Paclinor

Paclinor 100
Paclinor 260

Indications

Ovary cancer (first-line chemotherapy in case of spread form of the disease or residual tumors (with size over 1 cm) after laparotomy, in combination with cisplatin; second-line chemotherapy for metastatic ovary cancer in case of inefficacy of standard therapy with platinum preparations).

Breast cancer (adjuvant chemotherapy in breast cancer patients with lymphatic node lesion, after treatment with anthracyclines and cyclophosphamide); primary chemotherapy for locally spread or metastatic breast cancer in combination with anthracyclines or in combination with trastuzumab in case of revealed by immune histochemical method oncoprotein HER-2 (3+) overexpression or in case of present contraindications for anthracycline therapy; monotherapy for metastatic breast cancer in patients, who are not candidates for standard therapy with anthracyclines, or in case of inefficacy of previous therapy with anthracyclines.

Spread non-small cell lung cancer (NSCLC) (combined chemotherapy with cisplatin in case of impossibility of surgical treatment and/or radiation therapy).

Kaposi’s sarcoma in AIDS patients (second-line therapy for spread Kaposi’s sarcoma in case of inefficacy of previous therapy with liposomeal anthracyclines).

 



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CONFIRMED 
Order of the Ministry of 
Healthcare of Ukraine 
03.01.12 No 2
Registration Certificate
No _UA/11900/01/01
UA/11900/01/02

 

INSTRUCTION

for medical use of the preparation

PACLINOR 100

PACLINOR 260

Composition:

Active substance: paclitaxel;

1 ml of the preparation contains paclitaxel 6 mg;

Auxiliary substances: polyethoxylated ricinic oil, ethanol anhydrous, citric acid anhydrous, sodium hydroxide, concentrated hydrochloric acid.

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

Pharmacotherapeutical group. Antineoplastic agents. Taxanes. АТС code L01C D01.

Clinical characteristics.

Indications.

Ovary cancer (first-line chemotherapy in case of spread form of the disease or residual tumors (with size over 1 cm) after laparotomy, in combination with cisplatin; second-line chemotherapy for metastatic ovary cancer in case of inefficacy of standard therapy with platinum preparations).

Breast cancer (adjuvant chemotherapy in breast cancer patients with lymphatic node lesion, after treatment with anthracyclines and cyclophosphamide); primary chemotherapy for locally spread or metastatic breast cancer in combination with anthracyclines or in combination with trastuzumab in case of revealed by immune histochemical method oncoprotein HER-2 (3+) overexpression or in case of present contraindications for anthracycline therapy; monotherapy for metastatic breast cancer in patients, who are not candidates for standard therapy with anthracyclines, or in case of inefficacy of previous therapy with anthracyclines.

Spread non-small cell lung cancer (NSCLC) (combined chemotherapy with cisplatin in case of impossibility of surgical treatment and/or radiation therapy).

Kaposi’s sarcoma in AIDS patients (second-line therapy for spread Kaposi’s sarcoma in case of inefficacy of previous therapy with liposomeal anthracyclines).

Contraindications.

Hypersensitivity to paclitaxel or other components of the preparation, especially to polyethoxylated ricinic oil.

Neutropenia prior treatment (neutrophil count < 1.5×109/L, in case of Kaposi’s sarcoma in AIDS patients – neutrophil count < 1.0 ×109/L).

Pregnancy and lactation period.

Serious uncontrolled infections in case of Kaposi’s sarcoma.

Way of administration and doses.

All patients should receive pre-medication with corticosteroids, antihistamines and H2-receptor antagonists, for example, on the following scheme:

 

The preparation

Dose

Time of introduction

Dexamethasone

20 mg orally or intravenously

(8-20 mg orally in case of Kaposi’s sarcoma)

In case of oral administration: approximately 12 and 6 hours before paclitaxel introduction.

In case of intravenous administration: 30-60 minutes before paclitaxel introduction.

