Methotrexate Orion

General characteristics. Structure:

Active ingredient: 2,5 mg or 10,0 mg of a methotrexate.

Excipients: starch corn, lactoses monohydrate, starch pro-gelatinous, polysorbate 80, cellulose microcrystallic, magnesium stearate.

The drug having the expressed immunosuppressive effect even in rather low doses which do not have noticeable hematologic toxicity. Is more active concerning quickly growing cells.

Pharmacological properties:

Pharmacodynamics. The methotrexate (4-amino-10-methylfolic acid) is the antagonist of folic acid inhibiting recovery of folic acid and growth of cells of fabric. The methotrexate competitively oppresses enzyme to a digidrofolatreduktaz, preventing recovery of dihydrofolate to tetrahydrofolate which is necessary for synthesis of DNA and replication of cells. As a result of the poliglyutamation of a methotrexate caused by enzyme folilpoliglyutamilaty duration of cytotoxic effect of active ingredient in a cell increases.

The methotrexate is fazospetsifichesky substance which main effect is directed to a S-phase of a mitosis of cells. As a rule, most effectively it affects actively proliferating fabrics, such as malignant cells, marrow, fruit cells, a skin epithelium, a mucous membrane of an oral cavity and intestines, and also a bladder cell. As proliferation of malignant cells is higher, than at the majority of normal cells, the methotrexate can slow down proliferation of malignant cells, without causing at the same time to irreversible damages of normal fabric.

Pharmacokinetics. The effect of orally accepted methotrexate depends on dose size. Cmax in a blood plasma is reached within 1–2 h. The usual dose of a methotrexate of 30 mg/sq.m or is absorbed quickly and completely below. Absorption of the doses exceeding 80 mg/sq.m, incomplete.

About a half of the absorbed methotrexate reversibly contacts proteins of a blood plasma, however is easily distributed in fabrics. Removal is carried out according to the three-phase scheme. In the first phase the methotrexate is distributed in an organism, in the second — there is renal excretion and in the third it gets to enterogepatichesky blood circulation. It is excreted preferential by kidneys.

About 41% of a dose are removed in not changed view with urine within the first 6 h, 90% — for 24 h. At disturbance of renal function concentration of a methotrexate in a blood plasma and fabrics can quickly increase.

Indications to use:

Pseudorheumatism in an active form at adults. Extensive chronic psoriasis, especially at elderly people and disabled people, in case of insufficient efficiency of other types of therapy. Acute lymphocytic leukosis (maintenance therapy).

Route of administration and doses:

the pill Methotrexate Orion is taken without chewing for 1 h to or in 1,5–2 h after meal. Treatment by drug should be carried out under observation of the oncologist, dermatologist or rheumatologist, and also therapist.

Doses at a pseudorheumatism and psoriasis. Psoriasis. The recommended initial dose — 7,5 mg/week once or in the form of the divided doses (3 times on 2,5 bucketed mg of 12 h).

Pseudorheumatism. The recommended initial dose — 7,5 mg once a week.
The therapeutic effect is usually noted already in the first 6 weeks of treatment then the condition of patients continues to improve 12 more and more weeks. If in 6–8 weeks of therapy of signs of improvement, and also there are no toxic effects, the dose can be raised gradually on 2,5 mg/week.

Usually optimum week dose makes 7,5–15 mg. It is not necessary to exceed the maximum dose of 20 mg. If after 8 weeks of treatment by the maximum dose there is no effect, the methotrexate should be cancelled. In case of achievement of therapeutic effect continue treatment in minimal effective doses. The optimum duration of therapy is not determined by a methotrexate yet, however preliminary data confirm preservation of initial effect within not less than 2 years in case of continuation of a maintenance therapy. After the treatment termination by a methotrexate symptoms of a disease can return in 3–6 weeks.

Doses at malignant oncological diseases. It is possible to apply a methotrexate orally in doses to 30 mg/sq.m of a body surface. Higher doses should be entered parenterally. At a maintenance therapy of an acute lymphoid leukosis the methotrexate is appointed to children inside in doses to 20 mg/sq.m/week in combination with in/in and intrathecal introduction for prevention of defeat of TsNS.

