MabThera - Instructions For Use, Price, Analogs, Reviews

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Mabthera

MabThera: instructions for use and reviews

1. 1. Release form and composition
2. 2. Pharmacological properties
3. 3. Indications for use
4. 4. Contraindications
5. 5. Method of application and dosage
6. 6. Side effects
7. 7. Overdose
8. 8. Special instructions
9. 9. Application during pregnancy and lactation
10. 10. Use in childhood
11. 11. Drug interactions
12. 12. Analogs
13. 13. Terms and conditions of storage
14. 14. Terms of dispensing from pharmacies
15. 15. Reviews
16. 16. Price in pharmacies

Latin name: Mabthera

ATX code: L01XC02

Active ingredient: rituximab (rituximab)

Manufacturer: Genentech (USA), Pharmstandard-UfaVITA (Russia), Roche Diagnostics (Germany), F. Hoffmann-La Roche (Switzerland)

Description and photo updated: 2019-27-08

Prices in pharmacies: from 73,000 rubles.

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MabThera is an immunobiological drug based on monoclonal antibodies with antitumor and immunosuppressive effects.

Release form and composition

Dosage forms:

• Concentrate for preparation of solution for infusion: slightly opalescent, transparent, colorless or light yellow liquid (10 ml / 100 mg or 50 ml / 500 mg in vials made of glass of hydrolytic class 1 EF, sealed with butyl rubber corks, laminated with fluoropolymer, crimped with aluminum cap and closed with a plastic lid, 1 bottle of 50 ml or 2 bottles of 10 ml in a cardboard box);
• Solution for subcutaneous (s / c) administration: slightly opalescent, transparent, colorless or light yellow liquid (11.7 ml each in colorless glass bottles, 1 bottle in a cardboard box).

Each pack also contains instructions for the use of MabThera.

Composition of 1 ml of concentrate for solution preparation:

• Active ingredient: rituximab - 10 mg;
• Auxiliary components: polysorbate 80, sodium citrate dihydrate, sodium chloride, sodium hydroxide or hydrochloric acid, water d / i.

Composition of 1 ml solution for subcutaneous administration:

• Active ingredient: rituximab - 120 mg;
• Auxiliary components: recombinant human hyaluronidase (rHuPH20), L-methionine, L-histidine hydrochloride monohydrate, α, α-trehalose dihydrate, L-histidine, polysorbate 80, water d / i.

Pharmacological properties

Pharmacodynamics

MabThera is an antineoplastic and immunomodulatory agent. The active substance of the drug, rituximab, is a chimeric mouse / human monoclonal antibody that binds specifically to the CD20 transmembrane antigen.

The antigen is located on pre-B-lymphocytes and mature B-lymphocytes, but is absent on pro-B-cells, hematopoietic stem cells, normal plasma cells, cells of other tissues. In more than 95% of cases, this antigen is expressed in B-cell non-Hodgkin's lymphomas.

After expression on the cell and binding to the antibody, CD20 is not further internalized and does not enter the extracellular space from the cell membrane. As a free antigen, CD20 does not circulate in plasma, so that it does not compete for binding with the antibody.

As a result of therapy, rituximab binds to the CD20 antigen on B-lymphocytes and initiates immunological reactions that mediate B-cell lysis. Possible mechanisms of cell lysis: complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis. Rituximab increases the sensitivity of human B-cell lymphoma lines to the cytotoxic effects of certain chemotherapeutic drugs.

After the first administration of rituximab, the number of B cells in the peripheral blood decreases below normal; in patients with hematological malignant diseases, their level begins to recover after six months. Normal values are reached 12 months after the end of treatment, however, in some patients, the duration of the recovery period for the number of B cells may be longer.

Anti-mouse antibodies were not detected in the examined patients. The data obtained indicate that the formation of antibodies to rituximab (anti-chimeric antibodies) after SC administration of MabThera in the dosage form of a solution for subcutaneous administration is comparable to that observed after intravenous (intravenous) administration of the drug in the dosage form of a concentrate for preparing an infusion solution.

In patients with non-Hodgkin's lymphoma, with SC administration of MabThera in the form of a solution for SC administration, the frequency of formation / increase of antibodies to rituximab was low and had a similar value to that with IV administration (2% and 1%, respectively).

