Platikad

General characteristics. Structure:

Active ingredient: 50 mg or 100 mg of an oksaliplatin.

Excipients: lactoses monohydrate.

Pharmacological properties:

Pharmacodynamics. Oksaliplatin is the antineoplastic drug belonging to the new class of connections on the basis of platinum in which atom of platinum forms complex communication with 1,2 diaminocyclohexane (DATsG) and oxalic group. Oksaliplatin possesses a wide range of cytotoxic action. He shows activity of in vitro and in vivo on various models of the tumors steady against Cisplatinum. Action is shown regardless of a phase of a cellular cycle. At use with ftoruratsily a synergism of cytotoxic action is observed.
 
Studying of the mechanism of action of an oksaliplatin confirms a hypothesis that the biotransformed water derivatives of an oksaliplatin, interacting with DNA by formation of boundaries - and vnutrityazhevy bridges, suppress DNA synthesis that leads to cytotoxic and antineoplastic effect.

Pharmacokinetics. In vivo оксалиплатин is exposed to active biotransformation and does not come to light in plasma by the end of 2 h after introduction in a dose of 85 mg/mg/sq.m, at the same time 15% of the entered platinum are in blood, and other 85% are quickly distributed on fabrics or removed by kidneys. Platinum contacts albumine of plasma and is removed by kidneys within the first 48 hours. By 5th day about 54% of all dose are found in urine and less than 3% - in Calais.
 
Pharmacokinetics in special groups of patients. Removal of an oksaliplatin at patients with renal failures of varying severity. Removal of an oksaliplatin authentically correlates with the clearance of creatinine (CC). The general plasma clearance of the ultrafiltered platinum decreases at KK of 50-80 ml/min. by 34%, at KK of 30-49 ml/min. - for 57%, and at KK less than 30 ml/min., for 79% in comparison with that at KK more than 80 ml/min. At depression of function of kidneys the renal clearance of the ultrafiltered platinum and removal of platinum kidneys also decrease.

Indications to use:

- adjuvant therapy of a colorectal cancer of the III stage (With across Dyyuk) after a radical resection of primary tumor (in a combination with ftoruratsily and calcium folinaty);
 
- the disseminated colorectal cancer (as monotherapy or a combination therapy in a combination with ftoruratsily and calcium folinaty);
 
- ovarian cancer (as the second line of therapy).

Route of administration and doses:

Oksaliplatin is applied only at adults in the form of intravenous infusion within 2-6 hours.
 
Dosing mode. Adjuvant therapy of a colorectal cancer: on 85 mg/sq.m of 1 times in 2 weeks in a combination with ftoruratsily and calcium folinaty during 12 cycles (6 months).

Treatment of a metastatic colorectal cancer: on 85 mg/sq.m of 1 times in 2 weeks as monotherapy or in a combination with ftoruratsily and calcium folinaty (before progressing of a disease or development of the phenomena of unacceptable toxicity).
 
Cancer therapy of ovaries: on 85 mg/sq.m of 1 times in 2 weeks as monotherapy or in a combination with other chemotherapeutic drugs.
 
The modes of dosing of a ftorurotsil, calcium of a folinat at their combination with oksaliplatiny see in application instructions of these drugs.
 
Rules of preparation and administration of solution. At preparation and at introduction of Platikada® it is impossible to use needles and other equipment containing aluminum. For cultivation of drug it is necessary to use only the recommended solvents.
 
Not to use for dissolution of drug or cultivation of solution of drug (for preparation of infusion solution) 0,9% solution of sodium of chloride and not to mix with other alkaline solutions or solutions of sodium of chloride and chlorine-containing solutions.
 
Before use drug is dissolved in water for injections or 5% dextrose solution. At the same time into a bottle from 50 mg of Platikada® enter 10 ml of solvent, and into a bottle from 100 mg - 20 ml for receiving solution with concentration of an oksaliplatin of 5 mg/ml.
 
At once after dissolution of the lyophilized powder it is necessary to start preparation of infusion solution. For this purpose the recovered solution of the drug Platikad® is diluted by 250-500 ml of 5% of solution of a dextrose. Concentration of the received solution of an oksaliplatin has to make from 0,2 to 0,7 mg/ml; at the same time 0,7 mg/ml - the highest concentration applied in clinical practice at a dose of 85 mg/sq.m.
 
