Universal reference book for medicines
Product name: HEMATE® P (HAEMATE P)
ATC codes: B02BD06

Type: A drug of factors (VIII and Willebrand) coagulation

Registration number: ЛП-000596

Lyophilizate for the preparation of a solution for intravenous administration ofwhite or almost white.

1 f.
von Willebrand Factor 600 IU
Excipients: human albumin 40-60 mg, glycine 75-125 mg, sodium chloride 10-20 mg, sodium citrate dihydrate 17.5-35 mg.

Solvent: water d / and 5 ml

bottles of transparent colorless glass (I type, Hept.F.) (1) complete with a solvent (fl colorless transparent glass) and a device for adding a solvent with a built-in 15 micron filter ("Mix-2Vial 20/20"), in a blister - packs cardboard.
Vials with lyophilizate and solvent are sealed with a cork made of bromobutyl rubber and rolled with aluminum caps with a plastic disc. Kit for intravenous administration (disposable syringe, needle-butterfly, 2 disinfecting wipes in individual hermetic packaging and non-sterile adhesive plaster) in a separate cardboard bundle. A pack of cardboard with a preparation and a pack of cardboard with a set for iv introduction are stacked together and fastened with plastic tape.
Lyophilizate for the preparation of a solution for intravenous administration of white or almost white.

1 f.

coagulation factor VIII 500 IU

von Willebrand Factor 1200 IU

Excipients: human albumin 80-120 mg, glycine 150-250 mg, sodium chloride 20-40 mg, sodium citrate dihydrate 35-70 mg.

Solvent: water d / and 10 ml

bottles of transparent colorless glass (II type, Hept. F.) (1) complete with a solvent (colorless transparent glass flask) and a device for adding a solvent with a built-in 15 μm filter ("Mix-2Vial 20/20"), in a blister - packs cardboard.
Vials with lyophilizate and solvent are sealed with a cork made of bromobutyl rubber and rolled with aluminum caps with a plastic disc. Kit for intravenous administration (disposable syringe, needle-butterfly, 2 disinfecting wipes in individual hermetic packaging and non-sterile adhesive plaster) in a separate cardboard bundle. A pack of cardboard with a preparation and a pack of cardboard with a set for iv introduction are stacked together and fastened with plastic tape.
Lyophilizate for the preparation of a solution for intravenous administration of white or almost white.

1 f.

coagulation factor VIII 1000 IU

von Willebrand Factor 2400 IU

Excipients: human albumin 160-240 mg, glycine 300-500 mg, sodium chloride 40-80 mg, sodium citrate dihydrate 70-140 mg.

Solvent: water d / and 15 ml

bottles of transparent colorless glass (II type, Hept. F.) (1) complete with a solvent (colorless transparent glass flask) and a device for adding a solvent with a built-in 15 μm filter ("Mix-2Vial 20/20"), in a blister - packs cardboard.
Vials with lyophilizate and solvent are sealed with a cork made of bromobutyl rubber and rolled with aluminum caps with a plastic disc. Kit for intravenous administration (disposable syringe, needle-butterfly, 2 disinfecting wipes in individual hermetic packaging and non-sterile adhesive plaster) in a separate cardboard bundle. A pack of cardboard with a preparation and a pack of cardboard with a set for iv introduction are stacked together and fastened with plastic tape.


Description of the preparation is based on an approved instruction for use and approved by the manufacturer for the 2013 edition.


PHARMACHOLOGIC EFFECT



Hemostatic drug.

Willebrand factor

Hemate ® P exhibits the same properties as the endogenous factor of von Willebrand.

In addition to the function of protecting the coagulation factor VIII, von Willebrand factor causes adhesion of platelets at the site of vascular injury and plays an important role in platelet aggregation.

