DECISION OF COUNCIL OF THE EURASIAN ECONOMIC COMMISSION

of November 3, 2016 No. 88

About approval of requirements to the instruction on medical application of medicine and general characteristic of medicine for medical application

According to articles 4 and 8 of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014, Item 98 of appendix No. 1 to the Regulations of work of the Eurasian economic commission approved by the Decision of the Supreme Eurasian economic council of December 23, 2014 No. 98, and the Decision of the Supreme Eurasian economic council of December 23, 2014 "About implementation of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union" Council of the Eurasian economic commission solved No. 108:

1. Approve the enclosed requirements to the instruction on medical application of medicine and general characteristic of medicine for medical application.

2. This Decision becomes effective after 10 calendar days from the effective date of the Protocol signed on December 2, 2015 on accession of the Republic of Armenia to the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014, but not earlier than after 10 calendar days from the date of official publication of this Decision.

Members of council of the Eurasian economic commission: From the Republic of Armenia

V. Gabriyelyan

From the Republic of Belarus

V. Matyushevsky

From the Republic of Kazakhstan

A. Mamin

From the Kyrgyz Republic

O. Pankratov

From the Russian Federation

I. Shuvalov

Approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 88

Requirements to the instruction on medical application and general characteristic of medicine for medical application for medical application

I. General provisions

The general characteristic of medicine for medical application (further – OHLP) contains the official information on medicine for medical application intended for health workers for the purpose of the correct purpose of medicine and control of its use. Information in OHLP is subject to approval of state members of the Eurasian Economic Union by authorized bodies (further respectively – state members, the Union) in the field of drug circulation during registration and the subsequent address of the registered medicine in the territory of the Union. Content of OHLP can be changed only from approval of authorized bodies of state members in the field of health care or in case of the direction to them of the notification according to the rules of registration and examination of medicines for medical application approved by the Eurasian economic commission (further – the Commission).

OHLP is the main source of information for health workers on safe and effective use of medicine. The instruction on medical application (leaf insert) (further – LV) medicine is constituted according to OHLP.

OHLP is not intended for establishment of general recommendations about treatment of individual diseases, however in it specific aspects of treatment and effect of use of medicine shall be specified. OHLP shall not contain general recommendations about procedures of maintaining these or those patients, but at it there shall be specific aspects for purpose of the corresponding medicine.

These Requirements contain instructions concerning submission of information to OHLP. Information provided in each Section OHLP shall be to correspond as the document in general, and with heading of the Section to which it belongs. Some questions can be considered more than in one part of OHLP, and in such cases the reference to other Sections OHLP in which the relevant additional information is provided is allowed.

These Requirements should be considered in combination to the specific requirements to OHLP of separate groups of medicines (for example, vaccines, the pegylated proteins or medicines received from blood plasma, homeopathic medicines) specified in appendices No. 2, of 3, 13 and 19 to these Requirements.

As a rule, separate OHLP for each dosage form, and in certain cases and for dosage is required. Preparation of single OHLP for several dosage forms and (or) dosages is performed when the scheme of acceptance of medicine provides change of the mode of dosing or route of administration, the used dosage form in the course of treatment.

OHLP shall be posted on the website of authorized body of state member in the field of drug circulation of the Internet, and also on the official site of the Union on the Internet.

II. The principles of submission of information on medicine, and also questions, the concerning creation (changes), examinations and approvals of information on medicine

1. Information containing in OHLP and LV shall be provided in accurate and laconic form. OHLP and LV join in the module of 1 registration file. In case of failure to meet requirements, OHLP and (or) LV specified in Items 7-9 shown to creation – for original medicine, in Items 7 and 8, subitems 10.1.1-10.1.3 – for reproduced, hybrid, biosimilar medicines (biosimilar), the registration file of such medicine or the file on modification of the registration file of medicine is recognized incomplete, and it is provided to the applicant by the provided rules of registration and examination of medicines for medical application approved by the Commission, term on representation of missing materials of the registration file according to notes of authorized body (the expert organization) of the reference state.

2. Each Section shall begin with information relating to the primary target group of patients for whom medicine intends, and if necessary it shall be supplemented with specific information on separate groups (for example, children or elderly people). If drug is intended for the single target group "adult patients", it is not obligatory to specify it in each Section.