The prepared solution of drug has to be transparent and should not contain not dissolved particles. Otherwise solution of drug cannot be applied. Solution with signs of loss of a deposit is liable to destruction.
 
Solution for infusion is recommended to be used right after preparation. Undiluted cannot administer the drug. Not to mix in one capacity and not to appoint at the same time in one infusional system with other drugs (in particular with ftoruratsily, trometamoly and the drugs of calcium of a folinat containing трометамол in the structure), with the alkaline solutions or solutions containing chlorides.
 
Drug is intended only for single use. Unused solution of drug has to be destroyed.
 
The drug is administered in the form of intravenous infusion through infusional system in peripheral veins or through the central venous catheter within 2-6 hours. Платикад® it can be appointed together with infusions of calcium of a folinat. In this case drugs should not be mixed in one capacity for infusions. Calcium фолинат for performing infusion it is necessary to dissolve 5% of solution of a dextrose with use, but it is not necessary to use the solutions containing sodium chloride, or alkaline solutions at all. Simultaneous intravenous infusion together with calcium folinaty has to be carried out within 2-6 hours by means of the Y-shaped system for intravenous administration connected just before an injection site.
 
If Platikad® is applied in a combination with ftoruratsily, infusion of Platikada® has to precede introduction of a ftoruratsil.
 
After the end of infusion of an oksaliplatin it is recommended to wash out a catheter with use of 5% of solution of a dextrose (it is not necessary to use the solutions containing sodium chloride, or alkaline solutions at all).
 
In case of an ekstravazation (hit of infusion solution with drug in the fabrics surrounding a vein) administration of drug has to be immediately stopped and begun a usual topical symptomatic treatment.
 
At use of an oksaliplatin the overhydratation is not required.
 
Corrections of the mode of dosing. Correction of the entered dose depending on individual portability of drug is recommended.
 
At hematologic disturbances (quantity of neutrophils <1,5Õ109/l and/or thrombocytes <75x109/l) after a course of treatment or prior to treatment (to the first course of treatment) carrying out the following course or the first course is postponed until recovery of acceptable values of laboratory indicators (to quantity of neutrophils> 1,5h109/L and/or thrombocytes> 75x109/l). Prior to treatment and before each following cycle the general blood test with exact determination of quantity of leukocytes and thrombocytes has to be carried out.
 
At development of heavy/life-threatening diarrhea, a heavy neutropenia (quantity of neutrophils <1x109/l), heavy thrombocytopenia (quantity of thrombocytes <50h109/L) introduction of an oksaliplatin has to be stopped before improvement or recovery of these indicators and the dose of Platikada® at the subsequent introductions has to be lowered by 25% (from 85 mg/sq.m to 65 mg/sq.m at therapy of the disseminated colorectal cancer and ovarian cancer; to 75 mg/sq.m at adjuvant therapy of a colorectal cancer) in addition to a usual dose decline of a ftoruratsil in case of their combined use. Patients at whom during infusion or within several hours after 2-hour infusion the acute laryngopharyngeal dizesteziya develops should carry out the following infusion of Platikada® within 6 hours.
 
At emergence of neurologic symptoms (paresthesia, a dizesteziya - displays of peripheral touch neuropathy) the following changes of the mode of dosing, proceeding from their duration and expressiveness are recommended:
 
- at the neurologic symptoms disturbing the patient lasting more than 7 days or to the following cycle of treatment of paresthesia without functional disturbances, the subsequent dose of Platikada® has to be lowered by 25%;
 
- at the paresthesia with functional disturbances remaining to the following cycle, Platikad® has to be cancelled;

- at reduction of expressiveness of neurologic symptoms after cancellation of Platikada® it is possible to consider a question of treatment resuming.
 
At development of stomatitis and/or mukozit of the II and more degree of toxicity, treatment of Platikadom® has to be suspended before their stopping or decrease in manifestations of toxicity to the I degree.
 
Use for special groups of patients. Patients with a renal failure. With normal function of kidneys or with a renal failure easy and moderate severity dose adjustment of an oksaliplatin is not required from patients and therapy can be begun with the recommended dose (85 mg/sq.m). Decrease in an initial dose of an oksaliplatin to 65 mg/sq.m is required from patients with a renal failure of heavy degree.
 
