VINCRISTINE SULFATE SOLUTION FOR INJECTION 1 MG / ML - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Vincristine sulfate, solution for injection 1 mg/ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of 1 ml contains 1 mg of Vincristine sulfate

Each vial of 2 ml contains 2 mg of Vincristine sulfate

Each vial of 5 ml contains 5 mg of Vincristine sulfate

1 ml of solution contains 1 mg vincristine sulfate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

Clear colourless solution or slightly yellow solution, free of particles other than gas bubbles.

The pH is 3.5 – 5.5 and osmolality is approximately 600 mOsm/l.

4 CLINICAL PARTICULARS

Vincristine sulfate is used either alone or in conjunction with other oncolytic drugs for the treatment of:

1. Acute lymphocytic leukaemia

2. Malignant lymphomas, including Hodgkin’s disease and non-Hodgkins lymphomas

3. Multiple myeloma

4. Solid tumours, including (metastatic) breast carcinoma, small cell lung carcinoma

5. Ewing’s sarcoma, embryonal rhabdomyosarcoma, primitive neuroectodermal tumours (such as medulloblastoma and neuroblastoma), Wilm’s tumour and retinoblastoma

Care should be taken to avoid infiltration of subcutaneous tissues. Extravasation during intravenous administration of vincristine sulfate can cause considerable irritation (see section 4.4). In order to prevent vascular irritation, the vein should be flushed well after the administration of vincristine sulfate.

The dose of vincristine sulfate should be calculated and administered with extreme care, because overdose can have severe and even fatal results.

The dose should not be increased beyond the level which produces therapeutic benefit. In general, individual doses should not exceed 2 mg; and white cell counts should be carried out before and after giving each dose

4.3 Contraindications

Vincristine sulfate is contra-indicated:

– in patients who are hypersensitive to active substance or to any excipients listed in section 6.1.

– in patients with neuromuscular disorders (such as the demyelinating form of Charcot-Marie-Tooth syndrome);

– in patients with a severe liver function disorder;

– in patients with constipation and impending ileus, especially in children;

– in patients who are treated with radiotherapy in which the liver is involved.

Careful notice should also be given to those conditions listed in Section 4.4 Special warnings and precautions for use.

4.4 Special warnings and precautions for use

Vincristine sulfate should only be used under the strict supervision of physicians experienced in the treatment with cytotoxic products.

Syringes containing this product should be labelled: ‘VINCRISTINE FOR INTRAVENOUS USE ONLY, FATAL IF GIVEN BY OTHER ROUTES’

After inadvertent intrathecal administration, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death. In a very small number of patients, life-threatening paralysis and subsequent death was averted but resulted in devastating neurological sequelae, with limited recovery afterwards.

Based on the published management of these survival cases, if vincristine is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection:

1. Removal of as much CSF as is safely possible through the lumbar access.

2. Insertion of an epidural catheter into the subarachnoid space via the intervertebral space above initial lumbar access and CSF irrigation with lactated Ringer's solution. Fresh frozen plasma should be requested and, when available, 25 ml should be added to every 1 litre of lactated Ringer's solution.

3. Insertion of an intraventricular drain or catheter by a neurosurgeon and continuation of CSF irrigation with fluid removal through the lumbar access connected to a closed drainage system. Lactated Ringer's solution should be given by continuous infusion at 150 ml/h, or at a rate of 75 ml/h when fresh frozen plasma has been added as above.

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:

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. Intravenous administration of glutamic acid 10 g over 24 hours, followed by 500 mg three times daily by mouth for one month. 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.

Care should be taken to avoid contact of vincristine sulfate with the eyes. This can result in severe irritation or ulcer formation of the cornea (especially if the medicinal product is administered under pressure). When contact with the eyes occurs, the eyes must be flushed immediately with large quantities of water. Patients should consult a physician or ophthalmologist if the irritation of the eyes persists.

In the event of accidental projection on the skin, wash abundantly with water then with a mild soap and rinse thoroughly.

Extravasation should be avoided. Should extravasation occur, the injection should be stopped immediately and the possible remaining dose should be injected in a different vein. Local injection of hyaluronidase 250 IU/mL (1 mL subcutaneous around the lesion and moderate heat application at the site where extravasation occurred can help disperse the drug and limit the discomfort and possible cellulitis to a minimum. In the unit where vincristine sulfate is administered, the hospital’s cy­tostatics extravasation set should be available.

Special attention should be paid to patients with existing neurological disorders or liver function disorders. Careful observation of the patient is required with the combined use of vincristine and pharmaceuticals with a potential neurotoxicity.