3. In OHLP the corresponding medical terminology shall be used.

4. OHLP contains information on specific medicine therefore it shall not include in sebyassylka on other medicines, except as specified, when it is the caution recommended by authorized body of state member and also if drug needs to be accepted according to the scheme exclusively in total with other medicines.

5. The principles established by these Requirements are applicable to all medicines. Use of these principles for specific medicine will depend on scientific data on it and legal features of its registration. The variation from these Requirements shall be proved in the corresponding overview or the summary of the registration file.

6. In OHLP the reference (according to appendix No. 10 to these Requirements) on the website of authorized body of state member on the Internet on which it is posted shall be contained.

7. For conducting examination the OHLP and LV projects are represented, among other, in the MS Word format with possibility of editing. During examination for the purpose of the most complete and correct reflection of notes experts have the right to make corrections in the reviewing mode (MS Word function) to the OHLP and LV projects provided by the applicant.

8. In case of modification of OHLP and (or) LV it is necessary to provide complete drafts of current versions of OHLP and (or) LV, and also the complete OHLP and (or) LV projects with the changes made in the reviewing mode. The complete OHLP and (or) LV projects with the changes made in the reviewing mode are intended for tracking of all made changes, the complete OHLP and (or) LV projects which are exclusively approved by results of modification are subject to approval. All brought in OHLP and (or) LV of change shall be evidence-based, except for changes of editorial nature.

9. In case of modification of the text of OHLP and LV the holder of the registration certificate of original medicine shall include in the module of 1 registration file, according to requirements of rules of registration and examination of the medicines for medical application approved by the Commission, OHLP and LV, approved in the manufacturing country, and (or) the country holder of the registration certificate, and (or) other country of ICH where medicine is registered (in the presence).

10. Concerning the reproduced, hybrid and biosimilar (biosimilar) medicines in case of modification of the text of OHLP and LV the following additional requirements are effective.

10.1. The holder of the registration certificate of medicine shall provide:

10.1.1. Copies of OHLP and LV of original (reference) medicine operating within the Union. If original (reference) medicine in the Union is not registered, it is necessary to provide OHLP and LV of original (reference) medicine (in the presence) operating in the manufacturing country, and (or) the country holder of the registration certificate, and (or) ICH country in language of the country which approved them.

10.1.2. The declaration that in the OHLP and LV projects of the reproduced or biosimilar (biosimilar) medicine there are no differences from the differences operating with OHLP and LV of original (reference) medicine, except for which are marked out and proved according to the requirements provided in subitem 10.1.3.10.1.3. Line-by-line (located in parallel on one leaf) comparison by existing OHLP and LV of original (reference) medicine and the OHLP and LV projects of the reproduced, hybrid or biosimilar (biosimilar) medicine with allocation and reasons for all differences. Distinctions in producers, period of validity, composition of excipients, insignificant distinctions in bioavailability or pharmacokinetics, and also distinctions in connection with restrictions, stipulated by the legislation state members about protection of copyright and related rights belong to typical distinctions. Also other evidence-based distinctions are possible. Distinctions available risks, allowing

divide divisible dosage form into equal shares, will not always be insignificant as they can affect opportunities of achievement of the mode of the dosing given in OHLP of reference medicine considerably.

10.2. If after registration of the reproduced, hybrid or biosimilar (biosimilar) medicine changes are made to OHLP and (or) LV of the corresponding original (reference) medicine, then the holder of the registration certificate of the reproduced, hybrid or biosimilar (biosimilar) medicine shall within 180 calendar days from the date of, specified in Section 10 OHLP and (or) the Section "This Leaf Insert Is Reviewed" LV of reference medicine, to make corresponding changes to OHLP and (or) LV of such reproduced, hybrid or biosimilar (biosimilar) medicine taking into account the admissible differences specified in subitem 10.1.3. In case of failure to meet requirements of this subitem relevant provisions of rules of registration and examination of the medicines for medical application approved by the Commission about suspension, withdrawal (cancellation) of the registration certificate, either use restriction, or modification of conditions registration udostovereniya.10.3 are applied to such reproduced, hybrid or biosimilar (biosimilar) medicine. If during examination of OHLP and (or) LV of the reproduced, hybrid or biosimilar (biosimilar) medicine (within registration confirmation (re-registration), reduction of the file in compliance, modification of the registration file) it is revealed that acting within the Union or in one of state members of OHLP and (or) LV of original (reference) medicine does not correspond to modern data on efficiency and safety of medicine (including the conclusions of examinations and the recommendation of authorized bodies in the field of drug circulation of the third countries) or does not correspond to OHLP and (or) LV approved in the manufacturing country or the country holder of the registration certificate on medicine the following polozheniya.10.3.1 is applied. The authorized body (the expert organization) of state member creates request to the holder of the registration certificate of the corresponding original (reference) medicine about need of correction of OHLP and (or) LV of such original (reference) medicine and sends it to authorized body of the reference state which registered this medicine.

