Paklikal - instructions for use, dosage, side effects, contraindications

Ingredients	1 f.	1 ml of the prepared solution
Active substance: Paclitaxel	60 mg	1 mg
Excipients: Sodium salt of methyl ester	40 mg	0.667 mg
N- (fully-trans-retinoyl) -L-cysteic acid (XMeNa) Sodium salt of methyl ester N- (13-	40 mg	0.667 mg
cis-retinoyl) -E-cysteic acid (13XMeNa)

Description:

Lyophilized powder or poresNet weight from greenish yellow to yellow. A mixture of powder and porous mass is allowed in the vial.

After dissolution, the solution should be clear, greenish-yellow in color.

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 related to the ability to stimulate the "assembly" of microtubules from dimer tubulin molecules, to stabilize their structure by suppressing depolymerization, and to inhibit dynamic reorganization in the interphase, which disrupts 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 Paclikal® in a dose of 175 mg / m², the area under the "concentration-time" curve (AUC) was 9950 ng-h / ml, the maximum concentration (Cmax) - 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 metabolized in the liver by hydroxylation with the participation of cytochrome P450 isoenzymes CYP2C8 (with the formation of a metabolite - 6-alpha-hydroxypaclitaxel) and CYP3A4 (with the formation of a metabolite of 3-para-hydroxy-paclitaxel). 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-alpha-hydroxypaclitaxel). Renal excretion plays an insignificant role in the process of excretion of paclitaxel.

Indications:

Therapy of epithelial ovarian cancer, primary peritoneal cancer or cancer of the fallopian tubes in combination with carboplatin.

Contraindications:

- Hypersensitivity to the active substance or to any component included in the preparation;

- The initial content of neutrophils is less than 1.5x10⁹/ l or platelet count less than 100x10⁹/ l;

- Liver disorders of severe severity;

- Pregnancy and lactation.

- Child age (safety and efficacy not established).

Carefully:

When oppression of bone marrow hematopoiesis (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 the anamnesis), arrhythmia.

Dosing and Administration:

The drug Paclikal® is administered intravenously as a 1-hour infusion (120-140 cap / min) at a dose of up to 250 mg / m² with an interval between courses of 3 weeks. Use of doses below 175 mg / m² Not recommended. Reduction of the administered dose to 200 mg / m² It is indicated to patients who have a high hematological toxicity after administration of a dose of 250 mg / m.

For the treatment of epithelial ovarian cancer, primary peritoneal cancer, fallopian vertebral cancer, the preparation Paclikal® is administered intravenously as a 1-hour infusion (120-140 cap / min) at a dose of 250 mg / m² in combination with carboplatin every 3 weeks in the form of six cycles. Carboplatin should be administered after infusion of Paclikal®.

Determine the initial dose of carboplatin according to Calvert's formula describing the dependence of glomerular filtration rate (GFR in ml / min) and the desired drug concentration on time (AUC in mg / m l min):

Total Dose (mg) = (AUC) х (СГФ + 25), where AUC from 5 to 6.

For patients who developed neutropenia during treatment (the number of neutrophils was less than 1.5x10⁹ / l for more than one week) or thrombocytopenia (platelet count was less than 100 x 10⁹ / l for more than one week), in subsequent courses should reduce the dose by 50 mg / m². Additional dose reduction of 25 mg / m² can be administered while maintaining these levels of neutropenia and thrombocytopenia after administration reduced by 50 mg / m² dose. The drug Paclikal should not be used until the amount of neutrophils is reached 1.5x10⁹ / l and more and the number of platelets up to 100x10⁹ / l and more. With sensory neuropathy of degree> 2, treatment should be deferred until recovery rates, with a dose reduction of 50 mg / m² at subsequent courses.

Preparation of solution for infusion:

A drug Paclikal® is dissolved in aqueous solutions to form a colloidal nano-micellar solution. As a diluting solution, Ringer should use only lactate or acetate solutions for infusion. The pH of the solution should be between 5.0 and 7.5, the concentration of calcium and magnesium ions should be within the limits given in Table 1:

Table 1. Admissible concentrations of calcium and magnesium ions in Ringer's solutions are lactate or acetate for infusions.

And he	Range (mmol / l)
Ca²⁺	1.0 - 3.5*
Mg2⁺	0 - 2*

* Solutions containing both calcium and magnesium ions should have a total concentration of calcium and magnesium ranging from 1.8 to 3.5 mmol / l.

