INSTRUCTION

for medical use of the preparation

PLATICARB 150

PLATICARB 450

Composition:

Active substance: carboplatin;

1 ml of the preparation contains carboplatin 10 mg;

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

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

Pharmacotherapeutical group. Antineoplastic agents. Platinum compounds.

АТС code L01Х А02.

Clinical characteristics.

Indications.

Epithelial ovary cancer and small cell lung cancer as monotherapy or in combination with other antineoplastic agents.

Contraindications.

Hypersensitivity to any component of the preparation, evident renal dysfunction (creatinine clearance < 30 ml/min), evident myelosupression, bleedings, recent significant loss of blood, impairment of hearing.

Way of administration and doses.

The preparation is indicated only for intravenous introduction.

Carboplatin may be used both as monotherapy, and in combination with other antineoplastic agents. The preparation is introduced as intravenous infusions for 15-60 min. The content of the vial is diluted in 5 % glucose solution or 0.9 % sodium chloride solution to achieve carboplatin concentration of 0.5 mg/ml. Reconstituted solution is stable at room temperature (about 25 °С) for 8 hours. The preparation does not contain any preservatives, that is why reconstituted solution should be used within this term.

At monotherapy regimen, in patients, who have never received therapy with this preparation before, under condition of their normal renal function carboplatin is used in the dose of 360-400 mg/m² of body surface with 4-week interval.

In case of combined chemotherapy with other antineoplastic agents, the recommended initial dose of carboplatin is 300 mg/m² of body surface with 4-week interval. The usual course of treatment is 6 cycles.

Patients, who have undergone courses of treatment with preparations having active myelosupressive action or have undergone courses of radiation therapy, carboplatin is indicated in the initial dose of 300-320 mg/m² of body surface.

Repeated coursed of carboplatin introduction should be conducted, if the count of blood corpuscles is within acceptable norms (platelets – not less than 100,000 in 1 mm³, white blood cells – not less than 2,000 in 1 mm³). If cell count is less than these levels, it is necessary to discontinue the therapy until normal index values are restored (usually in 5 – 6 weeks).

Introduction of liquid before or after carboplatin use, as well as forced diuresis are not required.

In patients with symptomatic renal dysfunction (creatinine clearance < 60 ml/min) there is an increased risk of toxicity effect development, that is why carboplatin dose should be adjusted according to the following scheme:

Creatinine clearance (ml/min)	Carboplatin doses, mg/m2 of body surface
40	400
20-39	250
0-19	150

If glomerular filtration rate is 15 ml/min and less, preparation is not indicated.

In order to prevent nausea and vomiting development, the duration of the intravenous infusion may be increased up to 24 hours, or total single dose of carboplatin is divided into 5 intravenous introduction for consecutive 5 days.

Dosed may also be calculated with the help of Calvert formula, basing on patient’s glomerular filtration rate (GFR) and desired area under pharmacokinetic curve “concentration-time” (AUC). It is necessary to pay attention to the fact that doses according Calvert formula are calculated in mg, rather than in mg/m².

Dose (mg) = desired AUC (mg/ml × min) × [GFR (ml/min) + 25]

Desired AUC	Chemotherapy	Patient’s status
5-7 mg/ml × min	Carboplatin monotherapy	Has not been treated before
4-6 mg/ml × min	Carboplatin monotherapy	Has been treated before
4-6 mg/ml × min	Carboplatin + cyclophosphamide	Has not been treated before

In case of treatment of elderly patients (aged over 60), carboplatin doses should be adjusted according to their general health state.

Precautions at preparation of the solution for infusions.

The preparation should not be diluted with infusion sets, which contain aluminum parts, as aluminum reacts with carboplatin leading to residue formation and causes decrease of its therapeutic activity.

Preventive measures during work with the preparation.

When working with the preparation, similar to the work with other antineoplastic agents, it is necessary to exercise caution. The solution for infusions should be prepared in special premises under aseptic conditions. It is necessary to use protective gloves and avoid contact of the preparation with skin and mucous membranes. In case of getting of the preparation on mucous membranes, they should be washed with water thoroughly, on skin – with water with soap.

Side effects.

From the side of blood system and lymphatic system.

Myelosupression is a dose-limiting factor at treatment with carboplatin. In case of monotherapy with carboplatin in maximally tolerated doses, thrombocytopenia (minimal platelet count < 50 × 10⁹/L) is observed in about 25 % patients. Blood platelet count usually decreases to the minimum in 14-21 days and is restored within 35 days after introduction of the preparation.

