CONFIRMED

Order of the Ministry of

Healthcare of Ukraine

__31.08.12 No __673___

Registration Certificate

No _UA/12300/01/01__

__UA/12300/01/02_

 

INSTRUCTION

for medical use of the preparation

PLATISAN 10

PLATISAN 50

Composition:

Active substance: cisplatin;

1 ml concentrate contains cisplatin 1 mg;

1 vial contains cisplatin 10 mg or 50 mg (1 mg/ml);

Auxiliary substances: mannitol (Е 421), sodium chloride, sodium hydroxide, concentrated hydrochloric acid, water for injections.

Medicinal form. Concentrate for preparation of the solution for infusions.

Pharmacotherapeutical group. Antineoplastic agents. Platinum compounds.

АТС code L01X A01.

Clinical characteristics.

Indications.

Spread or metastatic malignant tumours, in particular testicle cancer (as palliative agent and as a component of the complex polychemotherapy therapy), ovary cancer (Stages ІІІ and IV), epidermoid epithelioma of head and neck (as palliative agent).

As monotherapy or in combination with other antineoplastic agents.

Lung cancer, urothelial tumour, and cervical tumours.

Contraindications.

Cisplatin is contraindicated in patients:

with hypersensitivity to the active substance or other preparations that contain platinum;

with renal dysfunction;

in dehydration state (hydration before treatment and after it is necessary to prevent serious renal dysfunction);

with suppressed function of bone marrow;

with impairment of hearing;

with cisplatin-induced neuropathy;

during pregnancy and lactation period.

Way of administration and doses.

Solution for injections 1 mg/ml should be diluted under aseptic conditions before use. Solution for infusion may be administrated only via intravenous infusion.

When preparing the solution of the preparation and its introduction, one must not use any instruments with parts containing aluminium, if they may contact with the preparation (it is also applied to the systems for intravenous infusions, needles, catheters, syringes, etc.).

Solution for infusions should be prepared under aseptic conditions.

For concentrate diluting the following agents may be used:

0.9 % sodium chloride solution;

mixture of 0.9 % sodium chloride solution and 5 % glucose solution in 1:1 ratio (concentration of sodium chloride is 0/45 %, and the one of glucose is 2.5 %).

In case when pre-hydration before treatment with cisplatin is impossible, the concentrate can be also diluted with the mixture of 0.9 % sodium chloride solution and 5 % mannitol solution in 1:1 ratio (the concentration of sodium chloride is 0.45 %, and the one of mannitol is 2.5 %).

Preparation of solutions for infusions.

The necessary volume (dose) of the concentrate for preparation of the solution for infusions, calculated according to the recommendations indicated below, is diluted with 1–2 l of the solutions listed above.

Only transparent colourless solutions without mechanical inclusions may be used.

The vials may be used only once.

Doses.

The doses of cisplatin are determined according to the diagnosis, expected reaction of the patient, as well as due to the fact if cisplatin is used independently or as a part of the combined chemotherapy. The dosages indicated below are recommended both for adults and children.

In case of monotherapy, the following schemes of treatment are recommended:

single introduction of 50–120 mg/m² of body surface every 3–4 weeks;

daily introduction of 15–20 mg/m² of body surface for 5 days every 3–4 weeks.

The decision as for the initiation of the following course of treatment can be made only after complex estimation of the patient’s state (see Section “Peculiarities of the use”).

If the patient has renal dysfunction or suppressed function of bone marrow, the doses of the preparation should be reduces accordingly.

The prepared solutions for infusion are introduced via intravenous infusion for 6–8 hours.

In order to induce sufficient diuresis during and after cisplatin introduction, adequate hydration of the organism should be started 2–12 hours before introduction of the preparation and it should last at least for 6 hours after the termination of cisplatin infusion.

Hydration in adults is carried out via intravenous infusion of:

0.9 % sodium chloride solution or

mixture of 0.9 % sodium chloride solution and 5 % mannitol solution in 1:1 ratio.

Hydration before treatment with cisplatin:

is carried out at the rate of 100–200 ml/hour for 6–12 hours.

Hydration after treatment with cisplatin:

introduction of 2 more litters of the solutions indicated above at the rate of 100–200 ml/hour for 6–12 hours.