The incidence / increase of antibodies to recombinant human hyaluronidase (rHuPH20) with SC administration of rituximab to patients with non-Hodgkin's lymphoma is 9% compared to 6% with IV administration. Neutralizing antibodies were not detected in any of these patients. The overall proportion of patients with antibodies to rHuPH20 in general did not change during the follow-up period.

The clinical significance of the formation of antibodies to rituximab or antibodies to rHuPH20 after the end of therapy has not been evaluated.

Antibodies to rituximab or rHuPH20 did not affect the safety / efficacy of MabThera in the study.

Pharmacokinetics

Non-Hodgkin's lymphoma

According to the population pharmacokinetic analysis, in patients with non-Hodgkin's lymphoma, with a single / repeated administration of MabThera as monotherapy or in combination with chemotherapy according to the CHOP scheme (use of cyclosporine, doxorubicin, vincristine, prednisolone) values of non-specific and specific clearance (CL ₁ and CL ₂) are 0.14 and 0.59 l / day, respectively (this is probably due to B cells or tumor load), the volume of distribution in plasma (V ₁) is 2.7 liters.

The median terminal T _1/2 (half-life) is 22 days. The size of the tumor focus and the initial level of CD19-positive cells affect the CL _{2 of} rituximab, administered intravenously at a dose of 375 mg / m ² once a week for 4 weeks. In patients with a large tumor focus or a higher level of CD19-positive cells, the CL ₂ value is higher.

The individual variability of the CL ₂ index remains after the correction of the level of CD19-positive cells and the size of the tumor focus. Relatively small changes in the V ₁ value are determined by the body surface area (from 1.53 to 2.32 m ²) and chemotherapy according to the CHOP scheme and are 27.1% and 19%, respectively.

The pharmacokinetic parameters of rituximab are not influenced by gender, age, race and general condition. Thus, dose adjustment of MabThera depending on the factors listed above does not significantly affect pharmacokinetic variability.

The average C _max (maximum concentration of the substance) after each infusion increases: after the first infusion it is 0.243 mg / ml, after the fourth - 0.486 mg / ml, after the eighth - 0.55 mg / ml. C _min (minimum concentration of substance) and C _{max of} MabThera correlate inversely with the initial number of CD19-positive B-cells and the value of the tumor load.

In the case of effective treatment, the median C _ss (equilibrium concentration) of the drug is higher. The median C _ss value of rituximab is higher in patients with histological tumor subtypes B, C and D (according to the IWF classification - International Working Formulation) than with subtype A. In some cases, traces of the substance are found in the body for 3-6 months after the last infusion.

The pharmacokinetic profile of the substance (6 infusions at 375 mg / m ²) in combination with six cycles of CHOP chemotherapy was practically the same as during monotherapy.

Chronic lymphocytic leukemia

The mean C _max after the fifth infusion of 500 mg / m ^{2 of} rituximab is 0.408 mg / ml.

Rheumatoid arthritis

The average C _{max of} rituximab after two i.v. infusions of 1000 mg with an interval of 14 days is 0.369 mg / ml, the average T _1/2 is in the range from 19.2 to 20.8 days, the average systemic clearance is 0.23 L / day, V _d (volume of distribution) in equilibrium - 4.6 liters.

The value of the average C _max after the second infusion is 16–19% higher than in the first infusion. The pharmacokinetic parameters of rituximab during the repeated course of therapy are comparable to the first course of treatment.

Granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis

According to the population pharmacokinetic analysis, after four infusions of rituximab at a dose of 375 mg / m ² once a week Median T _1/2 was 23 days, V _d - 4.5 liters, the average clearance - 0.313 L / day. The pharmacokinetic parameters of rituximab are practically the same as in rheumatoid arthritis.

Indications for use

MabThera is used to treat the following types of non-Hodgkin's lymphoma (NHL):

• Chemo-resistant or recurrent B-cell, CD20-positive low grade or follicular;
• Follicular (for maintenance treatment after a reaction to induction therapy), as well as follicular III-IV stages (in combination with chemotherapy in previously untreated patients);
• Diffuse CD20-positive large B-cell (CHOP regimen, in combination with chemotherapy).