Diphenhydramine (or another equivalent antihistamine)

50 mg intravenously

30-60 minutes before paclitaxel introduction

Cimetidine or ranitidin

Cimetidine – 300 mg intravenously,

ranitidin – 50 mg intravenously

30-60 minutes before paclitaxel introduction

 

Paclitaxel solution should be introduced intravenously drop-by-drop with the aid of infusion systems equipped with membrane filters with pore size of ≤ 0.22 µm.

First-line chemotherapy for ovary cancer. Combined scheme of treatment with paclitaxel and cisplatin is recommended. Paclitaxel is introduced in the dose of 135 mg/m2 of body surface during 24-hour intravenous infusions, followed by cisplatin introduction in the dose of 75 mg/m2 of body surface. The intervals between courses of treatment should be 3 weeks.

Second-line chemotherapy for ovary cancer. Paclitaxel introduction is recommended in the dose of 175 mg/m2 of body surface via 3-hour intravenous infusions. The intervals between courses of treatment should be 3 weeks.

Adjuvant chemotherapy for breast cancer. Paclitaxel is indicated after chemotherapy with anthracyclines and cyclophosphamide. Paclitaxel introduction is recommended in the dose of 175 mg/m2 of body surface via 3-hour intravenous infusions, totally 4 courses with 3-week intervals between them.

First-line chemotherapy for breast cancer. In case of combined use with doxorubicin (in the dose of 50 mg/m2 of body surface), paclitaxel should be introduced in 24 hours after doxorubicin. The recommended dose of paclitaxel is 175 mg/m2 of body surface in case of 3-hour intravenous infusions. The intervals between courses of treatment should be 3 weeks.

In case of combined use with trastuzumab, it is recommended to introduce paclitaxel in the dose of 175 mg/m2 of body surface via 3-hour intravenous infusions with 3-week intervals between them. Paclitaxel may be introduced the following day after the first dose of trastuzumab or immediately after the introduction of its following doses, if previous trastuzumab doses were tolerated well.

Second-line chemotherapy for breast cancer. Paclitaxel introduction is recommended in the dose of 175 mg/m2 of body surface via 3-hour intravenous infusions. The intervals between courses of treatment should be 3 weeks.

Chemotherapy for spread non-small cell lung cancer (NSCLC). Combined scheme of treatment with paclitaxel and is recommended. Paclitaxel is introduced in the dose of 175 mg/m2 of body surface via 3-hour intravenous infusions, followed by cisplatin introduction in the dose of 80 mg/m2 of body surface. The intervals between courses of treatment should be 3 weeks.

Chemotherapy for Kaposi’s sarcoma in AIDS patients. Paclitaxel introduction is recommended in the dose of 100 mg/m2 of body surface via 3-hour intravenous infusions. The intervals between courses of treatment should be 2 weeks.

The following doses of paclitaxel are calculated individually due to therapy tolerance. The following dose of paclitaxel may be introduced only when neutrophil count is increases to the level ≥ 1.5×109/L, and platelet count – to the level of ≥ 100×109/L. In patients with severe neutropenia (neutrophil count is < 0.5×109/L for 7 days and more) or severe peripheral neuropathy, the following doses should be decreased by 20 % (25 % in case of Kaposi’s sarcoma).

Preparation of the solution for intravenous infusions.

Concentrate for preparation of the solution for the infusions should be diluted under aseptic conditions with 0.9 % sodium chloride solution, 5 % glucose solution, 5 % glucose solution in 0.9 % sodium chloride solution or 5 % glucose solution in Ringer's solution to final concentration of 0.3-1.2 mg/ml.

In case of multiple sampling of the preparation from the vial, concentrate for preparation of the solution for infusions stays microbiologically, physically and chemically stable for up to 28 days at temperature 25 °C.

From microbiological point of view, the solution for infusions should be introduced immediately after preparation. If the solution is not used immediately, the user should control the duration and conditions of its storage. Usually, solutions for infusions prepared according to recommendations stay physically and chemically stable for up to 27 hours at temperature about 25 °С and room light conditions. The solution for infusions should be introduced via infusion system with incorporated membrane filter with pore size ≤ 0.22 µm.

Prepared solutions for infusions do not require protection from light.