If after hydration urine excretion is less than 100–200 ml/hour, conduction of forced diuresis may be necessary. In this case the patient is introduced 37.5 g mannitol intravenously as 10 % solution (375 ml) or use diuretics (in case of normal renal function). Mannitol or diuretics are also to be indicated in those cases when the dose of cisplatin exceeds 60 mg/m² of body surface.

Patients should consume much liquid for 24 hours after infusion cisplatin in order to provide sufficient urine excretion.

Side effects.

Adverse side effects depend on the dose of cisplatin and may be of cumulative character.

From the side of kidneys. Insignificant reversible renal dysfunction may be observed after single use of cisplatin in medium doses (20–50 mg/m² of body surface). In case of cisplatin introduction in high doses (50–120 mg/m² of body surface) or daily use of cisplatin, there may develop renal insufficiency with tubule necrosis, which is manifested as uraemia or anuria. Renal insufficiency may be irreversible.

Nephrotoxicity is of cumulative character. It is manifested mainly in 2–14 days after introduction of the first dose of cisplatin. Serum concentrations of creatinine and urea may increase. Forced diuresis and hydration before cisplatin introduction and after infusion decrease the risk of nephrotoxicity development. If there is no sufficient hydration after introduction of the single dose of 50 mg/m² of body surface, the symptoms of nephrotoxicity are observed in 28–36 % patients.

There is a possibility of hyperuricemy (asymptomatic or with gout symptoms). Hyperuricemy in combination with nephrotoxicity is observed in 25–30 % patients.

From the side of blood system. Myelosupression. There may be observed dose-dependent, cumulative and mainly reversible leukopenia, thrombocytopenia and anaemia. There have been cases of Cumbs-positive haemolytic anaemia (reversible). In addition the development of haemolysis is possible, probably caused by cisplatin use. After the use of cisplatin in high doses, severe suppression of bone marrow function is possible (including agranulocytosis and/or aplastic anaemia). Approximately in 14 days after cisplatin introduction, WBS count in most patients decrease significantly (in 5 % patients – down to 1.5x10⁹/L and lower). Platelet count reaches its minimum approximately in 21 days (in 10 % patients it decreases down to 50x10⁹/L and lower). The indexes return to the norm approximately in 39 days.

From the side of digestive tract. Usually in 1–4 hours after cisplatin use there is anorexia, nausea, vomiting, stomach-ache and diarrhea. The indicated symptoms resolve in most patients within 24 hours. Less evident nausea and anorexia may last up to 7 days after infusion of the preparation (as for additional preparation, see Section “Peculiarities of the use”). Seldom there may develop inflammation of the mouth mucous membranes.

From the side of hearing organs. Ototoxicity is observed approximately in 30 % of patients, who receive cisplatin in the dose of 50 mg/m² of body surface. Ototoxic action cisplatin is cumulative, sometimes irreversible. Sometimes, only one ear is affected. Symptoms of ototoxicity usually include niose in the ears and/or hearing disorder in high-frequency range (4000–8000 Hz). Hearing disorder in normal hearing range (250–2000 Hz) is observed in 10–15 % of patients. In addition, there is a possibility of combined deafness and disturbed work of the vestibular apparatus, which is accompanied with dizziness. Preliminary or concomitant irradiation of the scalp area increases the risk of hearing loss. After treatment with cisplatin, patients lose the ability of normal communication only in single cases. If treatment is conducted in children, complications may be more serious.

From the side of sight organs. Loss of sight due to combined therapy with several preparations, including cisplatin, is observed rarely. There have been noted single cases of optic disk edema with sight disturbance, but they are reversible and after treatment termination the sight restores. There has been registered only one case of one-side retrobulbar neuritis with loss of visual acuity after polychemiotherapy with further cisplatin treatment.

From the side of nervous system. During treatment with cisplatin, there has been observed peripheral neuropathy (usually bilateral and sensory), seldom – loss of taste or tactile function or retrobulbar neuritis with loss of sight, as well as disturbance of cerebral functions (which is accompanied by mental confusion, loss of expressive speech, in single cases – cortical blindness, loss of memory, paralysis). There have been noted cases of manifestation of Lhermitte's symptoms, autonomic neuropathy and myelopathy of the spinal marrow. There are reports about severe brain lesions (in particular, about one case of acute cerebrovascular complications, cerebral arteritis, occlusion of the carotid artery, encephalopathy). If the patient demonstrates any of the cerebral symptoms indicated above, treatment with cisplatin should be discontinued immediately. Neurotoxic influence of cisplatin may be reversible, however, not always. In 30–50 % of patients the disturbed functions do not restore even after the end of treatment. Manifestations of neurotoxic action of cisplatin may be noted both after introduction of the first dose, and after long-term therapy.