Treatment of patients with renal failures. Patients need to appoint a methotrexate with care with renal failures. Doses adjust depending on clearance of creatinine (at clearance> 50 ml/min. to reduce a dose there is no need, at clearance of 20-50 ml/min. the dose is lowered by 50%, and at clearance <20 ml/min. do not appoint a methotrexate).

Treatment of patients with abnormal liver functions. The methotrexate is appointed carefully (in case of need) to patients with the considerable abnormal liver functions (existing or in the anamnesis, especially caused by an alcohol abuse). It is contraindicated to apply a methotrexate at bilirubin level> 85,5 µmol/l.

Treatment of patients of advanced age. As with age function of a liver and kidneys worsens, and also reserves of folates decrease, decrease in doses for patients of advanced age is reasonable.

Features of use:

Only doctors with experience of performing therapy by antimetabolites can appoint a methotrexate. Simultaneous use of hepatotoxic or gematotoksichesky antirheumatic drugs, such as лефлуномид, it is not recommended.

Lethal cases of the acute and chronic intersticial pneumonitis associated with an eosinophilia are registered. Typical symptoms: short wind, cough (especially dry, unproductive) and fever. Patients need to be informed on a possible pneumonitis and the obligatory immediate address to the doctor when developing steady cough or asthma.

If at the patient note pulmonary symptoms, treatment by a methotrexate it is necessary to stop for an infection exception. If there is a suspicion that the disease of lungs is caused by a methotrexate, it is necessary to begin treatment of GKS. Use of a methotrexate should be stopped.

Treatment of psoriasis a methotrexate should be limited and applied at heavy, uncontrollable and wearisome psoriasis which does not give in to other types of treatment. Use of a methotrexate should be begun only after confirmation of the diagnosis by means of a biopsy and/or after consultation with the dermatologist. At treatment of psoriasis the methotrexate registered lethal cases.

It is necessary to apply carefully a methotrexate to patients with infections, stomach ulcer or a duodenum, ulcer colitis or exhaustion, to persons of very young or advanced age. If in the course of treatment there was a deep leukopenia, the threat of a bacterial infection is possible.

Before therapy by a methotrexate the doctor has to report to the patient about the possible heavy, even lethal toxic reactions associated with therapy by a methotrexate. Patients should be poinformirovat about symptoms of intoxication and to advise them to see immediately a doctor at their emergence.

During therapy it is necessary to watch a condition of the patients accepting a methotrexate carefully.

Patients also should emphasize importance of regular control inspections and laboratory analyses.

At emergence of side reactions it is necessary to lower a drug dose or to stop treatment. Besides, it is required to consider need of use of calcium of a folinat and/or periodic hemodialysis with the dialyzer with high intensity of a flow.

Diarrhea and aphthous stomatitis are widespread toxic reactions, at their emergence treatment should be stopped because of risk of development of hemorrhagic enteritis or deadly perforation of intestines.

The patient should be informed that at treatment of psoriasis and a pseudorheumatism drug should be used once a week accurately. The doctor, if considers it necessary, can specify a day of the week when it is necessary to accept drug in the recipe. The patient has to realize, how important to observe administration of drug once a week, and the wrong daily use can lead to heavy toxic reactions.

In an initiation of treatment it is necessary to conduct the following examinations: the developed blood test, a research of function of a liver and kidneys, radiological inspection of bodies of a thorax. At treatment of a pseudorheumatism and psoriasis it is recommended to carry out such control tests: hematologic inspection once a month, check of function of a liver and kidneys with an interval of 1-3 months. At considerable reduction of quantity of leukocytes or thrombocytes treatment should be stopped immediately. The patient has to report about other symptoms indicating existence of an infection. Any infections need to be cured before therapy by a methotrexate.

At treatment of an oncological disease control examinations should be conducted more often. With risk of increase in concentration of a methotrexate in a blood plasma, for example, because of a high dose or dehydration, hematologic inspection and check of function of a liver and kidneys if necessary should be carried out more often. During therapy by high doses of a methotrexate it is necessary to check alkalinity of urine also.

Removal of a methotrexate is reduced at patients with insufficiency of function of kidneys, ascites or a pleural exudate. These patients need especially careful monitoring, the dose decline of a methotrexate or the termination of therapy by a methotrexate can be required by them. The pleural exudate and ascites needs to be drained prior to treatment by a methotrexate.

