Sindaxel, 6 mg/ml 5 ml

Pharmacotherapeutic group: antitumor drug, alkaloid ATC code: L01CD01

Pharmacological properties

Packlitaxel is an antitumor drug produced semi-synthetically. Mechanism of action is related to the ability to stimulate the assembly of microtubules from dimeric tubulin molecules, stabilize their structure by inhibiting depolymerization and inhibit dynamic reorganization in interphase which disrupts mitotic function of the cell. In addition, paxitaxel induces the formation of abnormal clusters, 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 and causes decreased reproductive function.

Pharmacokinetics

Paclitaxel plasma concentration after intravenous administration decreases according to biphasic kinetics.

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

In multiple courses of treatment no cumulation of paclitaxel has been noted. Binding to plasma proteins averages 89%.

In in vitro studies on liver microsomes it was found that paclitaxel is metabolized in the liver with the participation of CYP2C8 isoenzyme to
6-alpha-hydroxypaclitaxel and with the participation of CYP3A4 isoenzyme to 3-para-hydroxypaclitaxel and 6-alpha, 3-para-hydroxypaclitaxel.

Evacuation. After intravenous infusion of paclitaxel (15-275 mg/m2) for 1, 6, or 24 hours, 1.3-12.6% of the administered dose was excreted unchanged by the kidneys. After a 3-hour infusion of radioactively labeled paclitaxel at doses of 225-250 mg/m2, within 120 hours 14% of the radioactivity was excreted by the kidneys, 71% – by the intestine. 5% of the administered radioactivity was excreted unchanged by the intestine, the remainder being metabolites, mainly 6-alpha-hydroxypaclitaxel.

Indications

Ovarian Cancer

Breast Cancer

Active ingredient

Composition

1 ml of the concentrate contains:

the active ingredient:

Paclitaxel 6.00 mg;

supplements: citric acid anhydrous 2.00 mg, macrogoal glycerylicinoleate (Cremophor® EL) 527.00 mg, ethanol (ethyl alcohol (absolute)) up to 920 mg (equivalent to 1.00 ml).

How to take, the dosage

In order to avoid severe hypersensitivity reactions, all patients should be premedicated with glucocorticosteroids, H1- and H2-histamine receptor blockers, such as:

Interaction

Cisplatin:

Paclitaxel administration after cisplatin causes greater myelosuppression and paclitaxel clearance is 20% lower than cisplatin administration after paclitaxel.

Doxorubicin:

The serum levels of doxorubicin and its active metabolite doxorubicinol may be increased when paclitaxel is used in combination with doxorubicin. Side effects such as neutropenia and stomatitis are more pronounced when paclitaxel is used before doxorubicin is administered and when a longer than recommended infusion is given.

Substrates, inducers and inhibitors of isoenzymes CYP2C8 and CYP3A4:

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

Other interactions:

An increased risk of fatal systemic vaccine disease is possible when co-administered with live vaccines. The use of live vaccines in immunosuppressed patients is not recommended.

Special Instructions

The use of Sindaxel should be under the supervision of a physician experienced in the use of antitumor chemotherapy drugs. Sindaxel should be used as a diluted solution. Patients must be premedicated with glucocorticosteroids, H1 and H2 – histamine receptor blockers before the drug is administered. If Sindaxel is used in combination with cisplatin, Sindaxel should be administered first, followed by cisplatin.

Anaphylaxis and serious hypersensitivity reactions

Less than 1% of patients have had serious hypersensitivity reactions during treatment with Sindaxel despite premedication. The frequency and severity of such reactions were independent of the dose and route of administration of the drug. When severe reactions developed, choking, hot flashes, chest pain, tachycardia, as well as abdominal pain, pain in the extremities, increased sweating, and increased blood pressure were the most frequently observed.

In case of severe hypersensitivity reactions, administration of Sindaxel should be stopped immediately and symptomatic treatment should be administered if necessary; repeated courses of treatment with the drug should not be prescribed in such cases.

Injection site reactions

The following usually mild injection site reactions have been observed during intravenous administration of the drug: swelling, injection site pain, erythema, injection site sensitivity, injection site thickening, hemorrhage, which may lead to development of cellulitis. Such reactions were more frequently observed with a 24-hour infusion than with a 3-hour infusion. In some cases, the onset of such reactions was observed both during the infusion and 7-10 days after it.