There have been single reports about residue formation in the solution for infusions during the introduction process (usually at the end of 24-hour period of introduction). Although exact reasons of residue formation have not been established, this phenomenon may possibly be conditioned by oversaturation of the solution for infusions. In order to decrease the risk of residue formation, the solution for infusions should be introduced immediately after preparation and avoid excessive shaking, vibrations and agitation. Infusion system should be washed thoroughly before use. During the process of introduction, it is necessary to control the appearance of the solution regularly and if any residue is revealed, the infusion should be discontinued.

In order to minimize getting of di(2-ethyl hexyl)phthalate (DEHP) into patient’s organism, as it may leach from infusion bags, systems or other medical equipment made of plasticized polyvinylchloride (PVC), the solution for infusions should be stored in containers made of materials, which do not contain PVC (glass or polypropylene bottles, polypropylene or polyolefine bags), and should be introduced via infusion systems, lined with polyethylene. In case of connection of filters (for example, IVEX-2®) with short PVC tubes, significant DEHP leaching does not occur.

Side effects.

Side effects in case of monotherapy with paclitaxel via 3-hour infusions.

Infections and invasions.

Very often (≥ 10 %). Infections (mainly infections of urinary tracts and upper respiratory tracts), in single cases with lethal outcomes.

Not often (≥ 0.1 % - < 1 %). Septic shock.

Single (≥ 0.01 % - < 0.1 %). Pneumonia, peritonitis, sepsis.

From the side of blood system and lymphatic system.

Very often (≥ 10 %). Myelosupression, neutropenia, anemia, thrombocytopenia, leukopenia, bleedings.

Single (≥ 0.01 % - < 0.1 %). Febrile neutropenia.

Rare (< 0.01 %). Acute myeloid leukosis, myelodysplastic syndrome.

From the side of the immune system.

Very often (≥ 10 %). Mild reactions of hypersensitivity (mainly hot flushes and rash).

Not often (≥ 0.1 % - < 1 %). Serious reactions of hypersensitivity, which require use of therapeutic measures (in particular, arterial hypotension, angioneurotic edema, respiratory distress, generalized urticaria, chill, pain in the back, pain in the chest, tachycardia, abdominal pain, pain in extremities, profuse perspiration, arterial hypertension).

Single (≥ 0.01 % - < 0.1 %). Anaphylactic reactions.

Rare (< 0.01 %). Anaphylactic shock.

Metabolic disorders.

Rare (< 0.01 %). Anorexia.

From the side of psychics.

Rare (< 0.01 %). Confused mental state.

From the side of nervous system.

Very often (≥ 10 %). Neurotoxic effects (mainly peripheral neuropathy).

Single (≥ 0.01 % - < 0.1 %). Motor neuropathy (which is manifested by moderately evident weakness of distal muscles).

Rare (< 0.01 %). Vegetative neuropathy (which leads to paralytic bowel obstruction and orthostatic hypotension), big epileptic attacks (“grand mal”), convulsions, encephalopathy, giddiness, headache, ataxia.

From the side of organs of vision.

Rare (< 0.01 %). Optic nerve lesion and/or visual impairment (scintillating scotoma), espessially in patients, who received doses higher than recommended ones.

From the side of organs of hearing and labyrinth lesions.

Rare (< 0.01 %). Ototoxic lesions, loss of hearing, tinnitus, vertigo.

From the side of heart.

Often (≥ 1 % - < 10 %). Bradycardia.

Not often (≥ 0.1 % - < 1 %). Cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia in combination with bigeminy, atrioventricular heart block and unconsciousness, myocardial infarction.

Rare (< 0.01 %). Auricular fibrillation, supraventricular tachycardia.

From the side of vessels.

Very often (≥ 10 %). Arterial hypotension.

Not often (≥ 0.1 % - < 1 %). Arterial hypertension, thrombosis, trombophlebitis.

Rare (< 0.01 %). Shock.

From the side of respiratory system.

Single (≥ 0.01 % - < 0.1 %). Dyspnea, pleural effusion, interstitial pneumonitis, pulmonary fibrosis, pulmonary embolism, respiratory insufficiency.

