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

Excipients: macrogol glycerylricinoleate (Cremophor EL) - 527.00 mg; citric acid monohydrate - 1.81 mg; Ethanol (ethanol anhydrous) - 49.7% by volume.

Description:Pa clear, colorless or light yellow viscous solution.

Pharmacotherapeutic group:Antitumor agent - alkaloid

ATX: & nbsp

L.01.C.D. Taxoids

L.01.C.D.01 Paclitaxel

Pharmacodynamics:

Paclitaxel is an antitumor drug produced by a biosynthetic pathway. The mechanism of action is associated with the ability to stimulate the "assembly" of microtubules from tubulin dimer molecules, stabilize their structure due to the suppression of depolymerization, and inhibit the dynamic reorganization of interphase, which violates the mitotic function of the cell. Besides, paclitaxel induces the formation of abnormal clusters or "bundles" of microtubules throughout the cell cycle and causes the formation of multiple microtubule stars during mitosis.

Pharmacokinetics:

After a three-hour intravenous infusion of the drug Paclitaxel in a dose of 175 mg / m², the area under the concentration-time curve (AUC) was 9950 ng x h / ml, the maximum concentration (C_mOh) - 2350 ng / ml, clearance - 43 l / h / m² (range 17-74 l / h / m²), the volume of distribution - 207 liters and the half-life was 9.3 hours.

Paclitaxel is metabolized in the liver by hydroxylation with the participation of cytochrome P450 isoenzymes CYP2C8 (with the formation of the metabolite - 6-alpha-hydroxypaclitaxel) and CYP3A4 (forming the metabolite 3-para-hydroxypaclitaxel). The main way of elimination is the intestine, where 5% is excreted unchanged, the rest in the form of metabolites (mainly in the form of 6-α-hydroxypaclitaxel). Renal excretion plays an insignificant role in the process of excretion of paclitaxel.

Indications:

Ovarian Cancer

First-line therapy in combination with platinum drugs 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 within 6 months after initiation of adjuvant therapy, including anthracycline-based drugs, in the absence of indications 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+ expression level HER2.

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.

Kaposi's sarcoma caused by AIDS

Therapy of the 2nd line.

Contraindications:

- Hypersensitivity to paclitaxel or to any component in the formulation, especially macrogol glycerylricinoleate (polyoxyethylated castor oil);

- initial neutrophil count less than 1500 / μL in patients with solid tumors;

- the initial or recorded neutrophil count 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:

When thrombocytopenia is less than 100,000 / mm3 (including after chemotherapy or radiation therapy), liver failure, acute infectious diseases (including shingles, chicken pox, herpes), severe course of coronary heart disease, myocardial infarction (in anamnesis ), arrhythmias.

Pregnancy and lactation:

The drug is contraindicated for use during pregnancy and during breastfeeding.

Dosing and Administration:

To avoid severe hypersensitivity reactions, all patients should be premedicated with glucocorticosteroids, blockers H₁- and H₂-gistamine receptors, for example:

- 20 mg dexamethasone (or its equivalent) orally approximately 12 and 6 hours before the administration of the drug or 20 mg dexamethasone intravenously about 30 minutes before the administration of the drug or

- 20 mg of dexamethasone intravenously about 30-60 minutes before the administration of the drug, 50 mg of diphenhydramine (or its equivalent) intravenously and 300 mg of cimetidine or 50 mg of ranitidine intravenously 30-60 minutes before the administration of the drug.

Patients with solid tumors repeated courses of treatment with the drug Paclitaxel are assigned only after reaching a neutrophil count of 1500 / μL (1000 / μL in patients with AIDS-related Kaposi's sarcoma) and platelet count is 100,000 / μL (75,000 / μL in patients with AIDS-related Kaposi's sarcoma). For patients who developed severe neutropenia (the number of neutrophils was less than 500 / μL for more than one week) or with severe periphyric neuropathy in subsequent courses of treatment with the drug Paclitaxel should reduce the dose by 20% (by 25% in patients with Kaposi's sarcoma caused by 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 followed by the administration of a platinum drug or
1 every 3 weeks: 135 mg / m² in the form of a 24-hour infusion with subsequent administration of the platinum drug.

Therapy of the second line (monotherapy)

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

Mammary cancer

Adjuvant therapy is performed after a standard combination treatment. A drug Paclitaxel is administered at a dose of 175 mg / m² in the form of a 3-hour intravenous infusion. In total, 4 courses of therapy are recommended with an interval of 3 weeks.

Therapy of the first 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 of trastuzumab, 175 mg / m² preparation Paclitaxel 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 / m²): 24 hours after the administration of doxorubicin - 220 mg / m² preparation Paclitaxel in the form of a 3-hour intravenous infusion, every 3 weeks.

