Taxol - instructions for use, dose, side effects, contraindications

The mechanism of action is associated with the ability to stimulate the assembly of microtubules from dimeric tubulin molecules, stabilize their structure by suppressing depolymerization, and inhibit dynamic reorganization in the interphase, which disrupts the mitotic function of the cell. Besides, paclitaxel induces the formation of abnormal clumps, or "bundles," of microtubules throughout the cell cycle and causes the formation of multiple microtubule stars during mitosis.

According to experimental data it has mutagenic and embryotoxic properties, it causes a decrease in reproductive function.

Pharmacokinetics:

The concentration of paclitaxel in the blood plasma after intravenous administration decreases in accordance with two-phase kinetics.

The pharmacokinetics of paclitaxel was determined after infusion of the drug at doses of 135 and 175 mg / m² for 3 and 24 hours. The half-life and total clearance of paclitaxel are variable and depend on the dose and duration of administration: from 13.0 to 52.7 parts, from 12.2 to 23.8 l / h / m² respectively. Average volume distribution ranges from 198 to 688 l / m.

With multiple courses of treatment, cumulation of paclitaxel is not noted.

The connection with plasma proteins is an average of 89%.

In studies in vitro on liver microsomes revealed that paclitaxel metabolized in the liver with the participation of isoenzyme CYP2C8 up to 6-alpha-hydroxypaclitaxel and with the participation of isoenzyme CYP3A4 up to 3-para-hydroxy-paclitaxel and 6-alpha, 3-para-dihydroxy paclitaxel.

Excretion

After intravenous infusion of Taxol® (15-275 mg / m²) for 1 hour, 6 hours or 24 hours, 1.3-12.6% of the administered dose was excreted by the kidneys unchanged. After a 3-hour infusion of radioactive paclitaxel in doses of 225-250 mg / m, for 120 h.

14% of the radioactivity was excreted by the kidneys, 71% by the intestine.

5% of the introduced radioactivity was excreted intestine unchanged, the rest were metabolites, mainly 6-alpha-hydroxy-paclitaxel.

Indications:

Ovarian Cancer

-Therapy of the first line in combination with platinum preparations in patients with advanced ovarian cancer or with a residual tumor (more than 1 cm) after the initial laparotomy.

- Therapy of the 2nd line in patients with metastatic ovarian cancer after standard therapy, which did not lead to a positive result.

Mammary cancer

- Adjuvant therapy in patients with lymph node metastases after standard combined treatment;

- First-line therapy in patients with advanced cancer or metastatic cancer after relapse of the disease within 6 months after initiation of adjuvant therapy, including anthracycline-based drugs, in the absence of indications for their use;

- Therapy 1st line treatment for patients with advanced cancer or breast cancer in combination with a number of anthracycline drugs metastatic cancer in the absence of contraindications for their use, or in combination with trastuzumab in patients with confirmed immunohistochemically 2+ or 3+ level of expression HER-2;

- Second-line therapy in patients with advanced cancer or metastatic cancer with progression of the disease after combined chemotherapy. Prior therapy should include anthracycline-based drugs in the absence of contraindications for their use.

Non-small cell lung cancer

First-line therapy in combination with cisplatin or in the form of monotherapy in patients who do not plan surgical treatment and / or radiation therapy.

Sarcoma Kaloshi, due to AIDS

Therapy of the 2nd line.

Contraindications:

- Hypersensitivity to paclitaxel or any component preparation, especially to macragol glycerylricinoleate (polyoxyethylated castor oil);

- The initial content of neutrophils is less than 1500 / μL in patients with solid tumors;

- The initial or recorded neutrophil count in the treatment process is less than 1000 / μl in patients with Kaloshi's sarcoma caused by AIDS;

- Concomitant severe uncontrolled infections in patients with Kalosha's sarcoma;

- Pregnancy and the period of breastfeeding;

- Children's age (there is insufficient data on the safety and efficacy of the drug).