At prolonged treatment of patients with a pseudorheumatism or psoriasis it is necessary to pay attention to the increased risk of damage of a liver. The methotrexate can have a hepatotoxic action, but usually only after prolonged use. Cases of an atrophy, fatty degeneration, a necrosis and periportal fibrosis of a liver are recorded. Liver diseases in the anamnesis, the overestimated indicators of hepatic tests, alcohol intake belong to risk factors of severe damage of a liver. Because of a hepatotoxic action of a methotrexate it is necessary to avoid whenever possible other hepatotoxic drugs during treatment. It is necessary to avoid or to sharply reduce alcohol intake. The risk of toxic impact on a liver is increased at the patients applying insulin.

Research of functions of a liver. Special attention should be paid on signs of damage of a liver. Treatment should not be begun or it is necessary to stop already begun treatment at an aberration of level of hepatic tests or a biopsy of a liver.

Functions of a liver are usually normalized during 2 weeks then it is possible to consider therapy continuation. The biopsy of a liver is the only reliable method of definition of extent of damage of a liver, and its result should be considered at making decision on treatment.

Monitoring of level of serumal liver enzymes. Short-term increase in level of liver enzymes by 2–3 times in comparison with the upper bound of norm is revealed at 13–20% of patients. If the level of liver enzymes repeatedly increases, it is necessary to lower a dose or to stop treatment. It is necessary to control the level of liver enzymes, especially at the patients who are at the same time accepting other hepatotoxic or myelotoxic means (for example лефлуномид).

Patients with risk of disturbance of functions of a liver. Primary risk factors: excessive alcohol intake, numerous increase in level of liver enzymes, an abnormal liver function in the anamnesis, including a chronic, autoimmune or viral hepatitis, inherited disorders of function of a liver.

Secondary risk factors: a diabetes mellitus, obesity, influence of hepatotoxic agents in the anamnesis.

As a small amount of patients stop treatment for various reasons after 2–4 months of therapy, patients with high risk should carry out the first biopsy within 3–6 months after an initiation of treatment.

The biopsy of a liver is recommended in the course of treatment to patients with increase in laboratory indicators (ASAT or ALAT more than twice). This recommendation also concerns patients without tendency to abnormal liver functions.

The biopsy of a liver is optional in such cases: advanced age, acute disease, contraindications to a biopsy (disturbance of cordial function, change of indicators of a blood coagulation), is expected short life expectancy.

Kidneys. The methotrexate is preferential allocated with kidneys. It is necessary to control carefully function of kidneys in time and after treatment. The renal failure is possible as a result of considerable accumulation of a methotrexate or even injury of kidneys. It is necessary to be careful at a renal failure.

The dose of a methotrexate should be lowered for patients with a renal failure. High doses can lead to sedimentation of a methotrexate or its metabolites in renal tubules. The recommended preventive measures are sufficient hydration and alkalization of urine to the pH 6,5-7 level with in/in or oral administration of sodium bicarbonate (5х625 mg in tablets each 3 h) or acetazoleamide (500 mg in 4 times a day).

The considerable renal failure is a contraindication to therapy by a methotrexate.

Immune system. As the methotrexate influences immune system, it can change reaction to vaccination and results of immunoassays. During therapy it is necessary to avoid vaccination by live vaccines.

The immunosuppressive effect of a methotrexate should be considered if the patient requires preservation of an immune response.

Special attention should be paid at inactive persistent infections (such as shingles, tuberculosis, hepatitis B or C) because of a possibility of their potential activation.

At patients with fast-growing tumors therapy by a methotrexate can provoke a syndrome of "disintegration of a tumor". Patients who apply low doses of a methotrexate can have malignant lymphoma. In such cases treatment should be stopped. If the lymphoma does not disappear, it is necessary to begin cytostatic therapy.

Simultaneous use of a methotrexate and radiotheraphy can increase risk of a necrosis of soft tissues and bones.

Therapy by high doses of a methotrexate has to be followed by use of a folinat of calcium. At use of a folinat of calcium, hydration and alkalization of urine for the patient it is necessary to control constantly potential toxic effects and removal of a methotrexate.

Therapy folinaty calcium should be stopped when concentration of a methotrexate in a blood plasma <5·10-8 mol/l. At increase in concentration of creatinine in a blood plasma the dose of a folinat of calcium should be raised.

