Dosage - 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, the drug has mutagenic and embryotoxic properties, causing 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 in doses of 135 and 175 mg / m for 3 and 24 hours. Half-life and total clearance of paclitaxel are variable and depend on the dose and duration of administration: 13.0 - 52.7 hours and 12.2 - 23.8 l / h / m, respectively. The average volume of distribution is from 198 to 688 l / m.

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

The connection with plasma proteins is 89%.

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

After intravenous infusion of paclitaxel (15 - 275 mg / m) for 1, 6 or 24 h, 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 to 250 mg / m for 120 h, 14% of the radiopharmaceutical was excreted by the kidneys, 71% by the intestine.5% of the administered radiopharmaceutical was excreted unchanged in the intestine, the rest being metabolites, mainly 6-alpha-hydroxypaclitaxel.

Indications:

Ovarian Cancer

- First-line therapy in combination with platinum in patients with advanced ovarian cancer or with a residual tumor (more than 1 cm) after initial laparotomy;

- Therapy of the 2nd line in patients with metastatic ovarian cancer after

standard therapy that did not give 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 the initiation of adjuvant therapy with the inclusion of anthracycline-based drugs, in the absence of contraindications for their use;

- First-line therapy in patients with advanced cancer or metastatic breast cancer in combination with anthracycline-based drugs in the absence of contraindications for their use, or in combination with trastuzumab in patients with immunohistochemically confirmed 2+ or 3+ levels of expression HER-2;

- Second-line therapy in patients with advanced cancer or metastatic breast cancer in the 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 a platinum drug or in the form of monotherapy in patients who do not plan surgical treatment and / or radiation therapy.

Kaposi's sarcoma caused by AIDS

- Therapy of the 2nd line.

Contraindications:

- Hypersensitivity to paclitaxel or any component in the formulation, especially macrogol 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 Kaposi's sarcoma caused by AIDS;

- Concomitant severe uncontrolled infections in patients with Kaposi'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 coronary heart disease, myocardial infarction (in history), arrhythmias.

Pregnancy and lactation:

The use of the drug is contraindicated in pregnancy and during breastfeeding.

Dosing and Administration:

Premedication

To prevent severe hypersensitivity reactions, all patients should undergo premedication with glucocorticosteroids, H1 and H2-histamine receptor blockers, for example:

- 20 mg dexamethasone (or its equivalent) orally about 12 and 6 hours before the administration of the drug Taxachad or 20 mg dexamethasone intravenously about 30 to 60 minutes before the administration of the drug Taxackad®,

- 50 mg of diphenhydramine (or its equivalent) intravenously 30-60 minutes before the administration of the drug,

- 300 mg of cimetidine or 50 mg of ranitidine intravenously 30-60 minutes before the administration of the drug Taxackad®.

Ovarian Cancer

- Therapy of the 1st line

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

- 1 every 3 weeks: 135 mg / m² in the form of a 24-hour intravenous infusion, followed by the administration of platinum.

- Therapy of the 2nd line (monotherapy)

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

Mammary cancer

- Adjuvant therapy

It is performed after a standard combination treatment. Taxakad® is administered at a dose of 175 mg / m 3 as a 3-hour intravenous infusion. In total, 4 courses of therapy are recommended with an interval of 3 weeks.

- Therapy of the 1st line

■ Monotherapy:

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

■ Combination therapy:

- with trastuzumab: the day after the first dose trastuzumab 175 mg / m² Taksakad® in the form of a 3-hour intravenous infusion every 3 weeks; with good tolerability of trastuzumab - immediately after the introduction of subsequent doses of trastuzumab.

- with doxorubicin (50 mg / m): 24 hours after the administration of doxorubicin - 220 mg / m² of the drug® in the form of a 3-hour intravenous infusion every 3 weeks.

- Therapy of the 2nd line

- 175 mg / m as 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 drug, every 3 weeks

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

- Monotherapy

- 175 mg / m - 225 mg / m as a 3-hour intravenous infusion every 3 weeks.

Kaposi's sarcoma caused by AIDS

- Therapy of the 2nd line

- 135 mg / m as a 3-hour intravenous infusion every 3 weeks or

- 100 mg / m as a 3-hour intravenous infusion every 2 weeks (45 to 50 mg / m per week).