The appointment of von Willebrand factor allows to correct hemostasis disorders in patients suffering from a deficiency of von Willebrand factor at two levels:

- The von Willebrand factor promotes platelet adhesion at the site of vascular injury (since it binds both to the subendothelial layer of the vessels and to the platelet membrane), providing primary hemostasis, as evidenced by a decrease in bleeding time.
This effect occurs immediately. It is known that it depends on the presence of a large number of Willebrand factor multipers with a high molecular weight.
- Willebrand factor promotes delayed correction of associated factor VIII deficiency.
After intravenous administration, von Willebrand factor binds to endogenous factor VIII (which is produced in sufficient quantity in patients), and, stabilizing this factor, prevents its rapid degradation. Therefore, with the introduction of a pure vWF (low factor VIII), a slightly delayed normalization of the level of factor VIII (FVIII: C) after the first infusion is observed, and with the introduction of factor VIII vWF drugs, normalization of the level of factor VIII is noted immediately after the first infusion .
Coagulation factor VIII

Hemate ® P exhibits the same properties as the endogenous coagulation factor VIII.
Complex factor VIII / von Willebrand factor consists of two molecules (coagulation factor VIII and von Willebrand factor) performing various physiological functions.
After administration to patients with hemophilia, factor VIII binds to von Willebrand factor in the vascular bed.

Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X.

The activated factor X promotes the conversion of prothrombin to thrombin.
Thrombin, in turn, converts fibrinogen into fibrin and promotes the formation of a thrombus. Hemophilia A is a hereditary, sex-linked disorder in the blood clotting system due to a decrease in the level of factor VIII.
The disease manifests itself in the form of profuse bleeding and hemorrhages in the joints, muscles and internal organs spontaneously or as a result of accidental trauma or surgical intervention.
The substitution therapy of the deficiency of the factor of blood coagulation VIII in plasma allows temporarily normalizing the content of the factor, and also reducing the tendency to bleeding.
PHARMACOKINETICS



Willebrand factor

The pharmacokinetic properties of Hemate ® P were evaluated in 28 patients with von Willebrand disease [type 1 p-10;
type 2A n = 10; type 2M n = 1, type 3 n = 7] outside of bleeding. T 1/2 VWF: RCo (two-chamber model) is 9.9 hours (on average, from 2.8 to 51.1 hours). The initial T 1/2 is 1.47 hours (on average, from 0.28 to 13.86 h).
The increase in ristocetin-cofactor activity of VWF: RCo in vivo is 1.9 (IU / dl) / (IU / kg) [on average, 0.6 to 4.5 (IU / dL) / (IU / kg)].
The average area under the concentration-time curve is 1664 IU / dl xh (average, 142 to 3846 IU / dl x h), the average retention time (IED) was 13.7 hours (average, 3.0 to 44.6 hours) , the average clearance is 4.81 ml / kg / h (average, from 2.08 to 53.0 ml / kg / h).
The maximum level of von Willebrand factor in plasma was usually achieved approximately 50 minutes after administration.
The maximum level of coagulation factor VIII was observed 1-1.5 hours after administration.
Coagulation factor VIII

After intravenous administration, a rapid increase in the activity of coagulation factor VIII in plasma was first observed, followed by a rapid decrease in activity followed by a slow decrease in activity.
Studies in patients with hemophilia A showed that T 1/2 was 12.6 hours (on average, from 5.0 to 27.7 hours).The increase in activity of the clotting factor VIII in vivo was 1.73 IU / dL per IU / kg (average, 0.5 to 4.13). In one study, the average retention time was 19.0 hours (on average, from 14.8 to 40.0 hours), the average area under the concentration-time curve was 36.1 (% x h) / (IU / kg) (on average, from 14.8 to 72.4 ) (% x h) / (ME / kg), the average clearance is 2.8 ml / kg / h (average, from 1.4 to 6.7 ml / kg / h).
INDICATIONS



- treatment and prevention of bleeding or blood loss during surgery in patients with von Willebrand disease, if monotherapy with desmopressin is ineffective or contraindicated;

- Treatment and prevention of bleeding in patients with hemophilia A (congenital deficiency of the coagulation factor VIII);

- can be used to treat and prevent bleeding in patients with acquired coagulation factor VIII deficiency and in patients with antibodies to the coagulation factor VIII.

DOSING MODE



Treatment should be performed by a doctor who has experience in treating hemophilia.