Hepatic dysfunction may increase the circulating concentrations and the plasma half-life of vincristine with an increase in its adverse effects

The neurotoxic effect of vincristine sulfate may be additive with other neurotoxic agents or increased by spinal cord irradiation and neurological disease. Elderly patients may be more susceptible to the neurotoxic effects of vincristine sulfate.

Patients who received vincristine chemotherapy in combination with anticancer drugs known to be carcinogenic have developed second malignancies. The contributing role of vincristine in this development has not been determined.

Prophylactic measures for the prevention of constipation, such as an adjusted diet and the use of laxatives, in particular lactulose, are recommended.

Vincristine should be administered with caution to patients with ischaemic heart disorders.

Since leukopenia can occur, both the physician and the patient should be alert to the occurrence of an infection. When leukopenia occurs, suitable measures should be taken, amongst which a careful consideration about the time at which the next dose of vincristine sulfate should be administered. A complete blood count should be done before administration of each dose.

Due to an increased risk of leukopenia and thrombocytopenia, closer monitoring is necessary in patients in whom previous therapy or the disease itself has suppressed bone marrow function.

Acute elevation of the serum uric acid level can occur during the remissioninduction with acute leukaemia; therefore the serum uric acid levels should be frequently determined during the first 3–4 weeks of the treatment or suitable measures should be taken to prevent uric acid neuropathy.

Contraceptive measures should be taken by both the male and the female patients during the treatment and for 6 months after discontinuation of the treatment (also see section 4.6).

Excipient(s)

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions common to all cytotoxics

Due to the increase of thrombotic risk in case of tumeral diseases, the use of anticoagulative treatment is frequent. The high intra-individual variability of the coagulability during diseases, and the eventuality of interaction between oral anticoagulants and anticancer chemotherapy require, if it is decided to treat the patient with oral anticoagulants, to increase frequency of the INR (International Normalised Ratio) monitoring.

Inhibitors of cytochrome P450 isoenzymes and P-glycoprotein

Vinca alkaloids are metabolised by the cytochrome P450 3A4 iso-enzyme (CYP3A4) and are substrates for P-glycoprotein. Therefore increased plasma concentrations of vincristine can occur when CYP3A4 and P-glycoproteinin­hibitors, such as for instance ritonavir, nelfinavir, ketoconazole, itraconazole, erythromycin, cyclosporine, nifedipine and nefazodone, are administered concomitantly. Concomitant administration of itraconazole and vincristine has been associated with premature and/or increased severity of neuromuscular side effects, probably related to inhibition of the vincristine metabolism.

Phenytoin and fosphenytoin

It has been reported that concomitant administration of phenytoin and anti-neoplastic chemotherapy combinations, that contain amongst others vincristine, reduce the blood levels of phenytoin and increase theproconvulsant effect. This combination is not recommended. If it cannot be avoided, adjustment of the dose should be based on the blood level determinations.

Other cytostatics

Pharmacodynamic interactions can occur with other cytostatics: potentiation of therapeutic and toxic effect. Concomitant use of vincristine and other bone marrow depressive medicinal products such as doxorubicin (especially in combination with prednisone) can potentiate the depressive effects on the bone marrow.

Asparaginase/ isoniazid and other neurotoxic medicinal products

The possibility of severe and prolonged peripheral neuropathy with the administration of neurotoxic medicinal products (such as isoniazid and L-asparaginase, and cyclosporin A) to patients, who are treated with vincristine, should be taken into consideration. In these patients medicinal products with known neurotoxic effects should be administered with caution under continuous neurological monitoring.

Vaccines/killed virus

Because the normal immune system can be suppressed due to the treatment with vincristine, the formation of antibodies by the body may be reduced as a reaction to the vaccine. The time interval between the discontinuation of the use of the medicinal products that cause immuno-suppression and the recovery of the ability of the body to react to the vaccine is dependent on the intensity and the type of the immunosuppressive products, the underlying disease and other factors; estimates vary from 3 months to 1 year.

Vaccines/live virus

Because the normal immune system can be suppressed due to the treatment with vincristine, the concomitant administration of a live virus vaccine may enhance the replication and the side effects of the virus vaccine, and/or the formation of antibodies by the body as a reaction to the vaccine may be reduced; these patients should only be immunised with the utmost caution after careful evaluation of the haematological status of the patients and only with the approval of the treating physician. The time interval between the discontinuation of the use of the medicinal products that cause immuno-suppression and the recovery of the ability of the body to react to the vaccine is dependent on the intensity and type of the immuno-suppressive products, the underlying disease, and other factors; estimates vary from 3 months to 1 year.