Rare (< 0.01 %). Cough.

From the side of digestive system.

Very often (≥ 10 %). Nausea, vomiting, diarrhea, inflammation of mucous membranes.

Single (≥ 0.01 % - < 0.1 %). Intestinal obstruction, intestinal perforation, ischemic colitis, pancreatitis.

Rare (< 0.01 %). Mesenteric ischemia, pseudomembranous colitis, esophagitis, constipation, ascites, neutropenic colitis.

From the side of hepatobilliary system.

Rare (< 0.01 %). Liver necrosis, hepatic encephalopathy (cases with lethal outcome have been reported).

From the side of skin and subcutaneous tissues.

Very often (≥ 10 %). Alopecia.

Often (≥ 1 % - < 10 %). Transitory insignificant changes of nails and skin.

Single (≥ 0.01 % - < 0.1 %). Itching, rash, erythema.

Rare (< 0.01 %). Stevens-Johnson syndrome, epidermal necrosis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients, who receive paclitaxel, should wear corresponding clothes in order to protect them from the sun).

From the side of musculoskeletal system.

Very often (≥ 10 %). Arthralgia, myalgia.

General effects and local reactions.

Often (≥ 1 % - < 10 %). Injection site reactions (localized edema, pain, erythema, induration, occasional extravasation may cause cellulites, skin fibrosis and skin necrosis).

Single (≥ 0.01 % - < 0.1 %). Asthenia, increased body temperature, dehydration, edema, malaise.

Laboratory indexes.

Often (≥ 1 % - < 10 %). Significantly increased levels of AST and alkaline phosphatase.

Not often (≥ 0.1 % - < 1 %). Significantly increased levels of bilirubin.

Single (≥ 0.01 % - < 0.1 %). Increased levels of blood creatinine.

Side effects in case of combined chemotherapy.

In case of paclitaxel and cisplatin combination use, the most evident side effects are neurotoxic effects (mainly peripheral neuropathy, arthralgia, myalgia) and myelosupression.

In case of combination of paclitaxel with doxorubicin, predominant ones are the lesions of heart contractility, neutropenia, anemia, peripheral neuropathy, arthralgia, myalgia, asthenia, fever and diarrhea.

The use of paclitaxel with trastuzumab most often leads to the development of cardiac insufficiency, tachycardia, infectious complications, chill, fever, cough, rash, arthralgia, diarrhea, arterial hypertension, nasal bleedings, acne, insomnia, rhinitis, sinusitis, injection site reactions.

Overdose.

There is no specific antidote. In case of overdose one may expect more severe side effects, first of all suppressed function of bone marrow, peripheral neurotoxic effects and inflammation of mucous membranes. The treatment is symptomatic; detoxication therapy is recommended.

Use during pregnancy and lactation.

There is data that paclitaxel is embriotoxic and fetotoxic, it also has unfavorable influence on animal fertility.

There is no information as for paclitaxel therapy in pregnant women. Similar to other cytotoxic preparations, paclitaxel may be harmful for the fetus, that is why it should not be indicated during pregnancy. Female patients should exercise measures to avoid pregnancy during treatment with paclitaxel and inform the doctor immediately about possible pregnancy.

Paclitaxel excretion into human breast milk has not been studied. During treatment with paclitaxel breast feeding should be discontinued.

Children.

Specific information as for treatment of children is absent.

Special safety measures.

During work with paclitaxel, similar to other antineoplastic preparations, it is necessary to exercise caution. The preparation should be diluted under aseptic conditions in special premises. It should be carried out by the trained staff. It is necessary to employ all measures to prevent getting paclitaxel solution on skin and mucous membranes, in particular, protective clothes should be used (coats, caps, masks, eye-glasses and disposable gloves). If the preparation gets on the skin (in this case such local reactions as tingling, burning and reddening of the skin are possible), the affected area is washed with water and soap. If the preparation gets on mucous membranes, they are washed thoroughly with much water. There have been reports about dyspnea, pain in the chest, burning in the throat and nausea when breathing sprayed solutions of paclitaxel.