Preparation of a solution for infusion

Solution for infusion is prepared immediately before the introduction. The drug solution is prepared by diluting the concentrate to a final concentration of paclitaxel from 0.3 to 1.2 mg / ml. ATAs a diluting solution, 0.9% sodium chloride solution, or 5% dextrose solution in 0.9% sodium chloride solution, or 5% dextrose solution in Ringer's solution can be used. The prepared solutions may be opalescent due to the carrier base present in the formulation, after which the opalescence of the solution is retained.

Taxiade ® should be introduced through a system with a membrane filter (pore size not more than 0.22 microns).

If unopened vials are placed in the refrigerator, a precipitate may form which dissolves again with little stirring (or without stirring) when room temperature is reached. The quality of the product does not deteriorate. If the solution remains cloudy, or if there is an insoluble deposit, the vial should be destroyed.

Diluted solutions should not be stored in the refrigerator.

Correction of the dosing regimen

Patients with solid tumors repeated courses of treatment with the drug of the taxa® are assigned only after reaching a neutrophil count of at least 1500 / μL blood (1000 / μL in patients with Kaposi's AIDS-related sarcoma) and platelet count is 100,000 / μL of blood (75,000 / μL in patients with AIDS-related Kaposi's sarcoma). Patients who, after the administration of the taxa® severe neutropenia developed (neutrophil count <500 / μL for more than 7 days) or severe peripheral neuropathy, in subsequent courses treatment of the dose of the drug should be reduced by 20%. Neurotoxicity and neutropenia are dose-dependent.

Correction of the dose for Kaposi's sarcoma caused by AIDS

Depending on the level of immunosuppression in patients with advanced forms of AIDS, the following measures are recommended:

- Reduction of oral dose of dexamethasone (in the composition of premedication) to 10 mg;

- Use of the drug Taxapad ® only with a neutrophil content of at least 1000 / μL blood, platelets - 75,000 / μL;

- In severe neutropenia (less than 500 / μL blood for a week or more) or severe peripheral neuropathy - a reduction in the dose of the drug Taksakad® by 25% in subsequent courses of therapy;

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

Application for violations of liver function

Patients with hepatic impairment and associated increased risk of toxicity (in particular myelosuppression III-IV degree) is recommended dose adjustment of the drug.

Care must be taken to monitor the patient's condition.

Table 1. Recommended doses for patients with impaired liver function.

Degree of hepatic impairment			Dose * of the drug®
Activity of "liver" transaminases		Concentration of bilirubin in serum	Dose * of the drug®
24 hour infusion
<2 x VGN	and	≤ 26 μmol / l	135 mg / m²
2 - <10 x VGN	and	≤ 26 μmol / l	100 mg / m²
<10 x VGN	and	28 - 129 μmol / l	50 mg / m
≥ 10 x VGN	or	> 129 μmol / l	Not recommended
3 hour infusion
<10 x VGN	and	≤ 22 μmol / l	175 mg / m²
<10 x VGN	and	22 - 35 μmol / l	135 mg / m²
<10 x VGN	and	35 - 86 μmol / l	90 mg / m²
≥ 10 x VGN	or	> 86 μmol / l	Not recommended
* Recommended doses for the first course of therapy; dose adjustment in subsequent courses should be based on the individual tolerability of the drug. VGN - the upper limit of the norm.

Precautions for use

When preparing, storing and administering the Taxakad® preparation, it is necessary to use equipment that does not contain PVC parts, for example: glass, polypropylene or polyolefin.

Taxakad® is a cytotoxic substance that should be used with caution, use gloves and avoid contact with skin or mucous membranes, which in such cases must be thoroughly washed with soap and water or (eyes) with plenty of water.

Side effects:

Side effects, usually, do not differ in frequency and severity in the treatment of ovarian cancer, breast cancer, non-small cell lung cancer or Kaposi's sarcoma.

However, in patients with Kalosha's sarcoma caused by AIDS, infections (including opportunistic infections), oppression of hematopoiesis and febrile neutropenia are more frequent than usual.

Side effects with monotherapy

The incidence of side effects is shown 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), the frequency is unknown (can not be estimated with the help of available data).

Note: * post-marketing data on the side effects of paclitaxel are noted.