Von Willebrand's Disease

Typically, 1 IU / kg vWF: RCo) increases the level of circulating von Willebrand factor in the blood of the patient by 0.02 IU / ml (2%).
Willebrand factor> 0.6 IU / ml (60%) and factor VIII: C> 0.4 IU / ml (40%) should be sought.
Usually, in order to provide hemostasis, 40-80 IU / kg von Willebrand factor and 20-40 IU / kg factor VIII per kg body weight are recommended.
An initial dose of Willebrand factor of 80 IU / kg may be required, especially in patients with type 3 vWD disease, when maintaining adequate levels of vWF can require higher doses than other types of vWF disease.
Prevention of bleeding during surgery and serious injuries

To prevent excessive blood loss during and after surgery, the drug should be administered 1 or 2 hours prior to surgery.
Every 12-24 hours, the administration of appropriate doses should be repeated. The dose and duration of therapy depend on the clinical condition of the patient, the type and severity of bleeding, and the content of vWF and coagulation factor VIII. When using vWF drugs containing the coagulation factor VIII, the attending physician should consider the possibility of excessive increase in the level of factor VIII with prolonged treatment. After 24-48 hours of therapy, in order to avoid an uncontrolled increase in the content of factor VIII, the need to reduce the dose or increase the intervals between drug administration should be assessed.
The dosage regimen in children is calculated taking into account the body weight, that is, it is based on the same principles as in adults.
The frequency of drug administration should always depend on the clinical effectiveness in each individual case.
Haemophilia A

Doses and duration of substitution therapy depend on the severity of the deficiency of the coagulation factor VIII, the localization and severity of bleeding, and the clinical condition of the patient.
The number of units of factor VIII administered is measured in international units (ME), determined in relation to the current World Health Organization (WHO) standard for preparations containing the coagulation factor VIII. The activity of factor VIII in plasma is expressed as a percentage (relative to normal human plasma) or in ME (relative to the International Standard for Factor VIII Content in Plasma). One ME of factor VIII activity is equivalent to the amount of factor VIII in one milliliter of normal human plasma.
The calculation of the required dose of factor VIII is based on an empirically established pattern according to which 1 IU per kg of body weight increases the activity of factor VIII at approximately 2% of normal activity (2 IU / dl).
The required dose is calculated using the following formula:
Necessary number of units = body weight [kg] x required increase in factor VIII [% or ME / dL] x 0.5.

The dose and frequency of administrations should always be calculated taking into account clinical efficacy in each individual case.

In the event of the following bleeding, the activity of factor VIII for the relevant period should not be lower than the indicated level of plasma activity (in% of normal level or in IU / dL).

Table of calculation of doses of the drug for bleeding and in surgical practice

Severity of bleeding / Type of surgical procedure Necessary level of factor VIII (% or IU / dL) Frequency of doses (h) / duration of therapy (days)

Bleeding

Early hemarthrosis, muscle or mouth bleeding 20-40 Repeated infusions of the drug every 12-24 hours. At least 1 day until the bleeding stops (pain sensation) or healing occurs.

More massive bleeding, muscle bleeding or bruising 30-60 Repeated infusion of the drug every 12-24 hours for 3-4 days or more, until the pain or severe disability disappears.

Life-threatening hemorrhage 60-100 Repeated infusion of the drug every 8-24 h until the threat to life is eliminated

Surgery

Small, including tooth extraction 30-60 Every 24 hours, at least 1 day, until the healing takes place

Greater 80-100 (before and after surgery) Repeated infusions of the drug every 8-24 h until adequate wound healing, then therapy for at least 7 days to maintain factor VIII activity at 30-60% (IU / dL)

During the course of treatment, it is recommended to determine the level of factor VIII in order to calculate the administered dose and the frequency of infusions.
With extensive surgical intervention, monitoring of substitution therapy with coagulation analysis (factor VIII activity) is mandatory. There is a significant individual variability in the response to treatment with factor VIII, in vivo different recovery rates and T 1/2 are achieved.
With the long-term prophylaxis of bleeding in patients with severe hemophilia A, factor VIII is normally administered at a dose of 20-40 IU / kg with an interval of 2-3 days.