Carefully:- thrombocytopenia (less than 100,000 / μL),

- liver failure,

- acute infectious diseases (including herpes zoster, chicken pox, herpes),

- severe course of ischemic heart disease,

- myocardial infarction (in the anamnesis),

- arrhythmias.

Dosing and Administration:To avoid severe hypersensitivity reactions, all patients should undergo premedication with glucocorticosteroids, H1 and H2-histamine receptor blockers, for example: - 20 mg dexamethasone (or its equivalent) inside approximately 12 and 6 hours before administration of Taxol® or 20 mg of dexamethasone intravenously about 30-60 minutes prior to administration of Taxol®, 50 mg diphenhydramine (or its equivalent) intravenously and 300 mg of cimetidine or 50 mg of ranitidine intravenously 30-60 minutes before the administration of Taxol®.

In patients with solid tumors, repeated courses of treatment with Taxol® are prescribed only after reaching a neutrophil count of 1500 / μl (1000 / μl in patients with Kaposi's AIDS-related sarcoma) and platelet counts of 100,000 / μL (75,000 / μL in patients with sarcoma Kaposi, due to AIDS). For patients who developed severe neutropenia (neutrophil counts less than 500 / μL for more than one week) or with severe periphyric neuropathy, subsequent courses of treatment with Taxol® should reduce the dose by 20% (by 25% in patients with sarcoma Kaposi, due to AIDS). Neurotoxicity and neutropenia are dose-dependent.

Ovarian Cancer

Therapy of the first line

- 1 every 3 weeks: 175 mg / m² in the form of a 3-hour intravenous infusion with subsequent administration of a platinum drug

- 1 time in 3 weeks: 135 mg / m² in the form of a 24-hour clock infusion with subsequent administration of the drug platinum.

Therapy of the second line (monotherapy)

- 1 every 3 weeks: 175 mg / m² in the form of 3 hour intravenous infusion.

Mammary cancer

Adjuvant therapy is held after standard combined treatment.The drug Taxol® is administered at a dose of 175 mg / m²at as a 3-hour intravenous infusion. Total it is recommended to conduct 4 courses of therapy with an interval of 3 weeks.

Therapy of the first line

- monotherapy: 175 mg / m² in the form of 3 hours intravenous infusion every 3 weeks.

- combination therapy:

- With trastuzumab: the next day after the first dose of trastuzumab-175 mg / m² of Taxol® in the form of 3 hour intravenous infusion, every 3 weeks, with good tolerability trastuzumab immediately after administration subsequent doses of trastuzumab.

- With doxorubicin (50 mg / m²): after 24 hours after the administration of doxorubicin - 220 mg / m² of Taxol® in the form of 3 hour intravenous infusion, every 3 of the week.

Therapy of the second line

- 175 mg / m² in the form of a 3-hour intravenous infusion every 3 weeks.

Non-small cell lung cancer

combination therapy

- 175 mg / m² in the form of a 3-hour intravenous infusion, then - a platinum preparation, every 3 weeks

- 135 mg / m² in the form of a 24-hour infusion, then - a platinum drug, every 3 weeks.

monotherapy

- 175 mg / m² - 225 mg / m² in the form of 3 hours intravenous infusion, every 3 weeks.

Kaposi's sarcoma AIDS

Therapy of the second line

- 135 mg / m² in the form of a 3-hour intravenous infusion, every 3 weeks or100 mg / m²intravenously drip for 3 hours, every 2 weeks (45-50 mg / m²in Week). AT dependence on the level of immunosuppression in patients with far-reaching form of AIDS, the following measures are recommended:

- Decreased oral dose of dexamethasone (in premedication composition) up to 10 mg,

- Use of Taxol® only with the neutrophil count is at least 1000 cells / ml of blood, platelets - 75 000 / μL;

- with severe neutropenia (less than 500 cells / μl of blood for a week or more) or severe peripheral neuropathy - a reduction in the dose of Taxol® by 25% in subsequent courses of therapy;

- if necessary - the appointment of a granulocyte colony-stimulating factor (G-CSF).