From the hematopoiesis:

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

Rarely *: febrile neutropenia;

Very rarely *: acute myeloid leukemia, myelodysplastic syndrome.

From the immune system:

Very often: minor hypersensitivity reactions, mainly manifested as hyperemia ("hot flashes") and skin rashes;

Infrequent: pronounced hypersensitivity reactions requiring treatment, for example, lowering blood pressure, angioedema, impaired breathing, generalized urticaria, swelling, back pain, chills);

Rarely *: anaphylactic reactions (including fatal);

Very rarely *: anaphylactic shock.

From the nervous system:

Very often: neurotoxicity (mainly peripheral neuropathy);

Rarely *: motor neuropathy leading to minor weakness of the limbs;

Rarely*: confusion consciousness, vegetative neuropathy, manifested paralytic obstruction of the intestine and orthostatic hypotension, epileptic seizures of the type "grand mal", convulsions, encephalopathy, dizziness, headache, ataxia.

From the cardiovascular system:

Very often: changes in the electrocardiogram (ECG), lowering blood pressure;

Often: bradycardia;

Infrequent: increased blood pressure, thrombosis, thrombophlebitis, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with biigemia, atrioventricular blockade 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 digestive system:

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 of the optic nerve and / or visual impairment (ciliary scotoma, or eye migraine), photopsy, destruction of the vitreous 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 appendages of the skin:

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

Infrequent: increased bilirubin concentration;

Rarely *: increased serum creatinine concentration.

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

- Paclitaxel + Cisplatin in the first line of therapy for 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. The manifestations of severe neurotoxicity when used in combination with cisplatin at a dose of 75 mg / m are observed less frequently with paclitaxel at a dose of 135 mg / m as a 24 hour infusion than with its administration in a dose of 175 mg / m in the form of a 3-hour infusion.

- Paclitaxel + trastuzumab in the therapy of breast cancer

When paclitaxel was used in combination with trastuzumab in the first line of therapy for metastatic breast cancer, the following side effects were noted more often than with paclitaxel monotherapy: heart failure, infections, chills, fever, cough, rash, arthralgia, tachycardia, diarrhea, , epistaxis, acne, herpetic eruptions, accidental injuries, insomnia, rhinitis, sinusitis, reactions at the injection site.

With the use of paclitaxel in combination with trastuzumab in the second line of therapy (after anthracycline-based drugs), the frequency and severity of cardiac events (in rare cases fatal) compared with monotherapy with paclitaxel. In most cases, the side effects were reversible after the appointment of the appropriate treatment.

- Paclitaxel + doxorubicin in the treatment of breast cancer

There were cases of congestive heart failure in patients who had not previously received chemotherapy. Patients who received chemotherapy courses earlier, especially with the use of anthracyclines, often had cardiac abnormalities, a reduction in the left ventricular ejection fraction and ventricular failure. In rare cases, myocardial infarction was noted.

- Paclitaxel + Radiation Therapy

Patients who were simultaneously prescribed paclitaxel and radiation therapy, there were cases of radiation pneumonitis.

Overdose:

Symptoms: aplasia of the bone marrow, peripheral neuropathy, mucositis.

Treatment: symptomatic. The antidote to paclitaxel is not known.

Interaction:

Cisplatinum: With the introduction of paclitaxel after cisplatin, myelosuppression is more pronounced, and clearance of paclitaxel is lower by 33% than when cisplatin is administered after paclitaxel.

Doxorubicin: When using paclitaxel 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 when using paclitaxel before doxorubicin administration, as well as longer infusion than recommended.

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

Special instructions:

Treatment with the drug Taksakad ® should be carried out under the supervision of a doctor who has experience with antitumor chemotherapeutic drugs. Taxakad® should be used as a dilute solution. Prior to the administration of the drug, taxa-cad® patients should undergo glucocorticosteroid premedication, blockers Hl and H2-histamine receptors. If Taxol® is used in combination with cisplatin, you should first enter Dosacad®, and then cisplatin.

Anaphylaxis and severe hypersensitivity reactions

Less than 1% of patients, despite the premedication, severe hypersensitivity reactions were observed with paclitaxel. 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 pain, pain in the extremities, increased sweating, increased blood pressure were most often observed. When severe hypersensitivity reactions develop, the administration of the drug 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 intravenous administration of paclitaxel, 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 injection, hemorrhages that could 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 7-10 days after it.