Serious side effects and lethal cases are registered at a concomitant use of a methotrexate and NPVP.

At treatment by a methotrexate of a pseudorheumatism it is possible to continue treatment by acetylsalicylic acid and other NPVP, and also steroids in low doses. However it is necessary to consider that simultaneous use of NPVP and methotrexate can cause the increased risk of development of toxicity. For patients with therapeutic reaction to treatment by a methotrexate the dose of steroids can be reduced gradually.

Interaction between a methotrexate and other antirheumatic means, such as gold, Penicillaminum, hydroxychloroquine, Sulfasalazinum or other cytotoxic means, it is studied not completely, and their combined use can increase risk of frequency of side reactions.

Simultaneous use of a methotrexate with antagonists of folates, such as Trimethoprimum, sulfamethoxazole, in rare instances can cause an acute megaloblastny pancytopenia.

The acute intoxication caused by a methotrexate can demand therapy by folic acid.

The methotrexate can cause side reactions from an urinary system, such as cystitis and hamaturia.

Men and women who are treated by a methotrexate should be informed on an adverse effect of drug on reproductive system. Malformations of ova and sperm, an oligospermatism, disturbances of a menstrual cycle and infertility are registered.

The methotrexate can cause decrease in fertility, an oligospermatism, frustration of a menstrual cycle and an amenorrhea during treatment and for the short period after the therapy termination. The teratogenic effect of a methotrexate is revealed; it caused embriotoksichesky effect, spontaneous abortion, pre-natal death of a fruit and/or inborn malformations of a fruit. The methotrexate is not recommended for women of reproductive age if there are no corresponding proofs that advantage of use it is expected exceeds potential risk. It is not necessary to appoint a methotrexate at psoriasis during pregnancy.

Male fertility. The methotrexate can be genotoksichny. The men accepting a methotrexate have to use contraceptive means as it is established that the methotrexate increases quantity of defective spermatozoa. It is necessary to avoid fertilization within not less than 6 months after treatment. In case of reception of high doses of a methotrexate for cancer therapy the recommended period of use of contraception makes 2 years.

As the methotrexate can lead to heavy and irreversible pathological changes of formation of sperm, men should learn about a possibility of preservation of sperm prior to treatment.

The reproductive risk caused by treatment should be discussed with patients of reproductive age.

Drug contains lactose. Patients with rare hereditary intolerance of a galactose, a lactose intolerance of Lapp or malabsorption of glucose galactose should not apply this medicine.

During treatment by a methotrexate it is necessary to avoid the excessive use of the drinks containing caffeine and theophylline (the coffee, sweet drinks containing caffeine, black tea).

Use during pregnancy or feeding by a breast. Pregnancy period. Use of a methotrexate is contraindicated during pregnancy. There are messages on teratogenic influence on the person and several animal species (malformations of a front part of a skull, cardiovascular system and extremities). At women of reproductive age pregnancy should be excluded by appropriate methods, such as the test for pregnancy prior to treatment by a methotrexate.

Patients who are treated by a methotrexate should advise to apply reliable contraception during therapy and within not less than 6 months after its end. In case of reception of high doses of a methotrexate for cancer therapy the period of avoidance of pregnancy has to make 2 years. Women of reproductive age should be informed in detail on risk for a fruit if they become pregnant at treatment by a methotrexate.
However if the patient became pregnant during this period, she should be informed on risks and potential influence on development of the child. Also she has to get genetic advice.
As the methotrexate can be genotoksichny, the women planning pregnancy have to get genetic advice prior to treatment.
Feeding period breast. Feeding by a breast contraindicated at therapy a methotrexate as the methotrexate gets into breast milk and can cause intoxication in the child. It is necessary to stop breastfeeding prior to treatment.
Children. Drug is used at children with an acute lymphocytic leukosis (as a maintenance therapy).
Ability to influence speed of response at control of vehicles or work with other mechanisms. During treatment symptoms from TsNS, such as increased fatigue and dizziness can arise a methotrexate that can influence ability to manage vehicles and to work with mechanisms.

Side effects:

Usually the frequency and weight of side reactions depend on a dose, frequency and a route of administration and duration of treatment. At emergence of side reactions it is necessary to lower a dose or to stop therapy and to hold necessary therapeutic events, for example to apply calcium фолинат.