When cooled, unsealed vials of the preparation may have residue, which is dissolved at careful shaking or even without mixing at room temperature. This phenomenon has no influence on the quality of the preparation. If the solution stays turbid or contains insoluble residue, the preparation should not be used and this vial should be destroyed according to the set procedure of dangerous waste utilization.

Peculiarities of the use.

Paclitaxel treatment should be carried out under supervision of a qualified doctor-oncologist. As serious reactions of hypersensitivity are possible, appropriate resuscitation equipment should be present.

In case of combined use with cisplatin, paclitaxel should be introduced before cisplatin.

In case of paclitaxel introduction after appropriate pre-medication, severe reactions of hypersensitivity (that are manifested as dyspnea and arterial hypotension, which require therapeutic measures, angioneurotic edema and generalized urticaria) are observed in less than 1 % of patients. Possibly these reactions are histamine-mediated. In case of severe reactions of hypersensitivity, paclitaxel introduction should be discontinued immediately and symptomatic treatment should be initiated. These patients paclitaxel should not be indicated repeatedly.

Suppression of bone marrow function (mainly neutropenia) is the main dose-limiting toxic effect. During treatment with paclitaxel, it is necessary to control the quantity of blood corpuscles regularly. Repeated introduction of the preparation is allowed only after increase of neutrophil count to the level ≥ 1.5×109/L, and platelet count – to the level of ≥ 100×109/L.

Severe lesions of cardial conduction in case of paclitaxel monotherapy are observed seldom. In case of development of significant lesions of cardial conduction during paclitaxel therapy, corresponding treatment is indicated, and continuous monitoring of cardiac function is conducted during following introductions of paclitaxel. During paclitaxel introduction there has been observed arterial hypotension, arterial hypertension and bradycardia, usually they are asymptomatic and do not require therapeutic measures. Frequent control of vital indexes is recommended, especially during the first hour of paclitaxel introduction. Severe cardio-vascular lesions are observed more often in patients with non-small cell lung cancer, than in brest cancer or ovary cancer patients.

When paclitaxel is used in combination with doxorubicin or trastuzumab as primary chemotherapy for metastatic breast cancer, it is necessary to pay attention to control of cardiac function. Patients, who are candidates for such combined therapy, should undergo thorough cardiological investigation before treatment initiation, which includes ECG and EcoCG-investigations, as well as MUGA-scanning. During treatment it is necessary to control cardiac function regularly (for example, every 3 months). Such monitoring allows revealing the development of cardiac dysfunction. When making the decision about frequency of ventricle function control, it is necessary to consider the cumulative dose of anthracyclines (in mg/m2 of body surface). If the results of investigations demonstrate evidence of cardiac dysfunction, even asymptomatic one, it is necessary to weigh thoroughly the potential benefit of treatment continuation and possible risk of heart lesion, sometimes irreversible. In case of continued combined chemotherapy, it is necessary to control cardiac function more often (every 1-2 courses).

In spite of the fact that peripheral neuropathy is a frequent side effect at paclitaxel treatment, severe neuropathy develops seldom. In serious cases it is recommended to decrease all the following doses of paclitaxel by 20 % (25 % in case of Kaposi’s sarcoma). Peripheral neuropathy may develop after the first course of therapy and become more severe in case of further treatment with paclitaxel. Sensory disorders usually become weaker or disappear within several months after the end of paclitaxel therapy. Present neuropathy due to previous chemotherapy is not a contraindication for paclitaxel treatment.

The risk of toxic effects (in particular, myelosupression of III-IV degree of severity) is higher in patients with disturbed hepatic function. In case of paclitaxel introduction via 3-hour infusions, no enhancement of toxic effects in patients with mild hepatic dysfunction is observed. However, in case of more long-term introduction of paclitaxel in patients with moderate hepatic dysfunction, more evident myelosupression is observed. Paclitaxel should not be indicated in patients with severe hepatic dysfunction. Patients should be monitored carefully in order to reveal any signs of development of deep myelosupression. Up to date, there is no sufficient data for development of recommendation as for dose adjustment in patients with mild and moderate hepatic dysfunction. There is no information as for paclitaxel treatment in patients with severe cholestasis.