The necessary number of vials is extracted from the refrigerator, and the color of the lyophilizate must be yellow or greenish-yellow. In case the lyophilizate changes color to orange-red, it should be destroyed. To reach room temperature, the vials should be placed in a dark place from 20 to 30 minutes at a temperature of no higher than 25 ° C. To dissolve the contents of the vial with a sterile syringe, 60 ml of the solution is slowly introduced into the vial, while the jet with the solution should be directed to the inner wall of the vial, and not to the lyophilizate.The contents of the vial should be mixed with cautious rotational movements along the vertical axis of the vial, without flipping or shaking, for 20-30 seconds. Leave the bottle to stand for 3-5 minutes in a dark place, after which it is rotated again or rotated with a neck down to complete dissolution of the powder. To avoid foaming the bottle should not be shaken. If undissolved particles are found, the vial should be placed in a shaker for horizontal shaking and rotated for 15 minutes in a dark place. The resulting solution should be transparent, greenish-yellow in color, with no visible particles or visible sediment. In the event that particles, sediment or color irregularity (orange-red) occur, the solution bottle should be destroyed.

The contents of the required number of vials are introduced into an empty sterile infusion bag, which is placed in a light-protection bag.

For administration, do not contain DEHP (diethylhexyl phthalate) infusion systems with membrane filters (pore size from 5 to 15 μm).

Side effects:

The incidence of adverse events listed in the table below is determined using the following scale.

Very frequent (≥1/10); frequent (≥1/100 to <1/10); infrequent (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); unknown (can not be estimated based on available data).

From the hematopoiesis:

Often: neutropenia, anemia, thrombocytopenia and leukopenia; often: febrile neutropenia;

infrequently: disseminated intravascular coagulation, granulocytopenia, pancytopenia.

On the part of mechanisms of resistance to infections:

often: viral infection of the respiratory tract, infection urinary tract;

infrequently: sepsis, influenza, herpes simplex, inflammation at the injection site, skin infections, tonsillitis.

From the immune system: often: hypersensitivity.

From the side of metabolism and nutrition:

Often: anorexia;

infrequently: hyponatremia, cell-mediated cytotoxicity, hypomagnesemia.

Mental disorders:

often: insomnia;

infrequently: depression, anxiety.

From the nervous system:

Often: peripheral sensory neuropathy;

often: peripheral neuropathy, lowered tactile sensitivity, dizziness, paresthesia, headache, peripheral motor neuropathy, dysgeusia. drowsiness; infrequently: polyneuropathy.

From the side of the organ of vision:

often: decreased visual acuity;

infrequently: irritation of the eye mucosa, increased lacrimation.

From the side of the organ of hearing and balance:

infrequently: Vertigo (vestibular vertigo).

From the cardiovascular system:

often: tachycardia, stenocardia, lowering blood pressure, hyperemia, phlebitis, increased blood pressure, hot flashes;

infrequently: heart palpitations, sinus tachycardia, cyanosis, vascular insufficiency, vasculitis, impaired tone of blood vessels, lymphatic edema, pallor, superficial phlebitis, thrombosis, pain in the veins.

On the part of the respiratory system, chest organs and mediastinum:

often: dyspnoea, cough, nasal congestion, oropharyngeal dysphagia, rhinorrhea;

infrequently: respiratory insufficiency, asphyxia, dysphonia, epistaxis, allergic rhinitis, oropharyngeal discomfort, pharyngeal disturbances.

From the digestive system:

Often: nausea, vomiting, diarrhea, abdominal pain;

often: constipation, pain in the upper abdomen, bloating, dry mouth, dyspepsia, stomatitis, abdominal discomfort;

infrequently: fecalitis, gastritis, bleeding gums, flatulence.

From the liver and biliary tract:

infrequently: hepatitis, an increase in the activity of "hepatic" transaminases, in particular alanine aminotransferase.

From the skin and subcutaneous tissue:

Often: alopecia;

often: erythema, rash, itching, urticaria;

infrequently: facial puffiness, hyperhidrosis, dry skin, nail damage, skin lesions, cold sweat, papular rash, dyskinesia.

From the osteomuscular system and connective tissue:

Often: arthralgia;

often: myalgia, bone pain, pain in the extremities, back pain, muscle weakness, musculoskeletal pain; infrequently: discomfort in the extremities.

On the part of the reproductive system and mammary glands:

infrequently: vaginal bleeding.

Local reactions:

often: redness, pain at the injection site;

infrequently: edema (in particular generalized), inflammation, erythema, extravasation, hernia, phlebitis at the site of administration.

Other:

Often: asthenia, fatigue;

often: fever, hyperthermia, peripheral edema, discomfort and chest pain, weight loss;

infrequently: puffiness of the face, irritation, a feeling of heat, chills.