10.3.2. Examination of the file of the corresponding reproduced, hybrid or biosimilar (biosimilar) medicine stops.

10.3.3. The authorized body of state member within 5 working days sends the inquiry received from the expert organization to the holder of the registration certificate of the corresponding reference medicine.

10.3.4. The holder of the registration certificate of the corresponding original (reference) medicine shall within 60 calendar days from the date of receipt of request give to authorized body of the state member which sent the specified inquiry, the statement for modification of the registration file of such original (reference) medicine taking into account the requirements and recommendations containing in the received request or to provide written reasons for lack of need of introduction of such changes.

Based on the written reasons provided by the holder of the registration certificate, the authorized body shall remove or confirm the requirement about modification of OHLP and (or) LV within 30 calendar days. If the requirements specified in primary request are confirmed by authorized body, or they are adjusted taking into account the explanations provided by the holder of the registration certificate, modification of the registration file of the registered original (reference) medicine is performed according to the rules of registration and examination of medicines for medical application approved by the Commission.

10.3.5. After approval of OHLP and (or) LV of original (reference) medicine according to the specified procedure, examination of the registration file of the reproduced, hybrid or biosimilar (biosimilar) medicine is resumed. At the same time the request specified in subitem 10.3. 1, is not considered as request of the holder of the registration certificate of the reproduced, hybrid or biosimilar (biosimilar) medicine;

10.3.6. Due to possibility of initiation by authorized body of state member of the procedure specified in this subitem, modification of the operating OHLP and (or) LP of the reproduced, hybrid or biosimilar (biosimilar) medicine is not recommended to be grouped with other types of changes.

10.4. If the holder of the registration certificate of original (reference) medicine within 60 calendar days from the date of receipt of the request specified in subitem 10.3.4 of these Requirements does not submit the application for modification of the registration file of such original (reference) medicine to authorized body or does not represent written reasons for lack of need of introduction of such changes, relevant provisions of rules of registration and examination of the medicines for medical application approved by the Commission about suspension, withdrawal (cancellation) of the registration certificate, either use restriction, or modification of conditions of the registration certificate are applied. In this case examination of the file of the reproduced, hybrid or biosimilar (biosimilar) medicine is performed without irrelevant OHLP and (or) LV of original (reference) medicine.

10.5. If the situation specified in subitem 10.3 of these Requirements arises in case of registration of the reproduced, hybrid or biosimilar (biosimilar) medicine, then examination of the registration file of the reproduced, hybrid or biosimilar (biosimilar) medicine does not stop, and requirements of subitem 10.1 of these Requirements are applied. The expert organization initiates the procedure of modification of the registration file of the corresponding original (reference) medicine according to the procedure specified in Item 10.3 of these Requirements.

11. In case of detection of discrepancy to the operating OHLP and (or) LV of the medicine registered in one of state members, to modern data on efficiency and safety of medicine (including the conclusions of examinations and the recommendation of authorized bodies in the field of drug circulation of the third countries), including OHLP and (or) LV approved in the manufacturing country or the country holder of the registration certificate on medicine the expert organizations, authorized bodies of state members or other persons have the right to address authorized body of state member in which drug, with initiative about the direction to the holder of the registration certificate of request about need of reduction by the operating OHLP and (or) LV in compliance is registered such medicinal.

12. In case of receipt of the request specified in Item 11 of these Requirements the procedure specified in subitems 10.3.4 begins. and 10.4 these Requirements.