Additionally, the concentrate for the preparation of a solution for infusion is used to treat the following diseases:

• Chronic lymphocytic leukemia: in patients who have not previously received standard therapy (in combination with chemotherapy); chemotherapy resistant or recurrent (in combination with chemotherapy);
• Rheumatoid arthritis: severe and moderate (active form) in adult patients in combination with methotrexate in case of intolerance or inadequate response to current treatment regimens that include TNFα inhibitors (one or more), including for the purpose of inhibiting the destruction of joints, proven radiologically;
• Wegener's syndrome (granulomatosis with polyangiitis) and microscopic polyarteritis: severe active forms (as part of complex therapy with glucocorticosteroids (GCS)).

Contraindications

Absolute:

• Acute infectious diseases;
• Severe immunodeficiency (primary or secondary);
• End stage heart disease (NYHA class IV) in combination with rheumatoid arthritis;
• Children and adolescents up to 18 years of age (safety and efficacy have not been established);
• Pregnancy period;
• Lactation (breastfeeding);
• Increased individual sensitivity to the components of the drug, rituximab or mouse protein.

Relative (MabThera is used with caution due to the increased likelihood of complications):

• A history of respiratory failure or neoplastic infiltration of the lungs;
• High tumor load (the number of circulating tumor cells is more than 25,000 / μl);
• Neutropenia (less than 1500 / μl), thrombocytopenia (less than 75,000 / μl);
• Chronic infections.

MabThera, instructions for use: method and dosage

Before starting therapy, you must carefully study the instructions, make sure that the dosage form of MabThera corresponds to the prescribed one: a solution for subcutaneous administration or a concentrate for preparing a solution for infusion.

The solution prepared from the concentrate is intended for intravenous (IV) infusion of slow administration with the obligatory use of a separate catheter. Intravenous bolus or intravenous injection of a solution prepared from a concentrate is not allowed.

For the first infusion, an initial rate of 50 mg / h is recommended, with a further increase of 50 mg / h every half hour to a maximum of 400 mg / h. For subsequent infusions, an initial rate of 100 mg / h is allowed with an increase of 100 mg / h every half hour to a maximum of 400 mg / h.

Before each infusion, premedication is required: an analgesic / antipyretic (paracetamol) with an antihistamine (diphenhydramine). If MabThera is not part of the combination therapy with CVP (cyclophosphamide, vincristine, prednisolone) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy, corticosteroids should be included in the premedication.

The solution for subcutaneous administration is injected under the skin only in the region of the anterior abdominal wall, the administration time is approximately 5 minutes. There is no data on the introduction of MabThera in other areas. Solution for subcutaneous administration is not intended for intravenous administration.

The solution should not be injected into places with redness, hypersensitivity, hematomas, scar tissue, birthmarks, places with seals. If possible, you should avoid the introduction of MabThera solution with other drugs for subcutaneous administration in the same areas of the skin. If the injection had to be interrupted, it can be resumed at the same place or, if necessary, the injection site can be changed. Patients who received the full dose of MabThera in the form of a concentrate for the preparation of solution for infusion, as well as patients who could not receive the full dose of MabThera, in the following cycles can receive the drug in the form of a solution for subcutaneous administration.

The standard recommended dosage regimen is 375 mg / m ² once a week.

For dose adjustment during therapy, it is not recommended to reduce the dose of rituximab. For MabThera injections in combination with CVP or CHOP chemotherapy, the dose reduction of chemotherapeutic agents is carried out in accordance with standard recommendations.

Treatments for low-grade or follicular non-Hodgkin's lymphoma:

• Initial monotherapy for adult patients: 375 mg / m ² once a week for 4 weeks;
• Initial therapy combined with CVP: every first day of the chemotherapy cycle after intravenous administration of a corticosteroid as a component of the CVP regimen - 375 mg / m ², course duration - 8 cycles (each cycle - 3 weeks);
• A repeated course in case of relapse (in patients with a favorable response to the first course): 375 mg / m ² once a week for 4 weeks;
• Maintenance course: (after a positive reaction to induction therapy) 375 mg / m ² once every 3 months, duration - up to 2 years or until the disease progresses.