Patients with abnormal liver functions. Change of the mode of dosing with an abnormal liver function easy and moderate severity is not required from patients. There are no data on use of an oksaliplatin for patients with an abnormal liver function of heavy degree.
 
Patients of advanced age. Patients do not need correction of the mode of dosing at purpose of an oksaliplatin aged 65 years (are more senior including at use in a combination with ftoruratsily).

Features of use:

Pregnancy and lactation. Use of drug during pregnancy and breastfeeding is forbidden.

Платикад® it has to be applied only in specialized oncological departments under observation of the oncologist having experience with antineoplastic drugs.
 
At treatment oksaliplatiny constant control of development of possible toxic effects is necessary.
 
Regularly (weekly), and also before each administration of drug it is necessary to carry out control of uniform elements of peripheral blood and indicators of function of kidneys and a liver.
 
Due to the limitation of data concerning safety of use of drug for patients it is recommended to correlate to a renal failure of heavy degree carefully before drug use risk and advantage. It is necessary to control function of kidneys strictly. The initial dose of an oksaliplatin at patients with heavy renal failures has to make 65 mg/sq.m.
 
Before each cycle of therapy Platikadom® it is necessary to conduct neurologic examination regarding identification of signs of a neurotoxicity (peripheral touch neuropathy), especially, if drug is combined with other medicines possessing a neurotoxicity. Recommendations about dose adjustment and the mode of introduction of an oksaliplatin at a neurotoxicity, hematologic and gastrointestinal manifestations of toxicity are provided in the section "Route of Administration and Doses".
 
Patients should be informed on a possibility of preservation of symptoms of peripheral touch neuropathy after the termination of a course of treatment. The localized moderate paresthesias with functional disturbances can remain to 3 years after the end of use of drug for adjuvant therapy. Patients at whom during infusion or within several hours after 2-hour infusion the acute laryngopharyngeal dizesteziya develops should carry out the following infusion of an oksaliplatin within 6 hours. For prevention of development of a dizesteziya the patient is recommended to avoid overcooling, and also reception of too cold food and drinks during introduction and within several hours after administration of drug of an oksaliplatin.
 
At emergence of respiratory symptoms (dry cough, диспноэ, rattles or identification of pulmonary infiltrates at X-ray inspection), it is necessary to suspend treatment of Platikadom® to an exception of existence of an intersticial pneumonitis by means of an additional research of lungs.
 
Gastrointestinal toxicity which is shown by nausea and vomiting can decrease or be eliminated considerably at use of antiemetics. Such symptoms as dehydration, intestinal impassability, including paralytic, a hypopotassemia, a metabolic acidosis and a renal failure can be caused by the expressed diarrhea or vomiting, especially at use of Platikada®v of a combination with ftoruratsily. Patients have to be in detail informed on a possibility of development of diarrhea/vomiting and a neutropenia after use of an oksaliplatin in a combination with ftoruratsily in order that at their emergence the patient could see immediately the attending physician for urgent receiving necessary treatment in their occasion.
 
At a combination of an oksaliplatin with ftoruratsily (from calcium folinaty or without it), at development of the toxicity connected with ftoruratsily it is necessary to apply the dose adjustment of a ftoruratsil which is usually recommended in these cases (see the instruction on a medical use of a ftoruratsil). Patients with allergic reactions to other compounds of platinum in the anamnesis should be controlled on existence of allergic symptoms. In case of reaction to Platikad®, similar anaphylactic, infusion it is necessary to interrupt and appoint the corresponding symptomatic treatment immediately. Further use of Platikada® in case of development of allergic reactions contraindicated. The headache, disturbance of mental capacities, spasms, vision disorders (from an image vagueness to a blindness) which are combined or not with increase in arterial pressure (see the section "Side effect") can be signs and symptoms of a reversible back leukoencephalopathy. The diagnosis of a reversible back leukoencephalopathy is confirmed by means of a magnetic and resonant or computer tomography of a brain.
 
In case of the aberration of laboratory indicators of function of a liver or development of portal hypertensia which are not with evidence a consequence of existence of metastasises in a liver it is necessary to inspect the patient regarding very seldom found defeat of hepatic vessels.
 