In some cases, especially in young patients, shorter intervals and higher doses may be required.
The possibility of forming antibodies (inhibitors) to factor VIII should be taken into account. It is necessary to monitor the production of factor VIII inhibitors in patients. If the expected level of factor VIII activity is not achieved with the preparation or if bleeding is stopped when the calculated dose is administered, an analysis should be carried out for the presence of factor VIII inhibitors. In patients with a high content of inhibitors, factor VIII therapy may not be effective, and alternative therapies should be considered in such cases. Such patients should be administered by physicians with experience in the treatment of hemophiliacs (see also "Special instructions").
The dosage regimen in children is calculated taking into account the body weight, that is, it is based on the same principles as in adults.
The frequency of drug administration should always depend on the clinical effectiveness in each individual case.
Instructions for preparing a solution

General Instructions

1. The reconstituted solution varies from clear to slightly opalescent.
After filtration and before administration, it is recommended to inspect the reconstituted preparation for the presence of particles and discoloration. Even if the dissolution instructions are accurate, sometimes small flakes or particles remain in the solution. A device for adding a solvent with a built-in filter completely detains these particles. The filtration does not affect the calculation of the dose. Do not use a turbid solution or solution containing a precipitate (small particles) after filtration.
2. Preparation of the reconstituted solution of the preparation and the kit are carried out under aseptic conditions.

3. The unused preparation or solution of the preparation, as well as its packaging, should be disposed of in accordance with local requirements.

Preparation of the reconstituted solution

Heat the solvent to room temperature.
Make sure that the caps from the bottles with the solvent and the preparation are removed, the plugs are treated with an antiseptic solution and dried before opening the device for the addition of a solvent with a built-in filter *.
* The device for adding a solvent with a built-in filter ("Mix-2Vial ™ 20/20") is intended for single use;
Do not use the device in case of damage to the packaging, or after the expiry date indicated on the paper part of the blister pack as follows: "EXP. year-month »
1. Remove the cover from the packaging of the device for adding the solvent with the built-in filter.

Fig.
1.
Do not remove the device for adding the solvent with the built-in filter from the blister pack!

2. Place the solvent bottle on a flat, clean surface without opening it.
Take the device for adding the solvent with the built-in filter together with the blister packing and, firmly holding the bottle, with the sharp rod of the blue part of the device, pierce the stopper of the vial with the solvent, pressing vertically downwards.
Fig.
2.
3. Gently holding the edge of the blister pack, remove the blister pack vertically upwards from the solvent addition device.
Make sure that you have removed only the blister pack, not the device itself.
Fig.
3.
4. Place a vial of the drug on a flat surface and flip a solvent vial over it with the solvent addition device attached to it, then pierce the stopper of the vial with the drug with the stem of the transparent part of the device to add the solvent, pressing vertically downwards.
The solvent will automatically move into the vial with the drug.
Fig.
4.
5. With one hand, grasp the device for adding the solvent from the side of the vial with the preparation, the other from the side of the vial with the solvent, and gently unfold the device in two parts, avoiding strong foaming when dissolving the lyophilizate.
The solvent bottle with the blue part of the device for adding the solvent should be discarded.
Fig.
5.
6. Carefully twist the bottle with the drug and make sure that the drug is completely dissolved.
Do not shake the bottle.
Fig.
6.
7. Dial the air in the empty sterile syringe and hold vial in an upright position, connect the syringe to the Luer lug on the device for addition of a solvent with integrated filter. Enter the air, the vial.
Fig.
7.
Fence and recycling preparation
8. By pressing the syringe plunger, invert bottle with a syringe. Gently pulling the plunger of the syringe, draw up the reconstituted solution.
Fig.
8.
9. Once the dialed reconstituted solution into the syringe, hold the syringe barrel (holding the syringe plunger down) and disconnect means for adding a solvent with filter from the syringe.
Fig.
9.
For the introduction of hematite ® P recommended to use disposable plastic syringes as the solution can remain on the walls of the glass-glass syringes.
The drug should be heated to room temperature or body temperature before administration.
The drug is administered slowly in / in at a rate that does not cause discomfort to the patient, making sure that the blood does not fall into the syringe with the drug. The reconstituted solution preparation dialed into the syringe to be used immediately.
In the case shown the introduction of large amounts of drug can be used a drip. For this reconstituted drug solution is added to the required volume of infusion solution.
The rate of administration should not exceed 4 ml per minute.
If the patient has a reaction which may be caused by the introduction of hematite preparation ® P, the speed of injection is necessary to reduce or stop the introduction, depending on the clinical condition of the patient.
The reconstituted solution is physically and chemically stable for 48 hours at a temperature of not higher than 25 ° C. However, from the point of view of asepsis, since the drug hematite ® P does not contain preservatives, reconstituted drug solution should be administered immediately after reconstitution. Store reconstituted solution should not exceed 8 hours at room temperature.
SIDE EFFECT