Suppression of bone marrow function may be more severe and continuous in patients with renal dysfunction, in patients, who have received chemo- and/or radiation therapy, with bad general health state and aged over 60.

In case of monotherapy with carboplatin in recommended doses with recommended periods of introduction, myelosupression is usually reversible and non-cumulative.

Leukopenia is observed in about 14 % patients. Restoration of white blood cell count usually occurs more slowly in comparison with platelets – within 42 days after introduction of the preparation (minimal white blood cell count is observed in 14 - 28 days). Neutropenia (granulocyte count < 1 × 10⁹/L) is observed in about 20 % patients. Anemia with hemoglobin levels < 11 g/dL develops in over 2/3 patients with normal initial indexes.

From the side of immune system.

Similar to other preparations, which contain platinum, carboplatin may cause allergic reactions, in particular erythematous rash, itch, fever, angioedema, anaphylactic reactions, including bronchospasm, face edema. The treatment is symptomatic.

Metabolic dysorders.

Common – abnormal results of functional hepatic tests (usually deviations are insignificant or medium) are observed in about one third of patients with normal initial indexes. Increased level of alkaline phosphatase is observed more frequently than ALT, AST or total bilirubin levels. In most cases during therapy there occurs spontaneous regression of deviations.

Non-common – after carboplatin therapy there may be observed decreased levels of serum electrolytes (sodium, magnesium, potassium and calcium), but these deviations are not significant enough to cause the development of clinical signs or symptoms.

From the side of nervous system.

Common – peripheral neuropathy develops in 4 % patients. In the majority of these patients the symptoms of neurotoxic lesion limit to paresthesia and decrease of deep tendon reflexes. The frequency and severity of side effects is higher in elderly individuals and in patients, who have received cisplatin therapy before. Paresthesia that is present before carboplatin therapy initiation, may increase during treatment with carboplatin.

Taste disorders are possible. Hallucinations, anxiety and horrors.

Single – transitory sight disorders, sometimes – transitory decrease of visual acuity. These disorders are usually associated with high dose therapy and are observed in patients with renal dysfunction. Hallucinations, anxiety and horrors are possible.

From the side of hearing organs.

Very common – subclinical decrease of hearing acuity within high-frequency range (4000-8000 Hz). However, clinical symptoms, mainly noise in ears, have been observed infrequently. In case of carboplatin treatment in patients with decreased hearing acuity caused by cisplatin treatment, their hearing may be further worsened.

From the side of vascular system.

Hemorrhagic complications, arterial hypotension, anaphylaxis.

From the side of gastrointestinal tract.

Very common - nausea without vomiting. Vomiting is observed in more than half of patients. These symptoms usually resolve within 24 hours after introduction of carboplatin. They may be reduced by antiemetic use.

Common – diarrhea, constipation, abdominal pain.

Dermatological reactions.

Alopecia.

From the side of musculoskeletal system and connective tissue.

Asthenia.

From the side of sight organs.

Sight disturbance is possible.

From the side of kidneys and urinary tracts.

Increased serum levels of urea and creatinine are possible, as well as decreased creatinine clearance, which indicates renal dysfunction. The frequency and severity of nephrotoxic lesions may be higher in patients with existing renal dysfunction. In case of significant deviations of renal test results, it is necessary to decrease the doses or discontinue carboplatin therapy and conduct symptomatic treatment.

Hyperuricemy is observed in about 25 % patients. In order to decrease uric acid concentration in serum, Allopurinol may be used.

Hemolytic-uremic syndrome. There have been cases of hematuria and edema development.

Reproductive system.

Azoospermia and amenorrhea.

Infections and invasions.

Infectious complications are possible.

General side effects.

Chills and fever, headache.

Local reactions.

Erythema development and pain at the site of injection are possible.

Overdose.

Overdose is manifested by increased toxic action. There is no specific antidote.

In case of overdose, there develops evident suppression of bone marrow blood formation (neutropenia, thrombocytopenia, and anemia) and evident signs of hepatic and/or renal insufficiency. In case of development of evident nausea and vomiting, it is recommended to introduce antiemetic preparations (Ondansetron, Metoclopramide – intravenously in high doses).

If overdose is suspected, the patient should be provided with permanent medical control, including blood formula control. In such case, the treatment should be symptomatic and supportive. Within first 3 hours after the introduction of the preparation, use of hemodialysis is possible. If necessary, blood component transfusion is indicated. Bone marrow transplantation may decrease side effects from the side of blood system.

Use during pregnancy and lactation.