Application for violations of liver function

Patients with hepatic insufficiency and associated increased risk of toxicity (in particular, myelosuppression of grade III-IV) are recommended dose adjustment of Taxol®.

It is necessary to establish close monitoring of the condition of patients.

Table 1

Recommended doses for patients with impaired hepatic function

Degree of hepatic impairment
Activity of "liver" transaminases	Bilirubin concentration in blood serum, μmol / l	Dose * of the drug Taxol, mg / m²
24 hour infusion
<2 × VGN and	≤26	135
2−<10 × VGN and	≤26	100
<10 × VGN and	28-129	50
≥10 × VGN or	>129	Not recommended
3 hour infusion
<10 × VGN and	≤22 × VGN	175
<10 × VGN and	22-25 × VGN	135
<10 × VGN and	35-86 × VGN	90
≥10 × VGN or	>86 × VGN	Not recommended

* recommended doses for the first course therapy; dose adjustment for The following courses should be based on on individual tolerance preparation.

VGN - the upper limit of the norm

Side effects:Side effects are usually not differ in frequency and severity with treatment of ovarian cancer, breast cancer gland, non-small cell lung cancer or Kaposi's sarcoma. However, in patients with Kaposi's sarcoma caused by AIDS, more often than usual, infections are more severe (including opportunistic), oppression hemopoiesis, febrile neutropenia.

Side effects with monotherapy:

Frequency of occurrence of side effects is given in accordance with the following scale: very often (≥1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥ 1/10000, <1/1000), very rarely (<1/10000), frequency is unknown (can not be evaluated with the help of available data).

NOTE: marked with an asterisk postmarketing data on effects.

From the hematopoiesis:

Very often: myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, fever, bleeding.

Rare: febrile neutropenia.

Very rarely: acute myeloid leukemia, myelodysplastic syndrome.

From the immune system:

Very often: minor reactions hypersensitivity, mainly manifested in the form of hyperemia ("hot flashes" of blood) and skin rashes.

Infrequent: marked hypersensitivity reactions requiring treatment (eg, lowering blood pressure (BP), angioedema, impaired breathing, generalized urticaria, swelling, back pain, chills).

Rarely *: anaphylactic reactions (including fatal outcome).

Very rarely *: anaphylactic shock.

From the nervous system:

Very often: neurotoxicity (mainly peripheral neuropathy).

Rarely: motor neuropathy (leading to a slight weakness of the limbs);

Very rarely *: confusion, vegetative neuropathy, which manifests itself as a paralytic impassability intestinal and orthostatic hypotension, epileptic seizures of the type grand mal, convulsions, encephalopathy, dizziness, headache, ataxia.

From the cardiovascular system:

Very often: changes in the ECG, lowering blood pressure (BP).

Often: aetiology.

Infrequent: increased arterial pressure (BP), thrombosis, thrombophlebitis, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigemia, atrioventricular block and fainting, myocardial infarction.

Very rarely: atrial fibrillation, supraventricular tachycardia, shock.

From the respiratory system:

Rarely *: shortness of breath, pleural effusion, respiratory failure, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism.

Very rarely: cough.

From the gastrointestinal tract:

Very often: nausea, vomiting, diarrhea, mucositis.

Rarely: intestinal obstruction, intestinal perforation, ischemic colitis, pancreatitis.

Very rarely *: thrombosis of the mesenteric artery, pseudomembranous colitis, esophagitis, constipation, ascites, anorexia.

From the liver and bile ducts:

Very rarely *: hepatonecrosis (fatal), hepatic encephalopathy (fatal).

From the side of the organ of vision:

Very rarely: reversible lesions optic nerve and / or visual impairment (ciliary scotoma, or eye migraine), photopsy, destruction vitreous body of the eye;

Frequency unknown *: macular edema.

From the organ of hearing:

Very rarely *: loss of hearing, tinnitus, vertigo (vestibular dizziness), ototoxicity.

From the skin, subcutaneous tissue and skin appendages:

Very often: alopecia.

Often: temporary minor changes in skin and nails.