Adverse events reported below are listed in accordance with a lesion of organs and organ systems, and frequency of occurrence. The frequency of occurrence is defined as follows: very common (1/10?), Common (1/100 and <1/10?), Infrequently, rarely (1/10 000 and (1/1, 000 and <1/100?)? <1/1 000), very rare (<1/10 000), not known. Frequency categories were formed on the basis of post-marketing surveillance.
Classification according to the target organ (MedDRA) organs and systems of adverse events The frequency of
Disturbances in the blood and lymphatic system hypervolemia Formation Hemolysis inhibitors to von Willebrand factor inhibitors to factor VIII Unknown Unknown Very seldom very seldom
General disorders and injection site Fever burning and stinging at the injection site Very rare Very rare
disorders of immune hypersensitivity system (allergic reactions) Very rare
Violations by vascular thrombosis cases of thromboembolism is very rare Very rarely
the part of the vessel: if necessary, use higher doses drug or its frequent use, or in the presence of inhibitors, or the need for additional treatment before and after surgical operations, the possibility should be considered development of fluid overload. In addition, patients with blood groups A, B and AB should perform tests for intravascular haemolysis and / or decreasing hematocrit.
Immune system:Hypersensitivity or allergic reactions (including angioedema, burning and stinging at the infusion site, chills, flushing of the face and neck, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, , vomiting, wheezing) have been observed very rarely, and in some cases, led to severe anaphylactic reactions (including shock).
General reaction : in very rare cases, there is a fever, burning and tingling sensation at the injection site.
Von Willebrand disease
the part of the vessel:In rare cases, there is a risk of thrombosis / embolism cases (including pulmonary embolism), especially in patients with known risk factors for patients (eg, in the perioperative period without prophylaxis of thrombosis, without an early mobilization, obesity).
In patients receiving VWF products, there is the risk of increasing the level of activity of Factor VIII (FVIII: C) in the plasma, which increases the likelihood of thrombosis (see also "Special Instructions" section.).
Immune system:in patients with von Willebrand disease, especially 3 type, very rarely can be formed neutralizing antibodies (inhibitors) to von Willebrand factor. The appearance of antibodies leads to clinical failure of drug treatment. These antibodies are precipitating, and their occurrence can be associated with anaphylactic reactions. Therefore, in patients with anaphylactic reactions, patients should determine whether inhibitors. In all such cases, the recommended specialized care in hematology department or center.
Hemophilia A
Immune system:in patients with haemophilia A can be generated very rarely neutralizing antibodies (inhibitors) to factor VIII blood coagulation. The appearance of antibodies resulting in clinical failure of treatment. In these cases, the recommended treatment in specialized hematology departments.
Experience of using hematite ® P in previously untreated patients, obtained during clinical trials is very limited, however, statistically significant quantitative data on clinically proven cases develop specific inhibitors are absent.
CONTRAINDICATIONS



- increased sensitivity to clotting factor VIII, von Willebrand factor, or any other component of the formulation.
PREGNANCY AND LACTATION



Due to the fact that haemophilia A is rare in women, experience with the drug during pregnancy and lactation is not available.
With von Willebrand's disease the situation is different, since it is inherited in an autosomal. Women suffer even more often than men because of the additional risk associated with blood loss during menstruation, pregnancy, birth and the development of gynecological diseases. Based on post-marketing studies can recommend the use of substitutes of von Willebrand factor in the treatment and prevention of bleeding. Clinical data on substitution treatment of von Willebrand factor during pregnancy and lactation are not available.
Thus, during pregnancy and lactation the drug should only be used if there is undeniable evidence.
SPECIAL INSTRUCTIONS