In case of an ekstravazation infusion it is necessary to stop and begin a topical symptomatic treatment immediately. The remained dose of drug should be entered into other vein.
 
Women and men during treatment of Platikadom® and within 6 months after the end of therapy Platikadom® should use reliable ways of contraception.
 
Precautionary measures at use. When using an oksaliplatin it is necessary to observe all usual precautionary measures taken for use of cytotoxic drugs. In case of hit of drug in their eyes it is necessary to wash out immediately a large amount of water or solution of sodium of chloride. In case of hit of drug on skin it is necessary to wash out immediately the place of contact with drug a large amount of water. In case of inhalation of drug or its hit in a mouth it is necessary to see a doctor immediately.

Influence on ability to manage vehicles and mechanisms. Vision disorders, in particular passing loss of sight (reversible after therapy cancellation) can constitute danger to patients at control of vehicles and occupation other potentially dangerous types of activity. At emergence of the described undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

Frequency of the side reactions given below is stated according to the following gradation: very often (> 10%), it is frequent (> 1% and ≤ 10%), infrequently (> 0,1% and ≤ 1%), is rare (> 0,01% and ≤ 0,1%), is very rare (≤0,01%), including separate messages; frequency is unknown - it is not possible to determine occurrence frequency by the available data.
 
Disturbances from blood and lymphatic system: very often - anemia, a leukopenia, a neutropenia, thrombocytopenia, a lymphopenia.

Frequency of emergence of these side effects increases at treatment by drugs of an oksaliplatin (to 85 mg/sq.m there are each 2 weeks) in a combination with ftoruratsily ± calcium фолинат in comparison with monotherapy by drugs of an oksaliplatin in a dose of 130 mg/sq.m each 3 weeks, for example, anemia frequency (80% in comparison with 60%), neutropenia frequency (70% in comparison with 15%), thrombocytopenia frequency (80% in comparison with 40%).
 
Heavy anemia (hemoglobin <80 g/l) or heavy thrombocytopenia (thrombocytes <50x109/l) arose with an identical frequency (<5% of patients when drugs of an oksaliplatin were used in the form of monotherapy or in a combination with ftoruratsily).
 
The heavy neutropenia (quantity of neutrophils <1x109/l) arose with a bigger frequency when using drugs of an oksaliplatin in a combination with ftoruratsily in comparison with monotherapy oksaliplatiny (40% in comparison with 15% of patients); often - a febrile neutropenia (including 3-4 degree), sepsis against the background of a neutropenia; seldom - hemolitic anemia, immune thrombocytopenia.
 
Disturbances from digestive tract: very often - nausea, vomiting, diarrhea, stomatitis or mukozit (an inflammation of mucous membranes), pains in a stomach, a lock, appetite loss.
 
Development of dehydration, hypopotassemia, metabolic acidosis, intestinal impassability, renal failures can be associated with heavy diarrhea and/or vomiting, especially at use of a combination of drugs of platinum and a ftoruratsil; often - dyspepsia, a gastroesophageal reflux, a hiccups, gastrointestinal bleeding; infrequently - intestinal impassability, including paralytic; seldom - colitis, including cases of pseudomembranous colitis (the caused Clostridium difficile), pancreatitis.
 
Disturbances from a liver and biliary tract: very often - increase in activity of an alkaline phosphatase, lactate dehydrogenase, "hepatic" transaminases, increase in concentration of bilirubin; very seldom - the syndrome of hepatic sinusoidal obstruction also known under the name of a veno-occlusal disease of a liver or the pathological manifestations connected with this disease of a liver including peliozny hepatitis, a nodal regenerative hyperplasia, perisinusoidalny fibrosis which clinical displays can be portal hypertensia or increase in activity of "hepatic" transaminases, an alkaline phosphatase in blood serum.
 
Disturbances of mentality: often - a depression, sleeplessness.
 
Disturbances from a nervous system: very often - acute neurosensory manifestations, peripheral touch neuropathy, sensitivity disturbances, a dizesteziya, a headache, paresthesias of extremities, a dysgeusia (disturbance of flavoring feelings).
 