Treatment of diffuse large non-Hodgkin's lymphoma (in combination with CHOP chemotherapy according to the scheme): the first day of each of the eight cycles of chemotherapy after / in the corticosteroid - 375 mg / m ², other drugs administered after CHOP circuit MabThera.

Treatment for rheumatoid arthritis:

• Initial therapy: 1000 mg i.v. drip, slowly (half an hour after i.v. administration of methylprednisolone at a dose of 100 mg), once every 2 weeks, course - 1 month (only 2 infusions);
• A repeated course (allowed six months to a year after the first treatment): 1000 mg 1 time in 2 weeks for a month (only 2 infusions).

Rules for the preparation and storage of solution for infusion:

1. The required amount of the drug in aseptic conditions is taken and diluted to the calculated concentration (1-4 mg / ml) in an infusion bag (bottle) with 5% dextrose solution or 0.9% sodium chloride solution for injection (solutions must be sterile and pyrogen-free);
2. Carefully, so as not to form foam, turn the package (bottle) over until the contents are completely mixed;
3. Before the introduction, check the solution for the absence of impurities and the retention of color;
4. Since MabThera does not contain preservatives, it is recommended to use a freshly prepared solution immediately (chemically and physically at room temperature, the solution is stable for 12 hours, at a temperature of 2-8 ° C - no more than 24 hours);
5. The doctor is responsible for the preparation, time and storage conditions of the finished solution before its use.

Rules for the collection and storage of a solution for subcutaneous administration in a syringe:

1. The intake of the solution for subcutaneous administration (1400 mg / 11.7 ml) from the vial into the syringe is carried out under aseptic conditions;
2. In a syringe, the solution is chemically and physically stable for 8 hours at a temperature of 30 ° C and diffused daylight, or 48 hours at a temperature of 2-8 ° C;
3. Taking into account the microbiological safety, the solution is recommended to be used immediately;
4. If it is impossible to use the drug immediately after taking from the vial, the user should control the storage conditions and time.

Side effects

The scale for assessing the frequency of side effects: ≥10% - very often, ≥1% - <10% - often, ≥0, l% - <1% - infrequently.

Therapy for follicular or low-grade non-Hodgkin's lymphoma (monotherapy / maintenance):

• Infections and invasions: very often - viral and bacterial infections; often - pneumonia, sepsis, respiratory tract infections, herpes zoster, infections accompanied by hyperthermia, mycoses, infections of unknown etiology;
• Lymphatic system and blood: very often - neutropenia, leukopenia; often - anemia, thrombocytopenia; infrequently - hemocoagulation disorder, lymphadenopathy, hemolytic anemia, partial transient aplastic anemia;
• Respiratory system, chest and mediastinal organs: often - bronchospasm, rhinitis, cough, chest pain, shortness of breath, respiratory diseases; infrequently - obliterating bronchiolitis, impaired lung function, hypoxia, bronchial asthma;
• Immune system: very often - Quincke's edema; often - hypersensitivity reactions;
• Metabolism and nutrition: often - weight loss, hyperglycemia, facial edema, peripheral edema, hypocalcemia, increased lactate dehydrogenase (LDH) activity;
• Systemic and local disorders: very often - fever, asthenia, chills, headache; often - flu-like syndrome, pain in tumor foci, weakness, hot flashes; infrequently - pain at the injection site;
• Gastrointestinal tract (GIT): very often - nausea; often - diarrhea or constipation, vomiting, dyspepsia, dysphagia, lack of appetite, stomatitis, sore throat, abdominal pain; infrequently - an increase in the abdomen;
• Cardiovascular system (CVS): often - increased or decreased blood pressure (BP), tachycardia, orthostatic hypotension, atrial fibrillation, arrhythmia, cardiac pathology, myocardial infarction; infrequently - ventricular and supraventricular tachycardia, left ventricular heart failure, bradycardia, angina pectoris, myocardial ischemia;
• Nervous system: often - paresthesia, hypesthesia, vasodilation, dizziness, sleep disturbance, agitation, anxiety; infrequently - perversion of taste;
• Mind: infrequently - depression, nervousness;
• Musculoskeletal and connective tissue: often - arthralgia, myalgia, muscle hypertonia, pain in the back and neck;
• Skin and subcutaneous tissues: very often - rash, itching; often - hyperhidrosis, increased night sweats, urticaria, alopecia;
• Organ of vision: often - conjunctivitis, lacrimation disorders;
• Hearing organ and labyrinth disorders: often - tinnitus, ear pain;
• Instrumental and laboratory results: very often - a decrease in the concentration of immunoglobulins G (IgG).