The most widespread side reactions caused by a methotrexate are oppression of marrow which is shown by a leukopenia and injuries of a mucous membrane (stomacace), nausea and other gastrointestinal frustration. These side reactions are usually reversible and disappear approximately in 2 weeks after decrease in a single dose of a methotrexate or increase in an interval between receptions and/or use of a folinat of calcium. Treat other often arising side reactions, for example an indisposition, increased fatigue, attacks of cold and heat, dizziness and decrease in immunity.

The methotrexate causes side reactions most often at the high and often repeating doses, for example, at treatment of oncological diseases. Side reactions about which it was reported at use of a methotrexate are given below according to systems of bodies.

Frequency of emergence of side reactions has the following classification: often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100), it is rare (> 1/10 000 and <1/1000), is very rare (<1/10 000, including single messages).

Infections and invasions: often — infectious diseases; infrequently — opportunistic infections; seldom — shingles, sepsis.

High-quality, malignant and uncertain new growths (including cysts and polyps): infrequently — limfoma1.

From hemopoietic and lymphatic system: often — a leukopenia; infrequently — oppression of marrow, thrombocytopenia, anemia; very seldom — a hypogammaglobulinemia.

From immune system: infrequently — reactions of anaphylactic type.

From endocrine system: seldom — a diabetes mellitus.

Mental disorders: seldom — a depression, confusion of consciousness.

From a nervous system: often — a headache, dizziness, increased fatigue; seldom — a hemiparesis; very seldom — irritability, a dysarthtia, aphasia, a lethargy.

From an organ of sight: very seldom — conjunctivitis, a sight illegibility.

From cardiovascular system: infrequently — nasal bleeding; seldom — arterial hypotension, a thromboembolism; very seldom — a pericardiac exudate, a pericardis, a vasculitis.

From a respiratory organs: infrequently — a pneumonitis, an intersticial pneumonitis (can be lethal), intersticial fibrosis; seldom — an asthma; very seldom — the pneumonia caused by Pnevmocysta carinii, a chronic intersticial obstructive disease of lungs, pleurisy, dry cough.

From digestive trakta2: often — stomatitis, anorexia, nausea, vomiting, diarrhea; seldom — an ulitis, pharyngitis, gastrointestinal ulcers and bleeding, enteritis; very seldom — a hematemesis.

From gepatobiliarny system: often — the increased levels of transaminases; seldom — a hepatotoxic, periportal fibrosis, cirrhosis, an acute hepatitis.

From skin and hypodermic cellulose: often — erythematic rashes, an alopecia; infrequently — an itch, Stephens's syndrome — Johnson, a toxic epidermal necrolysis; seldom — a photosensitization, an acne, a depigmentation, a small tortoiseshell, a multiformny erythema, morbidity of psoriasis damages, skin ulcers; very seldom — teleangiectasias, a furunculosis, hemorrhages in skin.

From skeletal and muscular system and connecting fabric: seldom — osteoporosis, an arthralgia, a mialgiya, increase in rhematoid nodes.

From kidneys and urinary system: infrequently — a renal failure, a nephropathy; very seldom — a dysuria, an azotemia, cystitis, a hamaturia.

From reproductive system and mammary glands: infrequently — vagina ulcers; seldom — decrease in a libido, impotence, disturbances of a menstrual cycle; very seldom — formation of defective ova or spermatozoa, a temporary oligospermatism, infertility, vulval bleeding, a gynecomastia.

At a stomacace and diarrhea the therapy termination by a methotrexate because of possible development of an ulcerative enteritis and perforation of intestines is necessary that can lead to a lethal outcome.

Also it was reported about such side reactions, however their frequency is unknown: a pancytopenia, the sepsis leading to a lethal outcome, an abortion, disturbances of pre-natal fetation, the increased risk of toxic reactions (a necrosis of soft tissues, an osteonecrosis) during radiotheraphy, an eosinophilia, an alveolitis.

The state at psoriasis defeats can worsen because of simultaneous influence of a methotrexate and ultraviolet radiation.

Interaction with other medicines:

After absorption the methotrexate partially contacts blood plasma albumine. Some medicines (for example salicylates, sulfonamides, Phenytoinum, some antibiotics, such as penicillin, tetracycline, chloramphenicol, ciprofloxacin and cefalotin) reduce its linkng with proteins. In such cases at simultaneous use toxicity of a methotrexate can increase. As пробенецид and weak organic acids, for example loopback diuretics, and also pyrazols reduce canalicular secretion, it is necessary to be careful at use of these medicines combined with a methotrexate.