Patients with leukaemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy treatment.

Digoxin

The absorption of digoxin can be reduced in patients who are treated with chemotherapy. In some patients therefore the therapeutic effect of digoxin may be reduced. Therefore caution is needed when such combinations are administered and adjustment of the dose of digoxin may be needed.

Mitomycin C

Acute pulmonary reactions can occur.

Radiotherapy

Radiotherapy can enlarge the peripheral neurotoxicity of vincristine.

Ciclosporine, Tacrolimus

Excessive immunosuppression with risk of lymphoproliferation can occur.

Other

During concomitant administration of vincristine and colony-stimulating factors (G-CSF, GM-CSF) atypical neuropathies with stinging or burning sensations in distal extremities were reported more frequently.

In patients with Wilms tumour, severe liver toxicity was reported under the combination of vincristine and dactinomycin.

In combination with bleomycin, vincristine can cause Raynaud syndrome in a dosedependent manner.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is very limited amount of data from the use of vincristine in pregnant patients. Studies in animals have shown teratogenicity and other reproductive toxicity (see section 5.3). Based on results from animal studies and the pharmacodynamics of the substance, vincristine should not be used during pregnancy, particularly during the first trimester. If pregnancy occurs during treatment with vincristine the patient must be informed about the possible dangers to the fetus.

Contraceptive measures should be taken by both the male and the female patients during the treatment and for 6 months after discontinuation of the treatment (also see section 4.4).

If pregnancy occurs during treatment, the patient should be informed about the risks for the unborn child and should be monitored carefully.

Vincristine can have genotoxic effects. Therefore, the possibility of genetic counselling should be considered if pregnancy occurs during therapy with vincristine and is also recommended for patients wishing to have children after therapy

Lactation

It is unknown whether vincristine is excreted in human breast milk, Breastfeeding must be discontinued during treatment with vincristinesulfate.

Fertility

Treatment with vincristine may cause irreversible infertility. The reversibility of these antifertility effects depends on the age of the patient and the dose administered. Commonly, azoospermia has been observed in men who were treated with a chemotherapy combination consisting of vincristine and prednisone with cyclophosphamide or mechlorethamine and procarbazine. Less commonly, amenorrhea has been observed in women who were treated with vincristine containing chemotherapy.

Patients should be consulted about future fertility prospects. Male patients have to be consulted about sperm preservation.

4.7 Effects on ability to drive and use machines

There are no data available about the effect of this product on the ability to drive and use machines. Due to the (neurological) side effects the possibility that this product may affect the ability to drive should be taken into account.

4.8 Undesirable effects

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most important toxic effects of vincristine have been associated with the central nervous system. In general the side effects are reversible and dose dependent. The most often occurring side effects are neurotoxicity and alopecia; the most troublesome side effects are neuromuscular in origin.

Neoplasms, benign and malignant and unspecified (including cysts and polyps)

Treatment related secondary malignancy

Patients who have been treated with vincristine in combination with other cytotoxic products, of which it is known that they are carcinogenic, have developed secondary malignancies.

Common (>1/100 to <1/10)

Temporary thrombocytosis.

Uncommon (>1/1,000 to <1/100)

Severe bone marrow depression, anaemia, leukopenia and thrombocytopenia.

Common (>1/100 to <1/10)

Acute occurrence of shortness of breath and bronchospasms, which can be severe and life threatening. These symptoms were observed after the administration of vinca alkaloids (such as vincristine), particularly when administered concomitantly with mitomycin. The reaction can occur a few minutes to hours after the administration of a vinca alkaloid or to 2 weeks after a dose of mitomycin.

Rare (>1/10,000 to <1/1,000)

Allergic reactions, such as anaphylaxis, rash and oedema, possibly related to vincristine therapy have been observed in patients who were treated with vincristine as part of multi-drug chemotherapy regimes.

Nervous system disorders

The neurological toxicity is the most important side effect of vincristine. Neurological toxicity is dose and age related. As a result of neurotoxicity also constipation and ileus can occur (see “Gastrointestinal system disorders”).

Common (>1/100 to <1/10)

The most frequently occurring neurotoxic side effect is peripheral neuropathy (mixed sensorimotor), which occurs in almost all patients. Often a specific order in the development of neuromuscular side effects occurs. In the beginning only sensory disturbances and paraesthesia occur. With continuation of the treatment nerve pain (amongst other in the jaw and testicles) and further motor difficulties can occur. Loss of deep tendon reflexes, foot drop, muscle weakness, ataxia and paralysis have been reported with continuation of the treatment. Affection of the cranial nerve, amongst which isolated paresis and/or paralysis of muscles that are directed by the cranial nerves, can occur, without muscle weakness occurring anywhere else.