Myelosuppression

Suppression of bone marrow function (mainly neutropenia) depends on the dose and scheme of application of the drug and is the main toxic reaction that limits the dose of the drug. In patients with previous X-ray therapy, the history of neutropenia developed less frequently and in an easier degree, and did not worsen with the accumulation in the body.

Cases of infection were very often, sometimes fatal, including sepsis, pneumonia and pneumonitis. Urinary tract infections were noted as the most frequent complicated infections. In patients with immunosuppression (patients with HIV infection and patients with Kaposi's sarcoma caused by AIDS), at least one opportunistic infection was noted.

The use of maintenance therapy, including granulocyte colony-stimulating factor, is 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 treatment with paclitaxel, 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 paclitaxel and the regimen of administration.

With the application of the drug, regular monitoring of the blood picture is necessary. 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-related sarcoma and platelets less than 100,000 / μL (75,000 / μL in patients with AIDS-related Kaposi's sarcoma). If severe neutropenia develops (<500 / μL) for more than 7 days in subsequent courses of treatment, the dose of the drug should be reduced by 20% (in patients with Kaposi's AIDS-related sarcoma - by 25%).

Influence on the cardiovascular system

Decrease, increase in blood pressure and bradycardia observed during the administration of paclitaxel are usually asymptomatic and in most cases do not require treatment. Reduction of blood pressure and bradycardia were observed usually during the first 3 hours of infusion.

There have also been cases of abnormalities on the ECG in the form of violations of re-polarization such as sinus tachycardia, sinus bradycardia and early extrasystoles.

In severe cases, treatment with Taksacad® should be stopped or discontinued. It is recommended to monitor vital signs, especially during the first hour of infusion of the drug. If Rhesakad ® is used in combination with trastuzumab or doxorubicin for the treatment of metastatic breast cancer, cardiac function monitoring is recommended.

In the treatment of paclitaxel, severe cardiac conduction disorders are noted. If there are signs of cardiac conduction disorder, patients should be given appropriate therapy along with a 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. In the treatment of paclitaxel, peripheral neuropathy, usually mild, is often noted. 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. In severe neuropathy in subsequent courses of treatment, the dose of Taksakad® should be reduced by 20% (in patients with Kaposi's sarcoma caused by AIDS, by 25%).Peripheral neuropathy may be the reason for discontinuing therapy with the drug Taxackad®. Symptoms of neuropathy decreased or completely disappeared within a few months after discontinuation therapy with the drug. The development of neuropathy is not a contraindication for prescribing the Taksakad® drug)

Rarely were there cases of disturbance of the evoked potential of the optic nerve 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 preparation of the Taksakad®.

Effect on the gastrointestinal tract

Cases of nausea / vomiting / diarrhea, mild to moderate 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), despite the co-administration of granulocyte colony-stimulating factor, were observed in patients using paclitaxel in the form of monotherapy and in combination with other chemotherapeutic drugs.

Liver failure

Patients with hepatic impairment represent a special risk group for toxicity-related 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.

Contraception

Patients should be provided with reliable contraceptive methods during treatment with the drug Taksacad® and, at least 3 months after the end of therapy.

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

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

The premedication administered to the patient before the administration of the drug Taxakad® can also have a negative effect on the ability to concentrate.

Form release / dosage:Concentrate for solution preparation for infusions, 6 mg / ml.

Packaging:

5 ml (30 mg), 16.7 ml (100 mg), 23.3 ml (140 mg), 25 ml (150 mg), 35 ml (210 mg), 41.7 ml (250 mg), 43.3 ml (260 mg), 46 ml (276 mg), 50 ml (300 mg) and 60 ml (360 mg) of bottles of neutral glass I hydrolytic class, ukuporennye plugs with Teflon coating, with by rolling with aluminum caps. On each bottle is labeled. By 1 bottle together with the instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 C.

Keep out of the reach of children.

Shelf life:

2 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-001949/09

Date of registration:16.03.2013

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Information update date: & nbsp11.10.2015

Illustrated instructions

Instructions

Taxiade (Taxacad)