Rarely: itching, rash, erythema, phlebitis, inflammation of subcutaneous fat, exfoliation of the skin, necrosis and fibrosis of the skin, skin lesions reminiscent of the effects of radiation therapy.

Very rarely *: Stevens-Johnson syndrome, epidermal necrolysis, multiforme exudative erythema, exfoliative dermatitis, urticaria, onycholysis.

Frequency unknown: scleroderma, cutaneous lupus erythematosus *.

From the musculoskeletal system:

Very often: arthralgia, myalgia.

Frequency unknown *: systemic lupus erythematosus.

Local reactions:

Often: local edema, pain, erythema, induration.

From the laboratory indicators:

Often: increased activity aspartate aminotransferase (ACT), increased activity of alkaline phosphatase;

Infrequent: increased concentration bilirubin;

Rarely *: increased concentration of serum creatinine.

Other:

Very often: attachment of secondary infections;

Uncommon: septic shock;

Rarely *: pneumonia, sepsis, asthenia, general malaise, fever, dehydration, peripheral edema;

Frequency unknown *: tumor lysis syndrome.

Side effects with combination therapy

Preparation Taxol ® + cisplatin at therapy of the first line of ovarian cancer

The frequency and severity of neurotoxicity, arthralgia / myalgia and hypersensitivity are higher compared with cyclophosphamide and cisplatin. In contrast, manifestations of myelosuppression are less frequent and less pronounced than with cyclophosphamide and cisplatin.

Manifestations of severe neurotoxicity when used in combination with cisplatin at a dose of 75 mg / m² are less common with the use of Taxol ® in a dose of 135 mg / m² in the form of a 24-hour infusion, than when administered at a dose of 175 mg / m² in the form of a 3-hour infusion.

Preparation Taxol ® + trastuzumab in the treatment of breast cancer

With the use of Taxol ® in combination with trastuzumab for the treatment of the first line of metastatic breast cancer, the following side effects were noted more often than with monotherapy with Taxol®: heart failure, infections, chills, fever, cough, rash, arthralgia, tachycardia, diarrhea , increase blood pressure (BP), nasal bleeding, acne, herpetic eruptions, accidental injuries, insomnia, rhinitis, sinusitis, reactions at the injection site. The use of Taxol® in combination with trastuzumab for second-line therapy (after anthracycline-based drugs) led to an increase in the incidence and severity of cardiac abnormalities (in rare cases, fatal) compared with monotherapy with Taxol®. In most cases, the side effects were reversible after the appointment of the appropriate treatment.

Preparation Taxol ® + doxorubicin in the treatment of breast cancer

There were cases of congestive heart failure in patients who had not previously received chemotherapy. In patients who had previously received chemotherapy courses, especially with the use of anthracyclines,often there was a violation of cardiac activity, a decrease in the fraction of ejection from the left ventricle and a failure of the function of the ventricles. In rare cases, myocardial infarction was noted.

Taxol ® preparation + radiotherapy

In patients who were simultaneously prescribed the drug Taxol® and Radiation therapy, there were cases of radiation pneumonitis.

Overdose:

Symptoms: bone marrow aplasia, peripheral neuropathy, mucositis.

Treatment: symptomatic.

The antidote to paclitaxel is not known.

Interaction:Cisplatinum: With the administration of Taxol® after cisplatin, myelosuppression is more pronounced, and clearance of paclitaxel is lower by 20% than when cisplatin is administered after Taxol®.

Doxorubicin: With the use of Taxol ® in combination with doxorubicin, the content of doxorubicin and its active metabolite of doxorubicinol in the blood serum can increase. Such side effects as neutropenia and stomatitis are more pronounced with the use of Taxol® before doxorubicin, as well as with a longer infusion than recommended.

Substrates, inducers and inhibitors isozymes CYP2C8 and CYP3A4:

Paclitaxel is metabolized with the participation of isoenzymes CYP2C8 and CYP3A4, therefore caution should be exercised when using Taxol® on the background of treatment with substrates (for example, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin,triazolam, repaglinide and rosiglitazone), of data inducers (eg, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) or inhibitors (e.g., erythromycin, fluoxetine, gemfibrozil, ketoconazole, ritonavir, indinavir, nelfinavir) of these isoenzymes.