As with any preparation containing blood plasma protein, and input to the I / O, may develop hypersensitivity (allergic reactions). Patients should be informed of the early signs of hypersensitivity reactions such as hives, generalized urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. When these symptoms patients are advised to immediately stop using the drug and consult a doctor. It is necessary to follow the standard methods of treatment of shock in the event of a state of shock.
Hematite ® II comprises up to 70 mg of sodium per 1000 ME, which should be considered at a recommended diet for sodium control.
Viral safety
Standard measures to prevent transmission due to the use of medicines made from human blood or plasma, are made up of the selection of donors, screening of individual donor samples and plasma pools for the presence of markers, as well as included in the production process of inactivation procedures and / or remove viruses. Despite this, when using the products derived from human blood or human plasma, the occurrence of infectious diseases due to transmission of infectious agents can not be completely excluded. This provision applies in respect of unknown viruses and pathogens. Check the measures taken are effective for enveloped viruses such as human immunodeficiency virus, hepatitis viruses B and C, and non-enveloped viruses of hepatitis A.Measures taken may be less effective for non-enveloped viruses such as parvovirus B19.
Infection caused by parvovirus B19, can have serious consequences for pregnant women (fetal infection) and those with immunodeficiency or enhanced erythropoiesis (eg, hemolytic anemia).
Patients who regularly or repeatedly taking drugs Factor VIII derived from human plasma, it is recommended vaccination against hepatitis A and B.
Each time when administered hematite ® P necessary to fix the name and serial number of the drug used for communication between the patient and a series of drug.
von Willebrand's disease
There is a risk of thrombosis, including pulmonary embolism, especially in patients with known clinical and laboratory risk factors (e.g., in the absence of the prevention of thrombus formation in the perioperative period, in the absence of early mobilization, obesity, overdose, cancer). Therefore, patients at risk should be monitored in order to identify early signs of thrombosis. Prophylaxis of venous thromboembolism should be carried out in accordance with current recommendations.
When using hematite ®N von Willebrand's disease the physician should know that long-term treatment can lead to excessive increase in the level of activity of coagulation factor VIII (FVIII: C). In patients receiving drugs von Willebrand factor containing factor VIII, should monitor the level of factor VIII activity (FVIII: C) in the plasma in order to avoid a prolonged increase in factor VIII activity (FVIII: C), which is associated with an increased risk of thrombotic complications. It is also appropriate to carry out prevention of thrombosis.
Patients with von Willebrand disease, especially type 3, can be produced neutralizing antibodies (inhibitors) to von Willebrand factor. If the expected level of ristocetin-cofactor activity of von Willebrand factor in plasma is not reached, or use an adequate dose fails to stop the bleeding, should be analyzed for the presence of von Willebrand factor inhibitors. If the patient has high levels of von Willebrand factor inhibitors, therapy may not be effective, and in this case it is necessary to consider the use of other therapies.
Hemophilia A
Generation of neutralizing antibody - VIII factor inhibitors is known complication of the treatment of patients with haemophilia A.
Inhibitors of coagulation factor VIII actions are usually IgG class immunoglobulins which are measured in Bethesda units (BU) per milliliter of plasma. The risk of developing inhibitors associated with the degree of exposure VIII Antihemophilic Factor; This risk is greatest during the first 20 days of application. In rare cases inhibitors may begin to be produced after more than 100 days after initiation of blood coagulation factor VIII.
Patients treated with human coagulation factor VIII of, should be under close medical supervision and the laboratory to identify the production of antibodies to factor VIII. Treatment of hematomas ®P patients with high levels of antibodies to factor VIII may be inefficient in this case to consider the selection of other treatments (see. Also "Side effect" section).
Each time the introduction of hematite ® II is necessary to fix the name and batch number of the product used.
Effects on ability to drive vehicles and management mechanisms of
influence on the ability to drive a vehicle or moving is not mentioned mechanisms.
OVERDOSE


Symptoms overdose human clotting factor VIII was observed. In this case we can not exclude the risk of thrombosis when using very high doses, especially of von Willebrand factor preparations containing high concentration of factor VIII.

DRUG INTERACTION



No known drug interactions coagulation factor VIII with other drugs.
Pharmaceutical incompatibility
not mix the drug with other drugs and solvents, except the solvent constituting the drug.
STORAGE CONDITIONS AND SHELF LIFE


The preparation should be stored protected from light and the reach of children at a temperature not higher than 25 ° C; Do not freeze. Shelf life - 3 years.Do not use after the expiration date printed on the package.

The information is provided for your information, do not self-medicate, it is dangerous for your health.

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