13. In case of failure to meet requirements, specified in Item 12, provisions of subitem 10.4 of these Requirements are applied.

14. Requirements of Items 12 and 13 of these Requirements extend to holders of registration certificates of all medicines registered according to the rules of registration and examination of medicines for medical application approved by the Commission.

15. On the official site of authorized body of state member on the Internet and in the unified register of the registered medicines of the Union are published approved by authorized bodies of state members of OHLP and LV (in the PDF format with the recognized text).

16. For the medicines requiring additional monitoring of safety before Section 1 OHLP the special symbol (q) accompanied with the following formulation is placed: "This medicine is subject to additional monitoring. It will allow to reveal new information on safety quickly. We appeal to health care providers to report about any suspected undesirable reactions".

III. Sections OHLP

1. Name of medicine

In this Section the trade name of medicine, data on dosage and dosage form are specified. Further in the text of OHLP of the data on dosage and dosage form in the name of medicine it is allowed not to specify. In case of the description of active ingredient it is necessary to use the international non-proprietary name (further – MNN) recommended by the World Health Organization (further – WHO), and in the absence of MNN – the commonly accepted, chemical or grouping name of active ingredient. If necessary it is recommended to use pronouns (for example, "it").

1.1. Dosage

The dosage shall correspond to quantitatively determined content and use of drug and to match with the quantity specified in quantitative structure and the mode of dosing. Different dosages of the same medicine should be specified equally, for example, 250 mg, 500 mg, 750 mg. It is necessary to avoid use of decimal dividers, when applicable (for example, 250 mkg, but not 0,25 of mg). However if the dosage form is provided by two and more dosages expressed by several units of measure (for example, 250 mkg, 1 mg and 6 mg), then it is in certain cases more reasonable to specify dosage in the same units for the purpose of comparability (for example, 0,25 of mg, 1 mg and 6 mg). For the purpose of safety millions (for example, units) always should be written completely, but not to reduce. It is not necessary to specify insignificant zero (for example, 3,0 or 2,500).

For medicines at which expression of content of active ingredients in units of mass cannot characterize fully biological activity (in particular, for biological and immunobiological medicines) the dosage can be expressed:

in units used in pharmacopeias:

ME – the international unit of biological activity;

Lf – unit of biological activity of toxin (anatoxin);

PFU – plaque-forming units;

Ph. Eur. U. – unit of the European pharmacopeia;

and other units, for example:

PIECE – units of action of biological activity;

PNU – units of protein nitrogen.

If the international unit of biological activity was determined by WHO, then it is recommended to apply this unit.

1.2. Dosage form

The dosage form of medicine needs to be specified according to the complete standard term of the Pharmacopoeia of the Union, in plural, when applicable (for example, tablets) (according to Item 3 of this Section). In the absence of the suitable complete standard term, by combination of standard terms according to the nomenclature of dosage forms approved by the Commission the new term can be constituted.

If it is impossible, it is necessary to send the appeal to authorized body of state member about need of the new standard term at Pharmacopoeian committee of the Union. The way of introduction and primary (internal) package in the address are not specified, for exception of cases when these elements are part of the standard term, or are necessary for the purpose of safety, or in the presence of identical medicines which are possible for differentiating only by means of specifying of way of introduction or primary (internal) package.

The name and dosage of vegetable medicines shall conform to requirements of rules of registration and examination of the medicines for medical application approved by the Commission.

2. High-quality and quantitative structure

The complete description of high-quality and quantitative composition of active ingredient is given in this Section OHLP, and in need of Sections 4.3 and 4.4 OHLP the description of high-quality and quantitative composition of excipients is provided. For example, the high-quality and quantitative composition of the excipients specified in appendix No. 10 to these Requirements shall be specified in this Section OHLP under separate subtitle "Excipients". At the end of the Section OHLP it is necessary to specify the following standard formulation: "The complete list of excipients is provided in Section 6.1.".

If solvent is part of medicine, the information about him needs to be included in appropriate sections of OHLP (as a rule, Sections 3, 6.1, 6.5 and 6. 6).