It is necessary to avoid use in a combination with a methotrexate of others potentially nefro-and gepatotoksichny means (including alcohol). It is necessary to be especially attentive at observation of patients which carry out therapy by a methotrexate to combinations with Azathioprinum or retinoids.

Simultaneous use of a methotrexate and leflunomid can increase risk of a pancytopenia.

NPVP should not be applied to or along with a high dose of a methotrexate. Messages that the combined reception of some NPVP and a methotrexate in high doses increase concentration of a methotrexate in a blood plasma, and also gastrointestinal and hematologic toxicity of the last are received. At use of a methotrexate in lower doses these medicines as it is revealed in researches on animals, reduce canalicular secretion of a methotrexate and increase its toxicity. However patients with a pseudorheumatism usually well transferred additional therapy of NPVP. The methotrexate doses which are applied to treatment of a pseudorheumatism (7,5–15 mg/week), not much below those which apply at therapy of psoriasis. Higher doses can cause unexpected toxicity.

The vitamin drugs containing folic acid or its derivatives can change reaction to a methotrexate.

There are messages that reception of a combination Trimethoprimum/sulfamethoxazole in isolated cases raised marrow suppression because of the increased antifolatny effect.

It was reported about suppression of marrow and decrease in concentration of folates at the combined use of Triamterenum and methotrexate.

It is revealed that the combined use of a methotrexate and an omeprazol prolongs allocation of a methotrexate kidneys. At simultaneous use of inhibitors of a proton pomp, such as омепразол or пантопарзол, there can be their interaction.

The methotrexate can reduce clearance of theophylline. It is necessary to control concentration of theophylline at its use in a combination with a methotrexate.
The methotrexate increases Mercaptopurinum level in a blood plasma. Simultaneous use of a methotrexate and Mercaptopurinum can demand dose adjustment.

Vaccination by live vaccines during therapy by a methotrexate is contraindicated because of threat of heavy and deadly infections.

Cytotoxic drugs can reduce absorption of a fentoin that can reduce efficiency of a fentoin and increase risk of attacks. Influence of a fentoin on hepatic metabolism can reduce efficiency of cytotoxic drugs or increase toxicity.

Cyclosporine can exponentiate force of action and toxic effect of a methotrexate. Simultaneous use of these drugs is connected with risk of immunosuppression and limfoproliferation.

Contraindications:

Considerable abnormal liver functions (bilirubin level> of 85,5 mmol/l). Considerable renal failures (clearance of creatinine <20 ml/min.). Earlier diagnosed pathological changes of blood cells, in particular a marrow hypoplasia, a leukopenia, thrombocytopenia, anemia. Alcoholism. Heavy, acute or persistent infections, immunodeficiency. Hypersensitivity to active ingredient or any of excipients. Vaccination by live vaccines is contraindicated during treatment by a methotrexate. Ulcers on a mucous membrane of an oral cavity or GIT.

Overdose:

Overdose cases, including lethal, are registered when the methotrexate was mistakenly accepted 1 time a day instead of 1 time a week. In that case it was usually reported about hematologic and gastroenteric symptoms.

The main target of a methotrexate — bodies of a hemopoiesis.

Folinat of calcium effectively neutralizes direct gematotoksichesky action of a methotrexate. Parenteral therapy folinaty calcium should be begun not later than in 1 h after use of a methotrexate. The dose of a folinat of calcium has to be at least same, as well as the methotrexate dose accepted by the patient.

At considerable overdose hydration and alkalization of urine is necessary for the prevention of sedimentation of a methotrexate and/or its metabolites in renal tubules. It is revealed that the hemodialysis or peritoneal dialysis do not influence removal of a methotrexate. To the contrary, the effective clearance of a methotrexate was reached by means of a periodic hemodialysis with the dialyzer with high intensity of a flow.

Control of concentration of a methotrexate in a blood plasma is necessary for definition of an effective dose of a folinat of calcium and duration of therapy.

Storage conditions:

At a temperature not above 25 °C in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 30 млм 100 tablets in plastic bottles, on 1 bottle in cardboard packaging.