Severe side effects and / or effects occurring with a higher frequency, in addition to those observed with monotherapy / maintenance therapy, caused by rituximab in combination with chemotherapy (R-CHOP, R-FC, R-CVP) in the treatment of chronic lymphocytic leukemia and lymphosarcomas:

• Infections and invasions: very often - inflammation of the bronchi; often - acute bronchitis, sinusitis, hepatitis B (repeated exacerbation of hepatitis B, primary infection);
• Lymphatic system and blood: very often - thrombocytopenia, neutropenia, febrile neutropenia; often - granulocytopenia, pancytopenia;
• Skin and subcutaneous tissues: very often - pathological hair loss; often - skin diseases;
• Systemic and local disorders: often - chills, fatigue.

Adverse reactions from the use of MabThera in rheumatoid arthritis with a frequency of more than 2% and at least 2% difference in comparison with the control group:

• Immune system, general disorders, disorders at the injection site: very often - infusion reactions: increase and decrease in blood pressure, hot flashes, rash, hives, itching, chills, fever, nausea, rhinitis, sore throat, tachycardia, weakness, pain in the mouth and pharynx, peripheral edema, erythema; infrequently - clinically significant infusion reactions: bronchospasm, generalized edema, laryngeal edema, angioedema, wheezing, generalized itching, anaphylactoid reaction, anaphylaxis;
• Infections and invasions: very often - infections of the upper respiratory tract and urinary tract; often - sinusitis, gastroenteritis, bronchitis, dermatophytosis of the feet;
• Musculoskeletal system and connective tissue: often - arthralgia, osteoarthritis, bursitis, musculoskeletal pain;
• Mental disorders: often - anxiety, depression;
• Nervous system: very often - headache; often - paresthesia, sciatica, dizziness, migraine;
• Digestive system: often - diarrhea, dyspepsia, gastroesophageal reflux, ulceration of the oral mucosa, pain in the right upper quadrant of the abdomen;
• Skin and subcutaneous tissue: often - alopecia;
• Data from laboratory and instrumental studies: often - hypercholesterolemia.

With repeated use, the profile of adverse reactions does not differ from that of primary therapy and is characterized by a decrease (with each subsequent course) in the frequency of infusion reactions, exacerbations of the disease and infections, which are often observed in the first six months of treatment.

Side effects observed with the use of MabThera in Wegener's granulomatosis and microscopic polyangiitis (frequency ≥10%):

• Infections and infestations: herpes zoster, infections (the most common - the upper respiratory and urinary tract);
• Data from laboratory and instrumental studies: increased activity of alanine aminotransferase (ALT);
• Respiratory system, chest and mediastinal organs: cough, epistaxis, dyspnea;
• Mental disorders: insomnia;
• Nervous system: headache;
• Cardiovascular system: increased blood pressure;
• Gastrointestinal tract: nausea, diarrhea;
• Immune system: infusion reactions, including the most common ones, cytokine release syndrome, redness, throat irritation, tremors;
• Skin and subcutaneous tissue: rash;
• Musculoskeletal system and connective tissue: muscle spasms, arthralgia;
• Lymphatic system and blood: anemia, leukopenia;
• Violations at the injection site, general disorders: peripheral edema, weakness.

Cross replacement of the drug or substitution for another therapy is allowed based on a balanced clinical decision.

Overdose

There are reports of three cases of accidental overdose with intravenous administration of MabThera in the form of a solution for subcutaneous administration at a dose of 2780 mg. At the same time, the development of any side effects was not noted.

Overdose cases were not observed when using the infusion solution. Single doses of rituximab greater than 1000 mg have not been studied. Patients with chronic lymphocytic leukemia received a maximum dose of 5000 mg, no additional safety data were obtained.