2.1. High-quality structure

The name of active ingredient is provided according to MNN recommended to WHO and if necessary is supplemented with specifying of salt or hydrated form. In the absence of MNN it is necessary to use the name specified in the Pharmacopoeia of the Union and if active ingredient is not included in pharmacopeia – the commonly accepted, chemical or grouping name of active ingredient. In the absence of the commonly accepted, chemical or grouping name it is necessary to specify exact scientific designation. For the active ingredients which do not have exact scientific designation it is specified as well as what they are made of. It is not allowed to include references to pharmacopoeian quality.

If medicine is vegetable medicine, specifying of high-quality structure shall correspond to the rules of registration of examination and medicines for medical application approved by the Commission.

When specifying high-quality composition of the medicine representing radio pharmaceutical set it is necessary to designate accurately that the radioisotope is not part of set.

2.2. Quantitative structure

The amount of active ingredient needs to be expressed per unit of dosing (the dosed inhalation drugs – on the delivered dose and (or) the measured dose), per unit of amount or unit of mass, and it shall correspond to the dosage specified in Section 1 OHLP.

The amount of active ingredient needs to be expressed by means of the international acknowledged standard term which is supplemented if necessary with other term if it is more clear to health workers.

2.2.1. Salts and hydrates.

If active ingredient is salt or hydrate, the quantitative structure should be expressed in units of mass (or biological activity in international (or others) units, when applicable) the operating beginning (the basis, acid or anhydrous salt), for example, "60 mg of torimefen (as citrate)" or "torimefena the citrate equivalent to 60 mg of torimefen".

If during preparation of ready drug in reactionary mix (in situ) salt (for example is formed, when mixing the solvent and powder), it is necessary to reflect quantity of active part of molecule of active ingredient with indication of on in situ salification.

Concerning widely applied active ingredients as a part of medicine which dosage is traditionally expressed in salt or hydrated form the quantitative structure is allowed to express as salt or hydrate, for example, "60 mg of diltiazem of hydrochloride". This rule is applicable if salt is formed by in situ.

2.2.2. Ethers and pro-drugs.

If active ingredient is ether or pro-medicine, the quantitative structure needs to be expressed as amount of ether or pro-medicine.

For medicine – pro-medicine which active part of molecule of active ingredient is registered in the form of independent medicine also equivalent quantity of active part of molecule of active ingredient is specified (for example, "75 mg of fosfenitoin are equivalent to 50 mg of Phenytoinum").

2.2.3. Powder for preparation of solution or suspension for intake. The amount of active ingredient needs to be expressed per unit of dose if drug is one-dose, or per unit of volume dose after recovery. In some case it is reasonable to specify molar concentration.

2.2.4. Parenteral drugs, the powders except for recovered.

If general content of primary (internal) package of one-dose parenteral drugs is entered in the form of one dose ("complete use of content of primary (internal) package"), the amount of active ingredient should be expressed on release form (for example, 20 mg etc.) without specifying of excesses and excess. It is necessary to specify quantity 1 ml and the total declared amount also.

If the amount of one-dose parenteral medicines, is calculated based on body weight, surface area of body or other variable patient ("partial use of content of primary package"), the amount of active ingredient should be expressed in milliliters. It is necessary to specify also total declared amount. Excesses and excess are not specified.

The amount of active ingredient of multidose parenteral medicines and parenteral medicines in large volumes should be expressed on 1 ml, on 100 ml, on 1000 ml etc. in compliance with circumstances, except for the multidose vaccines containing "n" of identical doses. In this case the dosage should be expressed on volume dose. Excesses and excess are not specified.

When applicable, for example, concerning the X-ray contrast agents and parenteral drugs containing inorganic salts, the amount of active ingredient should be specified also in millimolyakh. For X-ray contrast agents with iodinated active ingredients in addition to amount of active ingredient it is necessary to specify amount of iodine 1 ml.

2.2.5. The powder which is subject to recovery before parenteral administration.

If medicine is the powder which is subject to recovery before parenteral administration it is necessary to specify the total quantity of active ingredient containing in primary (internal) package without specifying of excesses and excess, and also quantity 1 ml after recovery on condition of lack of several options of recovery and the different used quantities which lead to formation of different final concentration.

2.2.6. Concentrates.

The quantity needs to be expressed as content on 1 ml of concentrate and general content of active ingredient. It is also necessary to include content on 1 ml after recommended cultivation on condition of lack of cultivation of concentrate to different final concentration.