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 drug, every 3 weeks or
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 a 3-hour intravenous infusion, every 3 weeks.

Kaposi's sarcoma caused by AIDS

Therapy of the second line

135 mg / m² in the form of a 3-hour intravenous infusion, every 3 weeks or 100 mg / m² intravenously drip for 3 hours, every 2 weeks (45-50 mg / m² in Week). Depending on the level of immunosuppression in patients with advanced AIDS, the following measures are recommended:
decrease oral dose of dexamethasone (in the composition of premedication) to 10 mg,
drug administration Paclitaxel only when the neutrophil count is not less than 1000 klygok / mkl blood, platelets - 75 000 / mkl;
with severe neutropenia (less than 500 cells / μl of blood for a week or more) or severe peripheral neuropathy - a decrease in the dose of the drug Paclitaxel by 25% with 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 III-IV degree) are recommended to correct the dose of the drug Paclitaxel.

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		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 / m²
≥10 x VLN	or	> 129 μmol / l	Not recommended
3 hour infusion
<10 x VGN	and	≤ 22 x VGN	175 mg / m²
<10 x VGN	and	22-35 x VGN	135 mg / m²
<10 x VGN	and	35-86 x VGN	90 mg / m²
≥ 10 x VGN	or	> 86 x VGN	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.

Side effects:

Side effects, as a rule, 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 Kaposi's sarcoma caused by AIDS, infections (including opportunistic infections), oppression of hematopoiesis, febrile neutropenia occur more often than usual.

Side effects with monotherapy

The incidence of side effects is shown in accordance with the following scale: Often (≥1/10); often (≥1 / 100 to <1/10); infrequently (≥1 / 1000 to <1/100); rarely (≥1 / 10000 to <1/1000); rarely (<1/10000); frequency unknown (can not be estimated with the help of available data).

NOTE: The asterisk indicates post-marketing side effects data.

On the part of the organs of 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 - insignificantly, hypersensitivity reactions, mainly manifested in the form of hyperemia ("hot flashes" of blood) and skin rash; infrequently, high-sensitivity reactions requiring treatment (eg, lowering blood pressure (BP), angioedema,disruption of respiratory function, generalized urticaria, edema, 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, manifested by paralytic intestinal obstruction 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 bradycardia; infrequent - increased blood pressure (BP), thrombosis, thrombophlebitis, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with biigemia, atrioventricular blockade and syncope, 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; rarely * - cough.

From the gastrointestinal tract: very often - nausea, vomiting, diarrhea, mucositis; rarely * - intestinal obstruction, intestinal perforation, ischemic colitis, pancreatitis; very rare * - mesenteric artery thrombosis, pseudomembranous colitis, oesophagitis, constipation, ascites, anorexia.

Co side of the liver and bile ducts: very rare * - gepatonekroz (fatal), hepatic encephalopathy (fatal).

Co side of the organ of vision: very rarely * - reversible lesions of the optic nerve and / or visual impairment (ciliary scotoma, or ocular 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 skin appendages: Often - alopecia; often - temporary minor changes in skin and nails; rarely* - itching, rashes, erythema, phlebitis, inflammation of subcutaneous fat, exophosphation 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: 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 increase in bilirubin concentration; rarely * - increased serum creatinine concentration.

Other: very often - the attachment of secondary infections; infrequently - septic shock; rarely * - pneumonia, sepsis, asthenia, general malaise, fever, dehydration, peripheral edema; frequency unknown * - tumor lysis syndrome.

Side effects with combination therapy

The drug Paclitaxel + Cisplatin in the treatment 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 paclitaxel at 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.

The drug Paclitaxel + trastuzumab in the treatment of breast cancer

In applying paclitaxel in combination with trastuzumab therapy 1- th line metastatic breast cancer following items side effects were more frequent than with paclitaxel alone: heart failure, infection, chills, fever, cough, rash, arthralgia, tachycardia, diarrhea, high blood pressure (BP), nasal bleeding, acne, herpes, accidental injury, insomnia, rhinitis, sinusitis, injection site reactions. The use of paclitaxel in combination with trastuzumab therapy for the second line (after a number of anthracycline drugs) led to an increase in frequency and severity of abnormality of the heart (in rare cases - deaths) compared tomonotherapy with paclitaxel. In most cases, the side effects were reversible after the appointment of the appropriate treatment.

A drug 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, especially with the use of anthracyclines, often had cardiac abnormalities, a decrease in the left ventricular ejection fraction, and a lack of ventricular function. In rare cases, myocardial infarction was noted.

The drug Paclitaxel + radiation therapy

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

Overdose:

Symptoms: bone marrow aplasia, peripheral sensory neuropathy, mucositis.