Acute neurosensory manifestations - these symptoms usually arise at the end of the 2nd hour infusion of drugs of an oksaliplatin or within several hours after administration of drugs and independently decrease within several next hours or days and often again arise in the subsequent cycles. They can arise or amplify at influence of low temperatures or cold objects. Usually they are expressed in emergence of passing paresthesia, a dizesteziya and a hypesthesia.
 
The acute syndrome of a laryngopharyngeal dizesteziya arises at 1-2% of patients and is characterized by subjective feelings of a dysphagy or asthma/feeling of suffocation without any objective signs of respiratory frustration (absence of cyanosis or hypoxia) or a laryngospasm or a bronchospasm (lack of a stridor or goose breathing).
 
Others sometimes the found symptoms, in particular, the dysfunctions of cranial nerves or which are associated with the above-mentioned undesirable phenomena or found separately: ptosis; a diplopia (doubling in eyes); the aphonia, a dysphonia, hoarseness of a voice sometimes described as paralysis of phonatory bands; disturbance of sensitivity of language or the dysarthtia sometimes described as aphasia; epileptiform neuralgia, front pains, eye pains, decrease in visual acuity, narrowing of fields of vision. Besides the following symptoms were observed: masticatory spasm, muscular spasms, involuntary muscular contractions, muscular twitchings, myoclonus; lack of coordination, gait disturbance, ataxy, balance disturbances; feeling prelum/feeling throat or thorax pressure/discomfort/pain.
 
As a rule, these symptoms are quickly stopped both without use of medicamentous therapy, and at introduction of antihistaminic and broncholitic means. Increase in time of infusion at the subsequent cycles of therapy oksaliplatiny allow to reduce the frequency of similar symptoms.
 
The limiting toxicity of an oksaliplatin is neurologic toxicity. It is shown in the form of the peripheral touch neuropathy which is characterized peripheral dizesteziya and/or paresthesia with development or without development of convulsive muscular contractions that is often provoked by cold (85-95% of patients).
 
Time of preservation of these symptoms which usually decrease between treatment cycles increases with increase in quantity of the carried-out treatment cycles. Developing of pains or functional disturbances and their duration are indications for correction of the mode of dosing or even cancellation of treatment (see the section "Route of Administration and Doses, Recommendations of Correction of the Mode of Dosing of an Oksaliplatin"). These functional disturbances, including difficulties when performing exact movements, are effects of touch disturbances. The risk of emergence of functional disturbances for a cumulative dose about 800 mg/sq.m (for example, 10 cycles) makes <15%. In most cases neurologic manifestations and symptoms decrease after the treatment termination. In most cases these neurologic symptoms weaken or they are completely stopped. However at 3% of patients in 3 years after the end of treatment were observed or the steady localized paresthesias of moderate intensity (2,3%) or the paresthesias influencing functional activity (0,5%); seldom - a dysarthtia, disappearance of deep tendon jerks, Lermitt's symptom, a syndrome of a reversible back leukoencephalopathy.
 
Lermitt's symptom is the sudden feeling of blow by current extending from top to down along a backbone and in both legs. It arises at a ducking, other movements of a neck or cough. Possible options of a symptom of Lermitt - a pricking at the movements of a neck or pain at the movements of a neck, distribution of unpleasant feelings to both hands and emergence of unpleasant feelings at the movements in lumbar department of a backbone.
 
The headache, disturbance of mental capacities, spasms, vision disorders (from an image vagueness to a blindness) which are combined or not with increase in the ABP can be signs and symptoms of a reversible pariyeto-oktsipitalny leukoencephalopathy. The diagnosis of a reversible back leukoencephalopathy is confirmed by means of a magnetic and resonant or computer tomography of a brain.
 
Disturbances from skeletal and muscular and connecting fabric: very often - dorsodynias.
 
In case of such undesirable reaction it is necessary to inspect the patient for a hemolysis exception as there were rare messages on its development; often - an arthralgia, ostealgias.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often - cough, short wind; often - rhinitis, upper respiratory tract infections; seldom - acute intersticial damage of lungs, sometimes from the death, a pneumosclerosis.
 
Disturbances from heart: often - pains behind a breast.

Disturbances from vessels: very often - nasal bleeding; often - bleeding, heat "inflows", a deep vein thrombosis, a thromboembolism of pulmonary arteries, increase in arterial pressure.
 