The use of the preparation is contraindicated during pregnancy and lactation period due to high toxicity.

Children.

Not used.

Peculiarities of the use.

Before introduction of carboplatin and regularly during the therapy, it is necessary to determine blood corpuscle count, carry out functional renal and hepatic tests, as well as conduct neurological examinations and control hearing functions and adjust the dosed of the preparation accordingly.

Myelosupressive action of carboplatin is much dependant on its renal clearance. More severe and continuous suppression of bone marrow function is usually observed in patients with disturbed renal function, as well as in patients, who receive concomitant therapy with nephrotoxic preparations. That is why before initiation and during treatment with carboplatin, it is necessary to estimate renal function thoroughly. Usually, the duration of intervals between courses of treatment should be not less than 4 weeks. In case of combined therapy of carboplatin and other preparations with myelosupressive action, it is necessary to adjust the doses carefully and determine the time of introduction in order to minimize additional undesired effects. Patients with severe suppression of bone marrow may require transfusion therapy.

Premedicamentation with antiemetics may help reduce the frequency and severity of nausea and vomiting, caused by carboplatin use.

In case of treatment with very high dosed of carboplatin, there have been cases of hepatotoxic lesions, associated with nephrotoxic lesions.

Patients during treatment with carboplatin are recommended to use effective contraceptive agents.

Ability to influence the reaction rate when driving or operating other mechanisms.

Depending on individual sensitivity, carboplatin may disturb driving ability and operating mechanisms. That is why during treatment with the preparation it is not recommended to drive or operate mechanisms.

Interaction with other medicinal preparations and other forms of interactions.

Carboplatin is incompatible with aluminum salts (in case of interaction, there is residue formation, which leads to efficiency decrease). It increases (mutually) renal toxicity of propanolol, aminoglycosides, as well as effects of other preparations having nephrotoxic, neurotoxic, ototoxic and myelosupressive action. It decreases the effectiveness of immunization with inactivated vaccines; in case of vaccine use, which contains live viruses, it increases viral replication and side effects of the vaccination.

Carboplatin increases cicplatin-induced neurotoxic and ototoxic action (observed in 30 % patients). other myelotoxic preparations and radiation therapy increase bone marrow depression (potentiate neutropenia and thrombocytopenia).

It is known that carboplatin acts synergisticly with etoposide and vindesine.

Carboplatin should not be indicated concomitantly with the preparations that contain chelate compounds, as theoretically they may weaken antitumor action of carboplatin.

Pharmacological properties.

Pharmacodynamics. Carboplatin is antitumor preparation, which is inorganic complex platinum compound. Due to carboplatin interaction with cell DNA, there are formed internal and interspital cross-links, which change the structure and suppress synthesis of DNA, are the reason of growth arrest and reversible development of numerous types of tumors.

Regression of primary tumors and metastasis is connected with the influence of the preparation to the immune system of the organism. In experimental studies in vivo andin vitro carboplatin demonstrates mutagenic, embriotoxic and toratogenic properties.

Pharmacokinetics. After single introduction of carboplatin in the form of intravenous infusion for 1 hour, plasma concentration of total platinum and free platinum (which is liable to ultrafiltration) decreases according to biphasic kinetic model of the first order. Initial half-life of free platinum is about 1-2 hours, and terminal half-life is 3-6 hours. Total platinum is characterized by similar initial half-life, but its terminal half-life is longer (about 24 hoursи). In case of repeated dose introductions for 4 successive days, platinum accumulation in plasma has not been observed. About 85 % of platinum in plasma is bound to proteins within 24 hours after introduction.

Carboplatin is excreted mainly by kidneys. About 30 % of the dose is excreted in unchanged state. In patients with creatinine clearance over 60 ml/min, about 60-80 % of the used dose is excreted with urine within 12 hours after introduction.

Pharmaceutical characteristics.

Main physical and chemical properties:

Transparent, from colorless to pale yellowish color solution.

Incompatibility.

Do not mix or use concomitantly with other preparations in one and the same container.

Shelf life. 2 years.

Conditions of storage.

Store at temperature below 25 °С in the original package. Keep out of the reach of children.

Package.

Concentrate for preparation of the solution for infusions, 10 mg/ml in 15 ml (150 mg) or in 45 ml (450 mg) in vials No 1.

Category of dispensing.

On prescription.

Manufacturer.

Marksans Pharma Ltd.

Location.

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

Village Asaravad, Dudhia, Indor – 453 331, India.

Applicant.

Ananta Medicare Ltd.

Location.

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

Date of the last review. 25.01.2012.