Treatment: conduct symptomatic therapy. The specific antidote of paclitaxel is unknown.

Interaction:

Cisplatinum

With the introduction of paclitaxel after cisplatin, myelosuppression is more pronounced, and the clearance of paclitaxel is lower by 20% than when cisplatin is administered after paclitaxel.

Doxorubicin

When paclitaxel is used in combination with doxorubicin, the content of doxorubicin and its active metabolite of doxorubicinol in the 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, so you should be careful when using the drug Paclitaxel on the background of treatment with substrates (for example, 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:

Application of the drug Paclitaxel should be carried out under the supervision of a doctor who has experience with antitumor chemotherapeutic drugs.A drug Paclitaxel should be used as a dilute solution. Before the administration of the drug Paclitaxel patients should undergo premedication with glucocorticosteroids, blockers H₁- and H₂-gistaminovyh receptors. If the drug is used in combination with cisplatin, the drug should first be administered Paclitaxel, and then cisplatin.

Anaphylaxis and severe hypersensitivity reactions

In less than 1% of patients, despite the premedication, serious hypersensitivity reactions are noted in the treatment of paclitaxel. The frequency and severity of such reactions does 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, and increased blood pressure (BP) were most often observed.

With the development of severe hypersensitivity reactions, the administration of the drug Paclitaxel should immediately stop and, if necessary, prescribe symptomatic treatment; 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 paclitaxel, the following usually mild reactions at the site of administration were observed: edema, pain at the site of injection, erythema, sensitivity at the site of injection, compaction 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. So, for example, with the introduction of cisplatin in a dose of 75 mg / m²and paclitaxel 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 paclitaxel 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 paclitaxel + 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 had at least one opportunistic infection.

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 entire time of paclitaxel therapy, 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.

When using the drug Paclitaxel it is necessary 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-related 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 the drug Paclitaxel, in subsequent courses of treatment it 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 in arterial pressure (BP) and bradycardia, observed during the administration of paclitaxel, 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. There were also ECG disorders in the form of violations of re-polarization such as sinus tachycardia, sinus bradycardia and early extrasystoles. In severe cases, drug treatment Paclitaxel should be suspended or terminated. It is recommended to monitor vital signs, especially during the first hour of infusion of the drug.If the drug Paclitaxel Used in combination with trastuzumab or doxorubicin for the treatment of metastatic breast cancer, cardiac function monitoring is recommended.

Cases severe cardiac conduction abnormality were observed in the treatment with paclitaxel. If there are signs of cardiac conduction disorder, 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. In the treatment with the drug, peripheral neuropathy, usually mildly expressed, was 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. 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 drug therapy Paclitaxel. 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 prescribing the drug Paclitaxel.

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 Paclitaxel.

Effect on the gastrointestinal tract

Mild to moderate cases of nausea / vomiting, diarrhea, 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 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 drug treatment Paclitaxel and at least 3 months after the end of therapy, reliable methods of contraception should be used.

A drug Paclitaxel is a cytotoxic substance, when working with which you must be careful, use gloves and avoid getting the product on the skin or mucous membranes, which in such cases must be thoroughly washed with soap and water, or (eyes) with plenty of water.

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

Taking into account the profile of side effects (fatigue, dizziness and impaired concentration), patients are advised to refrain from driving and engaging in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:

Concentrate for solution for infusion, 6 mg / ml.

Packaging:

30 mg / 5 ml in vials (type I USP) 5 ml of dark glass, sealed with bromobutyl rubber stopper, sealed with aluminum caps with sealing flip- off disks.

100 mg / 16.7 ml in vials (type I USP) 20 ml of dark glass, sealed with bromobutyl rubber stopper, sealed with aluminum caps with sealing flip-off disks.

260 mg / 43.3 ml in bottles of the type (I USP) 50 ml of dark glass, sealed with bromobutyl rubber stopper, sealed with aluminum caps with sealing flip-off disks.

300 mg / 50 ml in vials (type I USP) 50 ml of dark bromobutyl rubber stopper, sealed with aluminum caps with sealing flip-off disks.

1 bottle is placed in a cardboard box together with instructions for use.

For hospitals. Five, 10, 30, 50, 100 vials, together with an equal number of instructions for use, are placed in a cardboard box.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004169

Date of registration:28.02.2017

Expiration Date:28.02.2022

The owner of the registration certificate:JODAS EKSPOIM, LLC JODAS EKSPOIM, LLC Russia

Manufacturer: & nbsp

NOVALEK PHARMACEITICAL, Pvt. Ltd. India

Representation: & nbspJodas Expoim, Open CompanyJodas Expoim, Open Company

Information update date: & nbsp31.03.2017

Illustrated instructions

Instructions

Paclitaxel (Paclitaxel)