Serum electrolytes. Rarely there is observed hypomagnesemia, hypocalcemia, hyponatremia, hypophosphatemia and hypokaliemia with muscle spasm and/or ECG changes due to renal system lesion induced with cisplatin use (with decreased resorption of the indicated cations in renal tubules).

Allergic reactions. Rarely there are observed anaphylactic reactions. Most often these are rash, urticaria, erythema, and itch. There are single reports about hypotension, tachycardia, dyspnoe, bronchiospasm, face edema and fever. In such cases treatment with antihistamines, epinephrine (adrenaline) and steroids may be necessary.

From the side of hepatobiliary system. There have been noted single cases of hepatic function disturbance with increased concentration of serum transaminases, however, these changes are reversible. Very seldom there is observed decrease of albumin level, which is probably connected with cisplatin treatment.

From the side of cardiovascular system. There have been registered single cases of cardiac rhythm disturbance, in particular bradycardia, tachycardia and other arrhythmias. Rarely there have been noted ECG changes. There is a report about cardiac arrest during treatment with cisplatin in combination with other cytostatic agents, however, it happens very seldom.

From the side of immune system. Immune suppression is observed.

Other. There is a possibility of local edema and pain, erythema, skin ulcers and phlebitis at the site of injection after intravenous introduction of the preparation.

Metal deposits on gums are possible.

Alopecia, disturbance of spermatogenesis and ovulation, as well as painful gynecomastia are possible.

There is information about connection between cisplatin use and the development of secondary non-lymphatic leukosis.

According to reports from several independent sources, there is a connection between the combined chemotherapy with cisplatin and other preparations and the development of vascular disorders (cerebral and coronary ischemia, disturbance of peripheral blood circulation, like Raynaud's syndrome).

Theoretically, the preparation is cancerogenic (according to cisplatin’s mechanism of action), but this fact has no practical evidence.

During treatment with cisplatin there also have been registered cases of hypercholesterolemia (seldom), inadequate secretion of antidiuretic hormone (single cases), and increased serum concentration of amylase (seldom), thrombotic microangiopathy in combination with hemolytic-uremic syndrome (single cases).

Sometimes increased blood concentration of iron is registered.

Overdose.

In case of overdose the intensity of toxic effects indicated above increases. Efficient hydration and osmotic diuresis immediately after overdose may decrease the toxic influence of cisplatin.

In case of significant overdose (≥ 200 mg/m² of body surface) due to cisplatin crossing blood-brain barrier, there may be observed certain influence onto respiratory centre with development of life-threatening respiratory disorders and disturbance of acid-base balance. The therapy is symptomatic.

Administration during pregnancy and lactation.

There is a stipulation that cisplatin may cause serious defects in foetus if it is used during pregnancy. That is why cisplatin is contraindicated in pregnant women.

Cisplatin has been found in mammal breast milk during animal studies of the preparation. That is why breastfeeding during cisplatin therapy is contraindicated.

Children.

The preparation is used in children.

Peculiarities of the use.

Treatment with cisplatin should be carried out under supervision of the experienced doctor oncologist.

Cisplatin is characterized by its ototoxic, nephrotoxic and neurotoxic action. Its toxicity increases at concomitant use of other medicinal preparations with toxic action towards the indicated organs and systems.

Before initiation of cisplatin treatment and before initiation of every further course of therapy, it is necessary to record audiograms.

Nephrotoxic action of cisplatin decreases in case of appropriate hydration before, during and after intravenous introduction of the preparation.

Before treatment, during therapy and after treatment with cisplatin the following functions should be monitored:

renal function;

hepatic function;

function of blood formation system (RBC, WBC and platelet counts);

levels of serum electrolytes (concentrations of calcium, sodium, potassium, and magnesium).

Analyses should be repeated weekly during the whole period of treatment with cisplatin.