2.2.7. Transdermalny plasters.

It is necessary to specify the following quantitative data: content of active ingredient in plaster, the average dose delivered for unit of time, the area of releasing surface, for example:

"Each plaster of 10 cm2 contains 750 mkg of oestradiol, releasing in 24 hours nominally 25 mkg of oestradiol".

2.2.8. Multidose firm and soft dosage forms. The amount of active ingredient needs to be specified whenever possible per unit of dosing, in other cases – 1 g, 100 g or as a percentage in compliance with circumstances.

2.2.9. Biological medicines.

2.2.9.1. Instruction of dosage.

The amount of biological medicines should be expressed in units of mass, units of biological activity or the international units depending on specific drug and reflecting the procedure accepted in the Pharmacopoeia of the Union in appropriate cases. Concerning pegylated proteins it is also necessary to consider appendix No. 2 to these Requirements regarding the description of structure pegylated (conjugated) proteins in OHLP.

2.2.9.2. Active ingredients of biological origin.

It is necessary to describe briefly origin of active ingredient, to specify properties of all cellular systems used in production and, when applicable, use of technology of recombinant DNA. The phrase is stated in the following edition: "It is received with use of cells of XXX [on technology of recombinant DNA].".

The examples illustrating use of this principle are below included:

"it is received with use of diploid cells of the person (MRC-5)";

"it is received with use of cells of Escherichia coli on technology of recombinant DNA";

"it is received with use of cells of chicken embryos";

"it is received from donor plasma of the person";

"it is received from urine of the person";

"it is received from blood [animals]";

"it is received from tissue of pancreas of pigs";

"it is received from mucous membrane of intestines of pigs".

2.2.9.3. Special requirements to normal immunoglobulins.

It is necessary to specify distribution of normal immunoglobulins on the subclasses IgG percentage of general content of IgG. Then the upper bound of content of IgA is specified.

2.2.9.4. Special requirements to vaccines.

It is necessary to specify content of active ingredient per unit of dosing (for example, ml 0,5). In the presence of adjuvants it is necessary to specify their high-quality and quantitative structure.

It is necessary to list the impurity representing the special importance (for example, ovalbumin in the vaccines received from eggs).

Appendix No. 3 to these Requirements contains additional recommendations about pharmaceutical aspects of submission of information on vaccines for medical application.

2.2.10. Vegetable medicines. Instruction of quantitative structure shall correspond to the rules of registration and examination of medicines for medical application approved by the Commission.

3. Dosage form

The name of dosage form is specified according to the nomenclature of dosage forms approved by the Commission. This term shall match with the term specified in Section 1 OHLP. However, if on primary (internal) package the reduced standard term is used, the term in this Section OHLP reduced in addition is provided in brackets.

It is necessary to provide the description of appearance of drug (color, signs, etc.) in the paragraph, separate of the standard term, including data on the actual sizes of firm dosage form for intake, for example: "Tablets

White, round tablets with flat slanted edges with a diameter of 5 mm with the sign "100" on one party"

If on tablets it is provided risk, it is necessary to specify whether the reproduced separation of tablets is confirmed. For example, "Risk it is intended only for razlamyvaniye for the purpose of simplification of proglatyvaniye, but not for separation into equal doses", "the tablet can be divided into equal half".

It is necessary to provide data on pH and osmolarity if necessary.

If medicine is subject to recovery before use, in this Section OHLP it is necessary to describe appearance before recovery. Appearance of medicine after recovery needs to be specified in Sections 4.2 and 6.6 OHLP.

4. Clinical data

4.1. Indications to use

Indications to use are specified accurately and laconically, and shall reflect target disease or condition with indication of therapy orientation (symptomatic, etiotropic or exerting impact on current or progressing of disease), for prevention (primary or secondary) and diagnoses. When applicable, information on target population, especially in the presence of restrictions for separate categories of patients is specified.

Information on final points of research, as a rule, is not provided.

Indications to use for the purpose of prevention and information on target population are allowed to be specified in general. Results of the subsequent researches specifying the formulation of the registered indications or the information about them can be included in Section 5.1 OHLP if they do not assume inclusion of the new indication.