Therapy: canceling MabThera, monitoring the patient's condition. An extensive general blood test may be required, which is associated with an increased likelihood of infectious complications when the pool of B-lymphocytes is depleted.

special instructions

The patient's medical record is required to indicate the trademark (name of the drug) - MabThera. The drug must be administered under the close supervision of an oncologist, rheumatologist or hematologist, if the conditions required for resuscitation are present.

Adverse reactions that occur during the infusion, or shortly after it, may be due to the release of cytokines and / or other mediators. Severe infusion responses are similar to hypersensitivity reactions or cytokine release syndrome. There is reliable information about fatal infusion reactions in the post-registration period of drug use. The majority of patients in the range of ¹ / ₂2 hours from the start of the first infusion, fever appears, accompanied by tremors or chills. Symptoms of severe reactions are a decrease in blood pressure, pulmonary responses, urticaria, angioedema, nausea, vomiting, weakness, headache, rhinitis, itching, swelling of the pharynx or irritation of the tongue (vascular edema), hot flashes, pain in the foci of the disease, and also, in some episodes, symptoms of rapid tumor lysis syndrome.

Infusion reactions take place after discontinuation of drug administration and interruption of drug therapy (including intravenous administration of acetaminophen and diphenhydramine, 0.9% sodium chloride solution, GCS, bronchodilators, etc.). After complete relief of symptoms, most often, the infusion can be resumed, but the rate should be 50% of the previous one; continuation of treatment in this case is rarely accompanied by the resumption of severe infusion reactions. In the majority of patients with infusion reactions that are not life threatening, the course of MabThera therapy was completed completely.

Given the potential for the development of anaphylactic effects and other hypersensitivity reactions due to intravenous administration of protein drugs, drugs are needed to stop them: antihistamines, adrenaline and GCS.

Application during pregnancy and lactation

MabThera is not prescribed during pregnancy / lactation.

IgG (immunoglobulins G) can cross the placental barrier. B-cell levels in newborns have not been studied when MabThera is administered to pregnant women.

Some infants whose mothers received rituximab during pregnancy have experienced temporary B-cell depletion and lymphocytopenia. The composition of the drug in the form of a solution for s / c administration includes recombinant human hyaluronidase, therefore, women who become pregnant during the period of therapy should emphasize the drug in order to avoid the potential risk of developing embryofetal toxicity. MabThera in the form of an infusion solution for pregnant women can only be prescribed if the expected benefit outweighs the possible harm.

During the entire period of use of the drug and for 12 months after the end of treatment, women of childbearing age should use effective methods of contraception.

Pediatric use

MabThera is not prescribed for patients under 18 years of age.

Drug interactions

Limited data on the interaction of MabThera with other medicinal substances / drugs.

Pharmacokinetic parameters do not change while taking rituximab with cyclophosphamide and fludarabine in the treatment of chronic lymphocytic leukemia.

In patients with rheumatoid arthritis, the simultaneous administration of methotrexate with MabThera does not change its pharmacokinetics.

The appointment of a drug with other monoclonal antibodies for diagnosis or therapy in patients with anti-chimeric antibodies or antibodies against mouse proteins leads to an increased risk of allergic reactions.

For infusion administration of MabThera, polyethylene or PVC bags or systems can be used as they are compatible with rituximab.

Analogs

MabThera's analogs are: Reditux, Rituxim, Avastin, Adcetris, Acellbia, Vektibiks, Herceptin, Kadsila, Trastumab, Erbitux.

Terms and conditions of storage

Store in a dark place at a temperature of 2-8 ° C. Keep out of the reach of children.

The shelf life is 2.5 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Mabthera

Reviews of Mabthera characterize it as a drug with high efficiency and poor tolerance. Often during the period of use, pronounced side effects develop, in some cases this requires a complete withdrawal of the drug.

The price of Mabthera in pharmacies

The approximate price for MabThera is: solution for subcutaneous administration 1400 mg / 11.7 ml (1 bottle) - 109,229 rubles, concentrate for the preparation of infusion solution 100 mg / 10 ml (2 bottles) - 28,554 rubles, 500 mg / 50 ml - 72 786 rubles.

MabThera: prices in online pharmacies

Drug name Price Pharmacy

MabThera 500 mg / 50 ml concentrate for preparation of solution for infusion 50 ml 1 pc. RUB 73,000 Buy

Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!