Special instructions:

The use of Taxol® should be carried out under the supervision of a doctor who has experience with antineoplastic chemotherapeutic preparations.

The drug Taxol® should be used as a diluted solution. Before introduction of preparation Taxol® to the sick Premedication with glucocorticosteroids, blockers H1- and H2 - histamine receptors. If the drug Taxol® used in combination with cisplatin, Taksol® should first be administered, and then cisplatin.

Anaphylaxis and severe hypersensitivity reactions

In less than 1% of patients, despite the premedication, serious reactions of hypersensitivity were observed in the treatment with Taxol®. The frequency and severity of such reactions did not depend on the dose and scheme of administration of the drug. With the development of severe reactions, choking, flushing, chest pain, tachycardia, as well as abdominal pains, pains in the extremities, increased sweating, increased blood pressure (BP) were most often observed.

With the development of severe hypersensitivity reactions, the administration of Taxol® should be stopped immediately and, if necessary, symptomatic treatment should be prescribed; in such cases, repeated courses of treatment with the drug can not be prescribed.

Reactions at the site of administration

During the intravenous administration of the drug, the following usually mild reactions at the site of administration were observed: edema, pain at the site of administration, erythema, sensitivity at the site of administration, sealing at the injection site, hemorrhages, which can lead to the development of cellulite. Such reactions were more often observed with 24-hour infusion than at 3-hour. In some cases, the onset of such reactions was observed both during infusion and through 7-10 days after it.

Myelosuppression

Suppression of bone marrow function (mainly neutropenia) depends on the dose and scheme of the drug and is the main toxic reaction that limits the dose of the drug. So, for example, with the introduction of cisplatin in a dose of 75 mg / m² and Taxol® in a dose of 175 mg / m² in the form of a 3-hour infusion, severe neurotoxicity is observed more often than with the administration of Taxol® at a dose of 135 mg / m² in the form of a 24-hour infusion, i.e. the duration of the infusion has a greater effect on the risk of developing myelosuppression than the dose. In patients with previous X-ray therapy, the history of neutropenia developed less frequently and to a lesser degree, and did not worsen with the accumulation of the drug in the body. In patients with ovarian cancer, the risk of renal failure is higher with the combination of Taxol® + cisplatin compared with cisplatin alone. Cases of infection were very often and sometimes fatal, including sepsis, pneumonia and peritonitis. Infections of the urinary and upper respiratory tract were noted as the most frequent complicated infections. In patients with immunosuppression, patients with HIV infection and patients with AIDS-related Kaposi's sarcoma were marked at least one opportunistic infection.

Use of maintenance therapy, including granulocyte colony-stimulating factor, Recommended for patients who have had severe neutropenia. A decrease in the number of platelets below 100,000 / μL was noted at least once during the entire treatment with Taxol®, sometimes the platelet count was below 50,000 / μL. There were also cases of bleeding, most of which were local, and the frequency of their occurrence was not associated with the dose of Taxol® and the administration schedule.

When using the drug Taxol ®, you need to regularly monitor the blood picture. Do not administer the drug to patients with a neutrophil count of less than 1500 / μL and less than 1000 / μL for Kaposi's AIDS-induced sarcoma and platelets less than 100,000 / μL (75,000 / μL in patients with AIDS-related Kaposi's sarcoma).

With the development of severe neutropenia (less than 500 / μL) or severe peripheral neuropathy during treatment with Taxol®, in subsequent courses treatment is recommended to reduce the dose by 20% (in patients with Kaposi's sarcoma caused by AIDS, by 25%).