It is necessary to specify information on compulsory provisions of use of drug if they properly are not mentioned in other Sections OHLP, but are significant, for example, about the accompanying dietary measures, changes of conduct of life or the accompanying therapy.

It is necessary to specify age groupes to which drug, with indication of age brackets is shown, for example:

"By X it is shown [to adults, newborns, babies, children, teenagers] aged from x to y [years, months].". For the purposes of these Requirements children's population is divided into age subgroups: premature newborns (with indication of gestation term), the full-term newborns (0–27 days), children of chest age and babies (28 days-23 of month); children (2–11 years), teenagers (of 12–18 years).

If the indication to use of drug depends on certain genotype, either gene expression, or certain phenotype, this circumstance needs to be reflected in the indication.

4.2. Mode of dosing and route of administration

In case of availability of special medical instructions on medicine use, including limited leave, this Section OHLP should be begun with the description of such conditions.

In the presence of special concerns concerning safety it is also necessary to reflect recommended restrictions concerning use conditions (for example, "only for stationary use" or "it is necessary to have the suitable resuscitation equipment").

4.2.1. Dosing mode.

It is necessary to specify accurately the dosing mode for each method (way of introduction) and for each indication to use.

When applicable, references to official recommendations are given (for example, on primary vaccination and antibiotics, and also revaccination).

When applicable, for each category (subgroups of population on age (to body weight, surface area of body) respectively are allocated) recommended doses are specified (for example, in mg, mg/kg, mg/m 2) for dosing interval. Frequency rate of use should be expressed in units of time (for example, 1 or 2 times in day (days) or each 6 hours), in order to avoid confusion it is not necessary to use reducings, for example, "1 r/d, 2 r/d, 1 time/days, 2 times/days".

When applicable, are specified:

maximum recommended single, daily and (or) general (course) dose;

need of matching of dose;

standard duration of use and all restrictions on its duration, and also, when applicable, need of gradual dose decline or recommendation about use cancellation;

the undertaken measures in case of the omission of one or more doses, or, for example, in case of vomiting after administration of drug (recommendations shall be as much as possible exact, considering recommended frequency rate of use and the relevant pharmacokinetic data);

preventive measures in order to avoid development of some undesirable reactions (for example, use of antiemetic drugs) with reference to Section 4.4 OHLP;

communication of administration of drug with acceptance of liquid and food together with the reference to Section 4.5 OHLP if interaction, for example, with alcohol, grapefruit or milk takes place;

recommendations about repeated use together with information on necessary intervals between courses of treatment, when applicable;

the interactions requiring special dose adjustment with references to other applicable Sections OHLP (for example, Sections 4. 4, 4.5, 4.8, 5.1, 5.2);

if necessary – recommendations of inadmissibility of early termination of therapy in case of the frivolous undesirable reaction which is frequent, but the passing or eliminated by means of matching dose.

For specific drug if this information is significant, it is necessary to specify the following:

"Activity of medicine [The trade name of medicine] is expressed in [to specify the name] units. These units are not interchanged with units used for expression of activity of other drugs with [the name of active ingredient].".

4.2.2. Special groups of patients.

Data on dose adjustment or other data concerning the dosing mode at special groups of patients in specially allocated subsections are provided. The specified data are located on importance degree, for example, in the relation:

elderly people. Accurately need of dose adjustment at any subgroups of elderly people with references to other Sections OHLP containing the specified data, for example, 4.4, 4.5, 4.8 or 5.2 is specified;

patients with renal failure. Recommendations about dosing shall correspond to the ranges of values of biochemical markers of renal failure used in clinical trials and results of these researches as much as possible precisely;

patients with liver failure according to data on the patients included in researches (for example, "alcoholic cirrhosis") and the determinations used in these researches, for example, point (class) on scale of Chayld-Pyyu;

patients with certain genotype with references to other Sections OHLP containing more detailed data, when applicable;

other significant special groups of patients (for example, patients with other associated disease or patients with excessive body weight).

Recommendations about dose adjustment, for example, based on observations of clinical symptoms and signs and (or) datas of laboratory, including concentration of medicine are in certain cases provided in blood, with references to other Sections OHLP, when applicable.