Disturbances from kidneys and urinary tract: often - increase in concentration of creatinine, a hamaturia, a dysuria, the speeded-up urination; very seldom - an acute canalicular necrosis, acute intersticial nephrite, an acute renal failure.
 
Disturbances from skin and hypodermic fabrics: very often - an alopecia (less than 5% of patients at monotherapy), skin rashes; often - a peeling of skin of palms and stop, erythematic rashes, rash, the increased perspiration, changes from nails.
 
Disturbances from an organ of sight: often - conjunctivitis, vision disorders; seldom - tranzitorny decrease in visual acuity, narrowing and/or loss of fields of vision, an optic neuritis, tranzitorny loss of sight, reversible after the treatment termination.
 
Disturbances from an acoustic organ and labyrinth disturbances: infrequently - ototoxicity; seldom - decrease in hearing, deafness, neuritis of an acoustical nerve.
 
Disturbances from immune system: very often - allergic reactions, such as skin rash (in particular a small tortoiseshell), conjunctivitis, rhinitis; often (in a combination with ftoruratsily ± than calcium фолинат, is more rare at monotherapy use) - anaphylactic reactions, including a bronchospasm, a Quincke's disease, hypotension, feeling of pains in a thorax and an acute anaphylaxis.
 
The general frustration and disturbances in an injection site: very often - weakness and increased fatigue, fervescence, fever, a fever (shiver) (or because of development of infections (with a febrile neutropenia or without it) or owing to a possible immune response), an adynamy, reactions in an injection site. It was reported about development of reactions in an injection site, including pain, a hyperemia, hypostasis and thrombosis. Ekstravazation (hits of infusion solution with drug in surrounding fabrics) can lead to developing of local pains and inflammations which can be sharply expressed and lead to complications, including a necrosis, especially when the drug is administered in a peripheral vein.
 
Disturbances from a metabolism and food: very often - a hypopotassemia, a hyponatremia, a hyperglycemia, anorexia, increase in body weight (when performing adjuvant therapy); often - dehydration, a body degrowth (when performing therapy concerning metastatic cancer); infrequently - a metabolic acidosis.

Post-marketing experience of use of drugs of an oksaliplatin.
 
Disturbances from blood and lymphatic system: frequency is unknown - a gemolitiko-uraemic syndrome.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum: frequency is unknown - a laryngospasm.

Disturbances from a nervous system: frequency is unknown - spasms, dizziness.

Interaction with other medicines:

Essential change of linkng of an oksaliplatin with proteins of plasma at simultaneous use with erythromycin, salicylates, granisetrony, paklitaksely and valproic acid was not observed.
 
At interaction with aluminum formation of a deposit and decrease of the activity of an oksaliplatin is possible.
 
Платикад® it is pharmaceutical not compatible from 0,9% the solution of sodium of chloride and other solutions containing chlorides and also alkaline solutions.
 
At the patients receiving оксалиплатин in a dose of 85 mg/sq.m just before introduction of a ftoruratsil changes in concentration of a ftoruratsil in blood were not observed.

Contraindications:

- hypersensitivity to an oksaliplatin, other derivatives of platinum or other components of drug;
- a miyelosupressiya prior to the beginning of the first course of therapy at the level of neutrophils less than 2x109/l and/or thrombocytes less than 100Õ109/l);
- peripheral touch neuropathy with functional disturbances prior to the beginning of the first course of therapy;
- pregnancy and period of breastfeeding;
- children's age up to 18 years.

With care:
- A renal failure of heavy degree (clearance of creatinine <30 ml/min.) (monitoring of function of kidneys and correction of the mode of dosing, see the section "Route of Administration and Doses", "Special Instructions" is required);
- abnormal liver function of heavy degree.

Overdose:

Symptoms: in case of overdose moleno to expect more expressed manifestation of side effects: miyelosupressiya, neurotoxicity, diarrhea, nausea, vomiting.
 
Treatment: the antidote to an oksaliplatin is not known. Careful observation of the patient, strict control of hematologic indicators and symptomatic therapy is recommended.

Storage conditions:

To store in the dry, protected from light place, at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 50 mg and 100 mg of active ingredient in the bottles of colourless neutral glass I of a hydrolytic class which are hermetically corked by rubber bungs with a running in caps aluminum. On 1 bottle with the application instruction place in a pack from a cardboard.