Myelosuppression

The suppression of bone marrow function (mainly neutropenia) depends on the dose and route of administration of the drug and is a major dose-limiting toxic reaction. For example, when cisplatin is administered at a dose of 75 mg/m2 and Sindaxel at a dose of 175 mg/m2 as a 3-hour infusion, severe neurotoxicity is more common than when Sindaxel is administered at a dose of 135 mg/m2 as a 24-hour infusion, meaning that the duration of infusion has a greater influence on the risk of myelosuppression than the dose. In patients with a history of prior radiotherapy, neutropenia developed less frequently and more mildly, and did not worsen as the drug accumulated in the body.

In patients with ovarian cancer, the risk of renal failure is higher with the combination of Cindaxel + cisplatin compared to cisplatin monotherapy. Cases of infections have been observed very frequently and sometimes with fatal outcome, including sepsis, pneumonia and peritonitis. Urinary tract and upper respiratory tract infections were reported as the most frequent complicated infections. At least one opportunistic infection was noted in immunosuppressed patients, patients with HIV infection, and patients with AIDS-related Kaposi’s sarcoma.

The use of maintenance therapy, including granulocyte colony-stimulating factor, is recommended for patients who have had severe neutropenia. A decrease in platelet count below 100,000/μL has been observed at least once during all therapy with Sindaxel, sometimes with platelet count below 50,000/μL. Bleeding incidents have also been reported, most of which were local, and their incidence was not associated with the dose of Sindaxel or the route of administration. Blood counts should be monitored regularly during Sindaxel administration. Do not prescribe the drug in patients with a neutrophil count less than 1500/μL and less than 1000/μL in AIDS-related Kaposi sarcoma and with a platelet count less than 100000/μL (75000/μL in patients with AIDS-related Kaposi sarcoma).If severe neutropenia (less than 500/

μL) or severe peripheral neuropathy develop during treatment with Cindaxel, it is recommended to reduce the dose by 20% (in patients with AIDS-related Kaposi sarcoma – by 25%) during subsequent courses of treatment.

Impacts on the cardiovascular system

Decreases, increases in blood pressure and bradycardia seen during administration of Sindaxel are usually asymptomatic and in most cases do not require treatment. Decreased blood pressure and bradycardia were usually observed within the first 3 hours of infusion. ECG abnormalities in the form of repolarization disorders such as sinus tachycardia, sinus bradycardia and early extrasystole have also been observed. In severe cases, treatment with Sindaxel should be suspended or discontinued. Monitoring of vital signs is recommended, especially during the first hour of infusion. If Sindaxel is used in combination with trastuzumab or doxorubicin for the treatment of metastatic breast cancer, cardiac function monitoring is recommended. Cases of severe cardiac conduction abnormalities have been reported during treatment with Sindaxel. If symptoms of cardiac conduction abnormalities are detected, patients should be given appropriate therapy along with ongoing cardiovascular ECG monitoring.

Synopsis

Contraindications

Hypersensitivity to paclitaxel or any constituent of the drug, especially macrogoal glycerylcyanoate (polyoxyethylated castor oil);

Side effects

Side effects generally 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, patients with AIDS-related Kaposi’s sarcoma have a higher than normal incidence and severity of infections (including opportunistic infections), depressed hematopoiesis, and febrile neutropenia.

Side effects during monotherapy:

The frequency of side effects is given according to the following scale: very common (≥1/10), common (≥1/100, ˂1/10), infrequent (≥1/1000, ˂1/100), rare (≥1/10000, ˂ 1/1000), very rare (˂ 1/10000), frequency unknown (cannot be estimated with available data).

Note: The post-marketing data on side effects are marked with an asterisk.

Hematopoietic side effects: very frequently, myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, fever, bleeding; rarely*, febrile neutropenia; very rarely*, acute myeloid leukemia, myelodysplastic syndrome.

immune system disorders: very common – minor hypersensitivity reactions, mainly manifested as hyperemia (“flushes” of blood) and skin rash; infrequent – serious hypersensitivity reactions requiring treatment (e.g., decreased blood pressure, angioedema, respiratory dysfunction, generalized urticaria, edema, back pain, chills); rare* – anaphylactic reactions (including those with lethal outcome); very rare* – anaphylactic shock.