The following courses of therapy should not be initiated unless the main indexes return to the norm. These include (in adults):

serum creatinine ≤ 130 µmol/L (1.5 mg/dL);

urea < 25 mg/dL;

WBC > 4000/µL (> 4.0 x 10⁹/L);

platelets > 100,000/µL (> 100 x 10⁹/L);

audiogram – results are within normal values.

In children before initiation of the following courses of treatment, the main indexes (serum creatinine, urea, WBC, platelets, and audiogram) should return to respective age norms.

Special caution is necessary when treating patients with peripheral neuropathy, which is not caused by cisplatin, as well as patients with acute bacterial and viral infections.

In case of extravasation it is necessary to do the following:

stop cisplatin introduction immediately;

without moving the needle, carry out aspiration of extravasate from tissues and wash them with 0.9 % sodium chloride solution, especially in those cases when cisplatin solutions with concentrations above the recommended ones have been used (see Section “Peculiarities of the use”).

Introduction of cisplatin often causes nausea, vomiting, and diarrhea. Preventive use of antiemetic agents may help to avoid nausea and vomiting or decrease their intensity.

Loss of fluid due to vomiting and diarrhea should be compensated.

Both men, and women of reproductive age, who take cisplatin, should use contraceptives in order to prevent pregnancy during the therapy and at least 6 months after termination of the treatment with the preparation. If after the end of therapy, the patient wants to have children, he/she should consult a specialist in the field of genetics. Due to the fact that treatment with cisplatin may cause irreversible sterility, men, who want to become fathers in future, should be advised as for sperm cryopreservation before therapy initiation.

Influence on the ability to drive and use mechanisms

Due to individual sensitivity, cisplatin may have a negative influence onto ability to drive and use mechanisms.

Instructions for the personnel

When working with cisplatin, as well as with other cytostatic agents, it is necessary to be careful and use gloves, masks and protective clothes. Any manipulations with the preparations should be preferably carried out under the air vent. It is necessary to avoid contact of the solutions with skin and mucous membranes. Pregnant women should not work with cisplatin.

In case of contact of skin with the preparation, the affected area should be washed with great volume of water and applied with cream in case of development of temporary feeling of burning. (Note. In some individuals, who are sensitive to platinum, skin reactions may be observed.)

Unused solutions, instruments and materials that have been used during manipulations with cisplatin should be utilized according to the approved procedure.

Ability to influence the reaction rate when driving or working with other mechanisms. During treatment it is recommended to avoid any type of activity that requires increased attention as well as psychic and locomotive reaction rate.

Interaction with other medicinal preparations and other forms of interaction.

At concomitant use of other preparations, which suppress the function of bone marrow, or radiation therapy myelosupressive action of cisplatin is increased.

Nephrotoxic action of cisplatin may increase at parallel treatment with antihypertensive preparations that contain furosemide, hydralazine, diazoxide and propranolol.

In case of parallel use of cisplatin and allopurinol, colchicine, probenecid or sulfinpyrazone, the doses of the latter preparations sometimes required adjustment, as cisplatin causes increase of serum concentration of uric acid.

Except those patients, who receive cisplatin in the doses over 60 mg/m² of body surface, and in those with urine secretion not exceeding 1,000 ml within 24 hours, patients should not be indicated forced diuresis with tubular diuretics, as it may lead to kidney lesion and increased ototoxicity.

Symptoms of ototoxic action of cisplatin (for example, dizziness and noise in the ears) may be masked at parallel use of antihistaminic preparations, buclizine, cyclizine, loxapine, meclozine, phenothiazines, thioxanthenes or trimethobenzamides.

Nephrotoxic preparations (for example, cephalosporins, aminoglycosides) and ototoxic medicinal agents (for example, aminoglycosides) increase toxic action of cisplatin towards respective organs. During or after treatment with cisplatin preparations that are excreted mainly be kidneys (for example, such cytostatic agents, as bleomycin and methotrexate) should be indicated with caution, as cisplatin slows renal excretion.

At concomitant use of ifosfamide and cisplatin, increased protein excretion is observed. Ifosfamide also potentiates ototoxic action of cisplatin, though ifosfamide is not ototoxic by itself.

During one randomized study it has been noted that the results of cisplatin treatment female patients with progressing ovary cancer are worse at parallel use of pyridoxine and geksametilmelamin.

