POLiSERA Snake Antiserum

POLiSERA Snake Antiserum

SUMMARY OF PRODUCT CHARACTERISTICS (SmPC)

1. NAME OF THE MEDICINAL PRODUCT
POLISERA 10 Ml IM/IV Vial containing Injectable Solution Against Snake Bites, Sterile, Apyrogen

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Active Substances:
Each milliliter of the POLISERA contains the following active ingredients:
Immunoglobulin fragments against Macrovipera lebetina snake venom (Equine) ≥ 50 LD50
Immunoglobulin fragments against Montivipera xanthia snake venom (Equine) ≥ 50 LD50
Immunoglobulin fragments against Vipera ammodytes snake venom (Equine) ≥ 100 LD50

Excipients:
Sodium chloride 8,5-9,5 mg
For excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Injectable solution
With light smell, clear, almost colorless or light yellow liquid solution

4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
Polisera is used as snakebite antiserum against Macrovipera lebetina, Montivipera xanthia and Vipera ammodytes viper species, which are from the vipera family and encountered in our country.

4.2. Posology and method of administration
Posology/frequency and time of application :
Local Signs;
Symptoms of viper bites usually occur locally as pain, edema, rubor, paresthaesia and famication in the bitten area. Bleeding and local ecchymosis may be seen. Compartment syndrome may develop at extremities.
Systemic Findings;
Following the viper bites, nausea and vomiting, perioral and oral paresthaesia, stomach ache, diarrhea, weakness, fasciculation, perspiration, circulatory disorders, hypotension, tachycardia, drowsiness, bronchospasm, kidney function disorders, fever, skin eruption, coagulopathy, (disseminate intravascular coagulopathy may also develop), confusion and loss of consciousness may be found.
The severity of the poisoning is assessed according to the size of the local edema, existence of systemic findings.
The severity of the snake bites are assessed as follows according to the parameters such as occurrence of the case, amount of the poison injected when bitten, age of the person bitten, his/her immune system and the bitten area.

Degree 0:
Fang marks can be seen but no local or systematic poisoning symptoms are found. Then no treatment is required. