Lynen-Str. 35, D - 30625 Hannover, Germany.

This leaflet was last approved in September 2014

* Velbe (vinblastine sulphate) is a registered trademark of Genus Pharmaceuticals Limited

reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Although the contribution of the vinca alkaloids has not been established, dosage adjustment of phenytoin, based on serial blood level monitoring, may need to be made when it is used in combination with vinblastine. Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulphate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side-effects.

4.6    Pregnancy and lactation

Usage in pregnancy: Caution is necessary with the use of all oncolytic drugs during pregnancy. Information on the use of vinblastine during human pregnancy is very limited but vinblastine can cause foetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women.

Animal studies with vinblastine suggest that teratogenic effects may occur. Laboratory animals given this drug early in pregnancy suffer resorption of the conceptus; surviving foetuses demonstrate gross deformities.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving vinblastine. If Velbe is used during pregnancy or if the patient becomes pregnant while receiving this drug she should be informed of the potential hazard to the foetus.

Usage in nursing mothers: It is not known whether vinblastine is excreted in human milk. Because of the potential for serious adverse reactions due to Velbe in nursing infants, a decision should be made whether to discontinue nursing or the drug taking into account the importance of the drug to the mother.

4.7    Effects on the Ability to Drive and Use Machines None known.

4.8    Undesirable effects. Leucopenia is the most common adverse reaction and is usually the dose-limiting factor.

In general, the incidence of side effects attending the use of Velbe appears to be related to the size of dosage employed. Symptoms commonly encountered when high doses are employed include constipation, abdominal pain, ileus and myalgia. The use of small amounts of vinblastine daily for long periods is not advisable, even though the resulting total dosage may be similar to the recommended dosage. Little or no therapeutic advantage has been demonstrated when such regimens have been used and side effects are increased. The constipation which may be encountered responds well to such usual measures as enemas and laxatives.

Constipation may take the form of upper colon impaction and the rectum may be found to be empty on physical examination. A flat film of the abdomen is useful in demonstrating this condition. A routine prophylactic regimen against constipation is recommended for patients receiving high doses of vinblastine.

The following symptoms may occur after usual doses of vinblastine:

Haematological: Leucopenia, thrombocytopenia, anaemia.

Gastro-intestinal: Nausea, vomiting, constipation, ileus, diarrhoea, anorexia, abdominal pain, rectal bleeding, pharyngitis, haemorrhagic enterocolitis, bleeding from an old peptic ulcer.

Neurological: Numbness, paraesthesiae, peripheral neuritis, mental depression, loss of deep tendon reflexes, headache, convulsions. Treatment with vinca alkaloids has resulted rarely in both vestibular and auditory damage to the eighth cranial nerve. Manifestations include partial or total deafness, which may be temporary or permanent, and difficulties with balance, including dizziness, nystagmus and vertigo. Particular caution is warranted when vinblastine sulphate is used in combination with other agents known to be ototoxic, such as the platinum-containing oncolytics.

Pulmonary: See under ‘Interaction with other medicinal products and other forms of interaction’. Cutaneous: Stomatitis, ulceration of the skin and alopecia. When alopecia develops it is frequently not total and, in some cases, hair regrows while maintenance therapy continues.

Cardiovascular: Hypertension. Cases of unexpected myocardial infarction and cerebrovascular accidents have occurred in patients undergoing combination chemotherapy with vinblastine, bleomycin and cisplatin.

Miscellaneous: Malaise, weakness, dizziness, bone pain, jaw pain, and pain in tumour-containing tissue.

Injection site reaction (see ‘Posology and Method of Administration’). Syndrome of inappropriate ADH secretion has been reported with higher than recommended doses. Raynaud's phenomenon has—

swallowed, activated charcoal in a water slurry may be given by mouth along with a cathartic. The use of cholestyramine in this situation has not been reported.

5 Pharmacological Properties

5.1    Pharmacodynamic Properties. Studies suggest that vinblastine sulphate acts by interfering with metabolic pathways of amino acids. Other studies have demonstrated that vinblastine sulphate produces a stathmokinetic effect and various atypical mitotic figures. The therapeutic responses, however, are not fully explained by the cytologic changes, since these changes are sometimes observed clinically and experimentally in the absence of any oncolytic effects. Reversal of the anti-tumour effect of vinblastine sulphate by glutamic acid or tryptophan has been observed. In addition, glutamic acid and aspartic acid have protected mice from lethal doses of vinblastine sulphate. Aspartic acid was relatively ineffective in reversing the anti-tumour effect. Some studies indicate that vinblastine sulphate has an effect on cell-energy production required for mitosis and interferes with nucleic acid synthesis. The mechanism of Velbe has been related to the inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.

5.2    Pharmacokinetic properties. Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous injection. The initial, middle, and terminal half-lives are 3.7 minutes, 1.6 hours, and 24.8 hours respectively. The volume of the central compartment is 70% of body weight, probably reflecting very rapid tissue binding to formed elements of the blood. Extensive reversible tissue binding occurs.

Low body stores are present at 48 and 72 hours after injection. Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic excretory insufficiency.

Following injection of tritiated vinblastine in the human cancer patient, 10% of the radioactivity was found in the faeces and 14% in the urine; the remaining activity was not accounted for. Similar studies in dogs demonstrated that, over 9 days, 30% to 36%of radioactivity was found in the bile and 12% to 17%in the urine.

A similar study in the rat demonstrated that the highest concentrations of radioactivity were found in the lung, liver, spleen and kidney 2 hours after injection.

5.3    Preclinical safety data Sperm abnormalities have been noted in mice. Additional studies in mice demonstrated no reduction in fertility of males. Breaks and aberrations were not observed on chromosome analysis of marrow cells from patients treated with vinblastine although chromosomal changes have been noted in some hamster lung cell in vitro tests.

6. Pharmaceutical Particulars

6.1    List of excipient(s). None

6.2    Incompatibilities. Velbe should never be mixed with any other drug and should not be diluted with solvents that raise or lower the pH from between 3.5 and 5.

6.3    Shelf-life. 3 years

6.4    Special precautions for storage Vials of Velbe should be stored in a refrigerator between 2° and 8°C.

After Reconstitution: After a portion of the solution has been removed from a vial, the remainder of the contents of the vial may be stored in a refrigerator for future use for 24 hours without significant loss of potency. When the reconstituted vial is to be stored for more than 24 hours, it is essential to reconstitute with sterile 0.9% sodium chloride intravenous infusion preserved with 2.0% benzyl alcohol. Where preserved diluent is used, the reconstituted solution may be stored in a refrigerator for up to 28 days without significant loss of potency.

6.5    Nature and contents of container Type 1 10 ml glass vial with rubber stopper, aluminium seal and polypropylene cap containing 10 mg of vinblastine sulphate powder for solution for intravenous injection.

6.6    Special Precautions for Disposal

Special dispensing information: When dispensing vinblastine sulphate in other than the original container, it is imperative that it be packaged in an overwrap bearing the statement ‘DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FATAL IF GIVEN BY OTHER ROUTES. FOR INTRAVENOUS USE ONLY.’

-A syringe containing a specific dose must be labelled, using the auxiliary sticker provided in the pack.

pharm

* Velbe (vinblastine sulphate) is a registered Trademark of Genus Pharmaceuticals Limited. 923 5408 1409

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Product Title	Velbe Injection lOmg			Colours used		Fonts used
Component	Leaflet			■	Black	Helvetica Neue 55 Reg 9pt
Pack Size	lOmg per 10ml					Helvetica Neue 75 Bold 9pt
IG code	25196601
Dimensions	300x420 mm
Proof No	04	Date	30/09/2014
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Operator	David Heaton			Approved by		Date
Artwork No	GEN-VLB-PIL-278
CRN	11368	Suffix	C
Reason for Change	Change to address and addition of reporting of side effects statement
				Issued by		Date
MHRA/IMB submission required	Yes

Product Title: VELBE Injection	Date Created: 19/08/2014
Strength/Form: 10 mg	Format: Leaflet
Size: 300 x420 mm	Client: Genus
Type of Print: Litho	Market: UK
	Job No. GEN-VLB-PIL-278
No of Colours: 1
BLACK
Typeface: Helvetica Neue 9 pt
Artwork prepared by David Heaton +44 (0)1462 431277 dc.heaton@ntlworld.com

No. of Draft	Date	Reason for Draft
_01	19/08/2014	New file
_02	04/09/2014	New page size
_03	09/09/2014	Corrections
_04	30/09/2014	Delete code

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