It has been found that in case of paclitaxel use after cisplatin therapy paclitaxel clearance may decrease by 70–75 %.

At combined treatment with isplatin, bleomycin and etoposide in some cases there have been determined decreased blood concentration of lithium. That is why during treatment it is recommended to control lithium values.

Cisplatin may worsen phenytoin absorption and, thus, decrease the efficiency of antiepileptic therapy.

Penicilamine and other chelating compounds may decrease the efficiency of cisplatin treatment.

For 3 months after cisplatin treatment one should not carry out vaccination with live vaccines.

Pharmacological properties.

Pharmacodynamics.

Cisplatin (cis-diaminedichlorplatinum-ІІ) is an inorganic substance, which contains a heavy metal, platinum. It suppresses DNA synthesis in the result of formation of cross bonds (links) inside DNA strands and between them. Synthesis of protein and RNA is also suppressed, however, not to such extend. Cytotoxic action of cisplatin is due to binding of all DNA bases, especially guanine and adenine in position N-7.

Although antitumor action of cisplatin is connected mainly with suppression of DNA synthesis, there is also another mechanism of its influence on the lesion. For example, cisplatin increases immunogenicity of the tumour. Cytostatic action of cisplatin resembles the action of alkylating substances. Cisplatin also has immunosuppressive and antibacterial properties and increases sensitivity to irradiation.

The action of cisplatin on cells does not depend of the cycle phase.

Pharmacokinetics.

After intravenous introduction in the dose of 20–120 mg/m² of body surface, cisplatin distributes quickly in all tissues. The highest platinum concentration is observed in liver, prostate gland and kidneys, somewhat lower one in urinary bladder, muscles, testicles, pancreas and spleen, and the lowest one in the bowels, adrenal glands, heart, lungs, brain and cerebellum. In 2 hours after introduction, over 90 % of the total volume of cisplatin in plasma is bound with proteins. This binding is probably of irreversible character. Protein-bound cisplatin has no antitumor properties. Pharmacokinetics of cisplatin is non-linear. Without enzymes it transforms into one or several metabolites. After intravenous injection in the dose of 50–100 mg/m² of body surface, bi-phase plasma excretion of cisplatin is observed. In human the duration of half-life during the first phase (distribution) is 10–60 minutes, and during the second (terminal) one is 2–5 days. The duration of plasma half-life is prolonged in case of renal function disturbances. In addition, theoretically it may increase in case of ascites, caused by active protein binding of cisplatin.

In the result of extensive protein binding of platinum, there is observed long or incomplete excretion of cisplatin from the organism. Within 84–120 hours, 27–45 % of the dose used is excreted with urine. At long-term infusions, the volume of cisplatin excreted with urine increases. Excretion with feces is minimal; small amount of platinum is found in gall bladder and large intestine.

Pharmaceutical characteristics.

Main physical and chemical properties: transparent, from colourless to pale yellow colour solution.

Incompatibility. Cisplatin reacts with aluminium and forms black platinum residue. That is why instruments that contain aluminium must not be used during any manipulations with the preparation.

Concentrate cisplatin must not be mixed with any medicinal preparation, except those indicated under Section “Way of administration and doses”. The concentrate must not be diluted with 5 % glucose solution or 5 % mannitol solution, but only with their mixtures with 0.9 % sodium chloride solution.

Antioxidants (for example, sodium metabisulfite), bicarbonates (sodium bicarbonate), sulphates, fluorouracil and paclitaxel may inactivate cisplatin in infusion systems.

Shelf-life. 2 years.

Storage conditions. Store in the original package at temperature between 15 °С and 25 °С. Keep out of the reach of children. Do not freeze.

Unused medicinal preparation should be utilized.

Packaging. 10 ml or 50 ml of the concentrate in a glass vial, 1 vial in the air-blister coating in a carton.

Category of dispensing. On prescription.

Name and location of the applicant. Ananta Medicare Ltd.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Name and location of the manufacturer. Marksans Pharma Ltd.

Juridical address: Floor 21, Lotus Business Park, Off New Link Road, Andheri (West), Mumbai – 400053, India;

Address of the manufacturing site: Village Asaravad, Dudhia, Indor – 453 331, India.

Date of the last review. 31.08.12