As the preparation contains ethanol, its possible influence on the central nervous system should be taken into consideration, as well as other effects.

There have been single cases of pseudomembranous colitis development, in particular, in those patients, who did not receive concomitant antibiotic therapy. It should be taken into account at differentiated diagnostics in case of development of sever or persisting diarrhea during or short after paclitaxel treatment.

In case of paclitaxel chemotherapy in combination with radiation therapy on lung area, irrespectively of their order, there have been cases of interstitial pneumonitis development.

In case of severe reactions, paclitaxel doses are decreased by 25 %.

In case of paclitaxel use in combination with other antineoplastic preparations (cisplatin, doxorubicin, trastuzumab), it is necessary to take into account corresponding recommendations as for the use of these medicinal preparations.

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

During treatment with paclitaxel it is recommended to avoid potentially dangerous types of activity that require increased attention as well as psychic and locomotive reaction rate. It should be taken into consideration that the preparation contains alcohol and some side effects may influence negatively the ability to drive or work with other mechanisms.

Interaction with other medicinal preparations and other forms of interactions.

Per-medication with cimetidine does not influence paclitaxel clearance.

In case of combined first-line chemotherapy for ovary cancer, paclitaxel should be introduced before cisplatin. In this case paclitaxel safety profile does not differ ftom that in case of monotherapy. If paclitaxel is introduced after cisplatin, more severe myelosupression is observed, and paclitaxel clearance decreases approximately by 20 %. The risk of renal insufficiency development in ovary cancer patients, who receive combined therapy with paclitaxel and cisplatin, is higher than that in case of cisplatin monotherapy.

As elimination of doxorubicin and its active metabolites may be decreased in case of decreased period of time between paclitaxel and doxorubicin introduction, at primary chemotherapy for metastatic breast cancer, paclitaxel should be introduced in 24 hours after doxorubicin.

Paclitaxel metabolism is partially catalyzed by CYP2C8 and CYP3A4 izoenzymes of cytochrome Р450 system. The main metabolic pathway in human is CYP2C8-mediated transformation of paclitaxel into 6α-hydroxypaclitaxel. Concomitant use of ketoconazole, a powerful CYP3A4 inhibitor, does not slow paclitaxel elimination from human organism, that is why both these preparations may be used concomitantly without dose adjustment. The information as for potentially possible interaction of paclitaxel with CYP3A4 inducers and inhibitors is limited, so, caution should be exercised in case of concomitant indication of inhibitors (for example, erythromycin, fluoxetine, gemfibrozil) or inducers (for example, rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) of CYP2C8 and CYP3A4 izoenzymes.

Paclitaxel pharmacokinetic study in Kaposi’s sarcoma patients, who received concomitant therapy with several preparations, demonstrates significant decrease of paclitaxel systemic clearance in case of concomitant use of nelfinavir and ritonavir, but not indinavir. There is not enough information as for interaction of paclitaxel with other protease inhibitors. That is why paclitaxel should be indicated with caution in patients, who receive concomitant therapy with protease inhibitors.

Pharmacological properties.

Pharmacodynamics. Paclitaxel is an antimitotic agent, which acts on cell microtubule apparatus. Paclitaxel’s mechanism of action lies in stimulation of microtubule construction from tubulin dimmers and their stabilization as well as prevention of depolymerization. As a result, normal process of dynamic reorganization of microtubule nets, which is important for cell functions at the stages of interphase and mitosis, is disturbed. In addition, paclitaxel causes formation of anomalous aggregations or “bundles”of microtubules during cell cycle, as well as multiple “stars” from microtubules during mitosis.

Pharmacokinetics. After intravenous introduction of the preparation there is observed two-phase decrease of paclitaxel plasma concentration.