4.2.3. Children.

The separate subsection "Children" shall be provided in OHLP. The provided data shall cover all subgroups of children, circumstances should use in conformity combination of the potential situations described below.

If drug is shown to children, the recommendation about the mode of dosing should be specified for each significant subgroup. Age framework shall reflect assessment of advantage and risks which is carried out for each subgroup.

If the dosing mode at adults and children matches, it is enough to specify of it, in addition it is not required to repeat the dosing mode.

It is necessary to specify recommended doses (for example, in mg, mg/kg, mg/m 2) for dosing interval concerning age subgroups to which drug is shown. Concerning different subgroups specifying of different data on dosing can be required. If necessary it is necessary to provide recommendations of rather premature newborns with indication of more suitable age, for example, gestational or post-menstrual.

Depending on subgroup, clinical these and available dosage forms the dose is expressed proceeding from weight or surface area of body, for example, "to children aged from 2 up to 4 years on 1 mg/kg of body weight 2 times a day".

When applicable, data on time of administration of drug shall consider daily routine of the child, for example, school or dream.

If drug is shown to children and it is impossible to develop suitable children's dosage form, with reference to Section 4.2 OHLP it is necessary to include detailed instructions on method of receipt of the drug ex tempore in Section 6.6 OHLP.

Doses and route of administration at different subgroups are allowed to be represented in the form of the table.

If drug is not shown to some or all age groupes of children, in case of impossibility to make recommendations about the dosing mode, the available data should be generalized with use of the following standard formulations (one or combination from several proceeding from circumstances):

"[Safety and efficiency] X at children aged from x to y [months, years] [or at any other significant subgroups, for example, on the body weight, puberty, floor] are at the moment not established".

It is necessary to add one of the following formulations:

"Data are absent".

"The data which are available today are provided in the Section [4.8; 5.1; 5.2], however it is impossible to make recommendations about the dosing mode".

"X should not be applied at children aged from x to y [months, years] [or at any other significant subgroups, for example, on the body weight, puberty, floor] in connection with concerns relatively [safety, efficiency] [are listed concerns] in detail stated in Sections [the Sections containing detailed data, for example, 4.8 or 5.1 are specified]".

"According to indications [to specify indications] to X at [children, children aged from x to y [months, years], or at any other significant subgroups, for example, on the body weight, puberty, floor] it is not applied".

"To X it is contraindicated at children aged from x to y [months, years], or at any other significant subgroups, for example, on the body weight, puberty, floor], [in case of the indication [to specify the name of the indication] (the reference to Section 4. 3)]".

In the presence of dosage, more suitable for use, and (or) dosage forms for some or all subgroups of children (for example, solution for intake for children), it is allowed to specify it in OHLP the provided (less suitable) dosage and (or) dosage form.

For example: "other dosage forms and (or) dosages can satisfy better needs of this group".

4.2.4. Route of administration.

Under separate subtitle ("The precautionary measures taken before use of drug or during the work with it") with reference to Section 6.6 (or 12) OHLP are specified all special precautionary measures during the work with drug or its use (for example, for cytotoxic drugs) health workers (including pregnant health workers), the patient and the looking after persons.

The way of introduction is specified, and exhaustive instructions for the correct introduction and use are provided. Instructions for preparation or recovery should be provided in Section 6.6 or in Section 12 OHLP (if necessary) and to give the reference to this Section OHLP.

In the presence of confirmatory data it is necessary to provide most clear data on the alternative methods improving use or the acceptability of use of medicine (for example, possibility of razlamyvaniye of tablet, cutting of tablet or transdermalny plaster, razmelcheniye of tablet, opening of capsules, mixing of their content with food, dissolution in drinks with indication of on possibility of use of part of dose), especially in case of introduction by means of probes for artificial feeding.

It is necessary to explain all special recommendations about use caused by dosage form, for example:

"in connection with unpleasant taste to chew tablets, coated, does not follow";

"it is not necessary to break the tablets covered with enterosoluble cover as it interferes [with pH-dependent disintegration, irritation of intestines]";

"it is not necessary to break tablet, coated as the cover is intended for ensuring the prolonged release (see Section 5. 2)".

It is necessary to provide data on rate of administering of parenteral drugs.

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