Nervous system disorders: very common – neurotoxicity (mainly peripheral neuropathy, which may last more than 6 months after discontinuation of paclitaxel); rare* – motor neuropathy (resulting in minor weakness of the limbs); very rarely* – confusion, autonomic neuropathy manifested by paralytic bowel obstruction and orthostatic hypotension, grand small type epileptic seizures, seizures, encephalopathy, dizziness, headache, ataxia.

Cardiovascular side: very common – ECG changes, decreased blood pressure; common – bradycardia; infrequent – increased blood pressure, thrombosis, thrombophlebitis, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigemia, atrioventricular block and syncope, myocardial infarction; rarely* – heart failure; very rarely* – atrial fibrillation, supraventricular tachycardia, shock.

Respiratory system: rarely* – shortness of breath, pleural effusion, respiratory failure, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism; very rarely* – cough.

Gastrointestinal tract side: very frequently, nausea, vomiting, diarrhea, mucositis; rarely*, intestinal obstruction, bowel perforation, ischemic colitis, pancreatitis; very rarely*, mesenteric artery thrombosis, pseudomembranous colitis, neutropenic colitis, esophagitis, constipation, ascites, anorexia.

Hepatic and biliary tract disorders: very rarely* – hepatonecrosis (fatal), hepatic encephalopathy (fatal).

Visual side: very rare* – reversible optic nerve damage and/or visual disturbances (atrial fibrillation scotoma or ocular migraine), photopsia, vitreous body destruction; frequency unknown* – macular edema.

Hearing organ: very rarely* – hearing loss, tinnitus, vertigo (vestibular vertigo), ototoxicity.

Skin and subcutaneous tissue: very common – alopecia; common – temporary minor changes in the skin and nails; rare* – itching, rash, erythema, phlebitis, inflammation of subcutaneous fatty tissue, skin exfoliation, skin necrosis and fibrosis, skin lesions resembling the effects of radiation therapy; very rare* – Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis; frequency unknown* – scleroderma, cutaneous lupus erythematosus, palmar and plantar erythrodysesthesia syndrome.

Muscular system disorders: very common – arthralgia, myalgia; frequency unknown* – systemic lupus erythematosus.

Local reactions: frequent- local edema, pain, erythema, induration.

From laboratory parameters: frequent – increased aspartate aminotransferase (AST) activity, increased alkaline phosphatase activity; infrequent – increased bilirubin concentration; frequent* – increased serum creatinine concentration.

Others: very often – accession of secondary infections; infrequently – septic shock; rarely* – pneumonia, sepsis, peritonitis, asthenia, general malaise, fever, dehydration, peripheral edema; frequency unknown* – tumor lysis syndrome.

Side effects with combination therapy:

Sindaxel + cisplatin in 1st-line therapy for ovarian cancer

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

The manifestations of severe neurotoxicity when used in combination with cisplatin at a dose of 75 mg/m2 are less frequently observed with Sindaxel at a dose of 135 mg/m2 as a 24-hour infusion than with its administration at a dose of 175 mg/m2 as a 3-hour infusion.

Sindaxel + trastuzumab in breast cancer therapy

. When Sindaxel was used in combination with trastuzumab for first-line therapy of metastatic breast cancer, the following side effects were noted more frequently than with Sindaxel monotherapy Heart failure, infections, chills, fever, cough, rash, arthralgia, tachycardia, diarrhea, increased blood pressure, nasal bleeding, acne, herpetic rash, accidental injury, insomnia, rhinitis, sinusitis, injection site reactions. The use of Sindaxel in combination with trastuzumab for second-line therapy (after anthracycline drugs) resulted in increased frequency and severity of cardiac events (rarely fatal) compared to Sindaxel monotherapy. In most cases, the side effects were reversible after appropriate treatment.

Syndaxel + doxorubicin in breast cancer therapy

There have been cases of congestive heart failure in patients who have not previously received chemotherapy. Patients who had received prior chemotherapy courses, especially with anthracyclines, often had cardiac dysfunction, decreased left ventricular ejection fraction and ventricular function failure. Rarely, myocardial infarction has been noted.

Syndaxel + radiation therapy

. There have been cases of radiation pneumonitis in patients who received Cindaxel and radiation therapy at the same time.

Overdose

Pregnancy use

Similarities