Paralysis of the cranial nerve and muscle weakness of the larynx can cause hoarseness and vocal cord paresis, amongst which potentially life threatening bilateral vocal cord paresis. Muscle weakness of the outer ocular muscles can cause ptosis, and optical and extra ocular neuropathy. Transient cortical blindness has been reported. Vincristine also causes autonomic toxicity and toxicity of the central nervous system, although less frequent than peripheral neuropathy. Double vision and optic atrophy are observed.

Uncommon (>1/1,000 to <1/100)

Convulsions, frequently with hypertension, have been reported in a few patients receiving vincristine sulfate. A few cases of convulsions followed by coma have been reported in children. Vincristine causes autonomic toxicity and toxicity of the CNS, although this occurs less frequently than peripheral neuropathy. Effects on the CNS e.g. altered state of awareness and mental changes like depression, agitation, sleeplessness, confusion, psychoses and hallucinations.

Not known

Leukoencephalopathy

Ear and labyrinth disorders

Uncommon (>1/1,000 to <1/100)

Deafness

Cardiac disorders

Uncommon (>1/1,000 to <1/100)

Coronary artery disease, myocardial infarction.

Coronary vascular disorders and myocardial infarction have occurred in patients who were treated with vincristine containing chemotherapy combinations and who were previously treated with radiotherapy of the mediastinum.

Rare (>1/10,000 to <1/1,000)

Hypertension and hypotension.

Respiratory, thoracic and mediastinal disorders

Severe bronchospasm and dyspnea have been reported with vinca alkaloids, some of which were used in combination with mitomycin C.

Common (>1/100 to <1/10)

Nausea, vomiting, constipation, abdominal pain. Constipation can occur as a result of impaction of the upper part of the intestines while the rectum is empty. Colic-like abdominal pains can then occur.

Uncommon (>1/1,000 to <1/100)

Reduced appetite, weight loss, anorexia, diarrhoea, paralytic ileus. Especially in young children paralytic ileus is a possibility.

Rare (>1/10,000 to <1/1,000)

Inflammation of the mucous membrane of the mouth, intestinal necrosis and/or perforation.

Very rare (<1/10,000), not known (cannot be estimated from the available data) Pancreatitis.

Rare (>1/10,000 to <1/1,000)

Hepatic veno-occlusive disease, particularly in children.

Skin and subcutaneous tissue disorders

Very common (>1/10)

Alopecia (is reversible when the administration of vincristine is discontinued).

In elderly patients the therapy with drug that causes urinary retention must be interrupted in the early days after the vincristine administration.

Uncommon (>1/1,000 to <1/100)

Polyuria, dysuria, urinary retention as a result of bladder atony, hyperuricaemia, uric acid nephropathy.

Rare (>1/10,000 to <1/1,000)

SIADH syndrome (syndrome of inappropriate antidiuretic hormone secretion). The syndrome may be related to the neurotoxicity of the medicinal product possibly due to a direct effect on the hypothalamus. In these patients hyponatraemia occurs, in combination with urinary sodium excretion, without indication of renal or adrenal disorders, hypotension, dehydration, azotemia or oedema. With liquid restriction the hyponatraemia and the loss of sodium through the kidneys can be improved.

Very rare (<1/10,000), not known (cannot be estimated from the available data) Incontinence.

Reproductive system and breast disorders

Irreversible infertility after vincristine-containing chemotherapy is more common in males than in females.

Common (>1/100 to <1/10)

Azoospermia has been observed in men who were treated with a chemotherapy combination consisting of vincristine and prednisone with cyclophosphamide or mechlorethamine and procarbazine.

Uncommon (>1/1,000 to <1/100)

Amenorrhea.

General disorders and administration site conditions

Common (>1/100 to <1/10)

Injection site irritation.

Uncommon (>1/1,000 to <1/100)

Fever, phlebitis, pain, cellulitis and necrosis. These symptoms can occur after irritation of the vessel wall or after extravasation during the administration.

Rare (>1/10,000 to <1/1,000)

Headache.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

An overdose with vincristine leads to the occurrence of the above mentioned undesirable effects, in an intensified manner. In children younger than 13 years of age, overdose of 10 times the recommended dose has had fatal results. In this patient group, severe symptoms can occur with doses of 3–4 mg/m2. Adults can expect severe symptoms after the administration of single doses of 3 mg/m2 or more. There is no known antidote to vincristine sulfate. Treatment is symptomatic and supportive. On appearance of an overdose, careful monitoring of the patient is required. The following measures should be considered.