Paclitaxel pharmacokinetics has been studied at intravenous introduction of the preparation for 3 and 24 hours in the doses of 135 mg/m2 and 175 mg/m2 of body surface. Mean duration of half-life period in the terminal phase was 3.0-52.7 hours, and mean general clearance from the organism – 11.6-24.0 L/h·m2. Probably, paclitaxel general clearance from the organism decreases in case of increase of its plasma concentration. Mean paclitaxel equilibrium distribution volume was 198-688 L/m2, which suggests wide extra-vascular distribution and/or binding with tissues. At infusions with 3-hour duration, paclitaxel pharmacokinetics had non-linear character. At dose increase by 30 % (from 135 mg/m2 to 175 mg/m2 of body surface), maximal plasma concentration, Сmax, and area under pharmacokinetic curve, AUC→∞, increases by 75 % and 81 %, respectively.

After paclitaxel introduction in the dose of 100 mg/m2 of body surface via 3-hour intravenous infusions, mean value of Cmax in 19 Kaposi’s sarcoma patients was 1530 ng/ml (range 761-2860 ng/ml), mean area under pharmacokinetic curve – 5619 ng·h/ml (range 2609-9428 ng·h/ml), clearance – 20.6 L/h·m2 (range 11-38 L/h·m2), distribution volume – 291 L/m2 (range 121-638 L/m2), and half-life period in the terminal phase – 23.7 h (range 12-33 hours).

Intrasubject variability of indexes of paclitaxel systemic exposition was minimal. No signs of paclitaxel accumulation at several courses of treatment were revealed.

Results of studies in vitro indicate to the fact that 89-98 % paclitaxel is bound to human plasma proteins. The presence of cimetidine, ranitidin, dexamethasone or diphenhydramine does not influence paclitaxel protein binding.

Paclitaxel metabolism in human organism is not studied enough. From 1.3 % to 12.6 % of the introduced dose is excreted with urine in unchanged state, which demonstrates extensive non-renal clearance. Possibly, paclitaxel is metabolized mainly in the liver with participation of izoenzymes of cytochrome Р450 system and are excreted with bile. After introduction of paclitaxel, marked with radioactive isotope, on average 26 %, 2 % and 6 % of radioactivity was excreted with feces as 6α-hydroxypaclitaxel, 3’-р-hydroxypaclitaxel and 6α-3’-р-dihydroxypaclitaxel, respectively. Formation of these hydroxilated metabolites is catalized by izoenzymes CYP2C8, CYP3A4 and CYP2C8+CYP3A4 together, respectively. The influence of renal abd hepatic dysfunction on paclitaxel pharmacokinetics in case of 3-hour infusions has not been studied formally. Pharmacokinetic indexes in one patient, who required hemodialysis and was treated with paclitaxel in the dose of 135 mg/m2 of body surface via 3-hour infusions, did not differ from indexes of patients without renal dysfunction.

In case of combined use of paclitaxel and doxorubicin,there was observed an increase in duration of distribution and elimination of doxorubicin and its metabolites. In case of immediate paclitaxel introduction after doxorubicin, the indexes of general exposition of doxorubicin in plasma were 30 % higher than in case of paclitaxel introduction in 24 hours after doxorubicin.

Pharmaceutical characteristics.

Main physical and chemical properties: transparent, from colorless to pale yellow color solution.

Incompatibility.

Polyoxylated ricinic oil, which is present on Paclinor composition, may cause leaching of di(2-ethyl hexyl)phthalate (DEHP) from plasticized polyvinylchloride (PVC). The intensity of this process depends on duration of the action and concentration of ricinic oil. That is why it is necessary to prepare, store and introduce the solution for infusions with the use of containers and systems, which do not contain PVC.

Should not be used with other solvents, except those indicated under Section “Way of administration and doses”.

Shelf life. 2 years.

Conditions of storage. Store at temperature below 25 °С in the original package. Keep out of the reach of children. Do not freeze.

Package. 16.7 or 43.4 ml of the solution in a vial, 1 vial in a carton.

Category of dispensing. On prescription.

Manufacturer. Marksans Pharma Ltd.

Location.

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.

Applicant. Ananta Medicare Ltd.

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

Date of the last review. 03.01.2012.