Overdose:

Symptoms: bone marrow aplasia, peripheral sensory

neuropathy, mucositis.

Treatment: conduct symptomatic therapy. Specific

the antidote of paclitaxel is unknown.

Interaction:

Studies on the interaction of the drug Paclikal® with other medicines have not been carried out.

In studies in vitro it was shown that simultaneous administration with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the binding of paclitaxel to blood plasma proteins. Inhibitors of microsomal oxidation (incl. ketoconazole, cimetidine, verapamil, diazepam, quinidine, ciclosporin and others) suppress the metabolism of paclitaxel.

Special instructions:When working with paclitaxel, as with other antitumor drugs, care must be taken. The preparation of infusion solutions should be carried out by trained personnel in a specially designed area for this purpose, with aseptic conditions. Wear protective gloves. Should take precautions to avoid contact with skin and mucous membranes.In case of contact with mucous membranes, rinse with water and contact with skin with soap and water.

Hematology:

Suppression of bone marrow function (mainly neutropenia) is a toxic effect limiting the dose of the drug. During treatment with the drug, it is necessary to determine the content of blood cells at short intervals. Patients should not re-administer the drug until the neutrophil content is restored to at least 1.5 x 10⁹ / l blood, and the content of platelets to a level of at least 100x10⁹/ l of blood.

Impaired liver function:

Patients with hepatic impairment and associated increased risk of toxicity (in particular, myelosuppression) need to establish close monitoring of the condition of patients. Patients with severe hepatic impairment of the drug is contraindicated.

Disturbance of the function of the gastrointestinal tract:

Nausea, vomiting and diarrhea are frequent undesirable phenomena on the part of the gastrointestinal tract. In this case, symptomatic therapy is used: antiemetics and diarrhea remedies.

Dehydration:

Expressed dehydration is a serious undesirable phenomenon, if suspected of being recommended by the patient for supplemental fluid.

Reactions at the site of intravenous infusion:

Enter with caution, avoiding getting the drug into surrounding tissues. With any signs of extravasation (swelling, erythema, pain), immediately stop the injection, aspirate the fluid from the catheter / cannula before removing the needle, inject sterile saline or Ringer's lactate / acetate solution for infusions and monitor the patient's condition.

Hypersensitivity:

Hypersensitivity reactions associated with taking the drug Paclikal®, mainly characterized by mild to moderate severity, representing disorders of the skin, subcutaneous tissue, general disorders and reactions at the site of administration. There were no pronounced hypersensitivity reactions associated with the use of the drug Paclikal®. Minor symptoms, such as redness or skin reactions, do not require discontinuation of therapy with the drug. Reactions of moderate severity may require premedication with corticosteroids,antihistamines and / or antagonists H₂ receptors during the subsequent cycles of therapy. Pronounced reactions, such as hypotension, dyspnea, angioedema, or generalized urticaria, require immediate discontinuation of paclitaxel and symptomatic therapy. Patients with severe hypersensitivity reactions should not reapply treatment with paclitaxel.

Patients should be closely monitored prior to the appointment of a treatment cycle, especially patients who have had a history of hypersensitivity reactions with other forms of paclitaxel.

Neuropathy:

Peripheral sensory neuropathy develops frequently and is usually of a moderate nature. In cases of severe peripheral neuropathyIt is necessary to suspend treatment before recovery, at subsequent courses treatment dose of paclikal® it is recommended to reduce.

Excipients:

After dissolution, the preparation contains approximately 28 mg of sodium per dose (0.063 mg of sodium per ml). This should be taken into account when prescribing the drug to patients on a controlled salt diet.

Patients during treatment with the drug Paclikal® and at least 3 months after the end of therapy, reliable methods of contraception should be used.

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:

Lyophilizate for solution for infusion.

Packaging:

For 60 mg in glass bottles (type I, Hebrew Pharm.), Sealed with butyl rubber stoppers and crimped with combined flip-off caps of aluminum and polypropylene. Labels are applied to vials. One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

Store in the original packaging, protected from light at a temperature of 2 to 8 ° 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.

After dissolution, use according to the instructions.It is recommended to use immediately after dissolution. The prepared solution is suitable for use for 8 hours if stored at a temperature of no higher than 25 ° C, in a dark place.

Terms of leave from pharmacies:On prescription

Registration number:LP-002952

Date of registration:09.04.2015

Representation: & nbspFARMSINTEZ, PAO FARMSINTEZ, PAO Russia

Information update date: & nbsp11.10.2015

Illustrated instructions

Instructions

Paclikal® (Paclikal)