Influence on the cardiovascular system

Decrease, increase of arterial The pressure (BP) and bradycardia observed during the administration of Taxol® are usually asymptomatic and in most cases do not require treatment. Reduction of blood pressure (BP) and bradycardia were observed usually during the first 3 hours of infusion. Also noted ECG disorders in the form of violations re-polarization such as sinus tachycardia, sinus bradycardia and early extrasystole. In severe cases, treatment with Taxol® should be stopped or discontinued. It is recommended to monitor vital signs, especially during the first hour of infusion of the drug. If the drug Taxol® Used in combination with trastuzumab or doxorubicin for the treatment of metastatic breast cancer, cardiac function monitoring is recommended.

Cases severe cardiac conduction disorders were observed in the treatment with Taxol®. When detected Symptoms of cardiac conduction disorders patients should be prescribed appropriate therapy along with constant ECG monitoring of the cardiovascular system.

Influence on the nervous system

The frequency and severity of disorders from the nervous system were mostly dose-dependent.When treating with Taxol ®, periphyric neuropathy was often noted, usually moderately expressed. The frequency of peripheral neuropathy increased with the accumulation of the drug in the body. Cases of paresthesia were often observed in the form of hyperesthesia. With noted severe neuropathy, a dose reduction of 20% is recommended in subsequent courses of treatment (in patients with Kaposi's sarcoma caused by AIDS, by 25%). Peripheral neuropathy may be the reason for discontinuing therapy with Taxol®. Symptoms of neuropathy decreased or completely disappeared within a few months after discontinuation of therapy with the drug. The development of neuropathy with prior therapy is not a contraindication for the administration of Taxol®.

Seldom were there cases of violation induced optic nerve potential in patients with persistent damage to the optic nerve.

It should be taken into account the possible effects of ethanol, which is contained in the drug Taxol®.

Effect on the gastrointestinal tract

Mild to moderate cases of nausea / vomiting, dairies, mucositis were very common in all patients.The cases of mucositis development depended on the drug administration schedule and were more often observed with 24-hour infusion than at 3-hour. Rare cases of neutropenic enterocolitis (tiflita), not being able to jointly assign a granulocyte colony-stimulating factor, have been observed in patients using Taxol® in the form of monotherapy and in combination with other chemotherapeutic drugs.

Liver failure

Patients with hepatic insufficiency are a risk group associated with the toxicity of side effects, especially myelosuppression of grade 3-4. Care should be taken to monitor the patient's condition and, if necessary, consider adjusting the dose of the drug.

Radiation pneumonitis is registered with concomitant radiotherapy.

Patients during treatment with Taxol® and at least 3 months after the end of therapy should use reliable methods contraception.

Effect on the ability to drive transp. cf. and fur:

Taxol® contains ethanol, therefore during the period of treatment should refrain from driving and working with potentially dangerous mechanisms.

Held patient premedication prior to administration of the drug Taxol® can also adversely affect the ability to concentrate. A drug Taxol® is an cytotoxic substance, when working with is necessary follow Caution, use gloves and avoid getting the drug to the skin or mucous membranes, which in such cases should be carefully washed with soap and water, or (eyes) with plenty of water.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 6 mg / ml.

Packaging:5 ml or 16.7 ml glass vial colorless glass type I (5 ml - shaped or tubular vial, to 16.7 ml - molded bottle), or a sealed ftorrezinovoy butilrezinovoy stopper with Teflon coated aluminum by burnishing with a plastic lid or protective plastic cap, with an inscription "NO CHEMO PIN " or "MULTIDOSE VIAL [MDV]" or a logo of the manufacturer with a logo, with the control of the first autopsy. 1 bottle contour in the protective cardboard liner together with instruction for use in a cardboard pack.

Storage conditions:

At a temperature of 15 to 30 ° C in the dark place.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013329 / 01

Date of registration:22.10.2007

The owner of the registration certificate:BRISTOL-MIYERS SQUIPB BRISTOL-MIYERS SQUIPB USA

Manufacturer: & nbsp

BRISTOL-MYERS SQUIBB, S.r.L. Italy

Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia

Information update date: & nbsp16.10.2015

Illustrated instructions

Instructions

Taxol® (Taxol®)