The serum electrolyte concentrations and fluid balance should be carefully monitored and when signs of inappropriate ADH secretion occur, fluid restriction must be initiated

Administration of an anti-convulsive agent to prevent seizures

Monitoring of the cardiovascular system

Monitoring of the blood, after which action should be based on the observed bone marrow depression

Use of enemas to prevent ileus

Folinate may be used. A proposed schedule is 100 mg intravenously every 3 hours for 24 hours followed by every 6 hours for at least 48 hours.

Because only very small quantities of the medicinal product end up in dialysis, haemodialysis in case of overdose is probably not effective.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agent-vinca alkaloid

ATC code: L01C A02

Vincristine sulfate is a salt of vincristine, an alkaloid obtained from the periwinkle plant Vinca rosea Linn.

Vinca alkaloids are classical “spindle poisons”, that bind to the microtubular protein tubulin and block cells during metaphase by both preventing polymerisation of tubulin and subsequent formation of microtubules and by inducing depolymerisation of existing microtubules.

Vica alkaloids can exert their effect on the process in a number of ways:

by binding to a specific site of tubulin and by forming a tubulin-alkaloid aggregation complex;

by binding to a high affinity site of tubulin, incorporated into microtubeles, and by inhibition of further incorporation of tubulin into the existing microtubule;

by binding to a low affinity site on the microtubule wall that cases protofilament separation.

Vincristine can also affect other cellular systems such as RNA and DNA synthesis, cyclic AMP, lipid biosynthesis and calmodulin-dependent Ca2+ transport ATPase”

5.2 Pharmacokinetic properties

Distribution

After the intravenous injection vincristine is rapidly cleared from the serum. Within 15–30 minutes more than 90% of the medicinal product is distributed from the serum to the tissues and other blood components. The distribution volume is 8.4 ± 3.2 l/kg during steady-state conditions.

Twenty minutes after the intravenous administration, more than 50% of vincristine is bound to blood components, particularly to platelets, which contain high concentrations of tubulin.

Penetration into the cerebrospinal fluid after an intravenous bolus injection appears to be very low. However, despite this low penetration vincristine can cause central nervous system side effects.

Metabolism

Vincristine appears to be largely metabolised, probably in the liver by the microsomal enzyme system cytochrome P450, amongst which CYP3A.

Excretion

Analysis of plasma particulars shows that the plasma elimination of vincristine after a rapid intravenous administration can best be described as a triphasic model. The initial, mean and final half-lives are respectively 5 minutes, 2.3 hours and 85 hours (range 19–155 hours).

Plasma clearance is slow and therefore an interval of at least one week between treatment periods is needed in order to avoid cumulative toxicity.

The liver is the most important excretion organ; approximately 80% of the injected dose is excreted in the faeces and 10–20% in the urine.

Patients with liver function disorders

In patients with liver function disorders the metabolism and because of that the excretion of vincristine is probably reduced, resulting in an increased risk of toxicity. If necessary the dose should be adjusted (See sections 4.2. and 4.4).

Children

In children there is a larger inter- and intra-individual variation in the pharmacokinetic parameters such as clearance, distribution volume and elimination half-life. The plasma clearance in children is generally larger than in adults or infants, but it is not certain that the vincristine clearance is reduced with the age during the childhood.

5.3 Preclinical safety data

In preclinical studies vincristine has been shown to be teratogenic. Also, in reproduction toxicity studies in animals, adverse effects on fertility and embryo toxicity have been observed. In chronic toxicity studies adverse effects including neurotoxicity, inhibition of the spermatogenesis, myelosuppression and gastrointestinal toxicity have been observed. In genotoxicity tests vincristine was shown to have the potential to cause chromosomal deviations, aneuploidia and polyploidia. There are no other relevant preclinical data.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol

Sulfuric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

Vial before opening

24 months

After dilution

Chemical and physical in-use stability of the solution prepared for injection or infusion has been demonstrated for 48 hours at 2–8 o C or 24 hours at 15 to 25 °C when diluted to a concentration range of 0.01 mg/ml to 0.1 mg/ml in 9 mg/ml (0.9%) sodium chloride solution for infusion or in 50 mg/ml (5%) glucose solution for infusion.

From a microbiological point of view, the diluted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions

6.4 Special precautions for storage

Store and transport refrigerated (2–8°C).

Keep vial in the outer carton in order to protect from light.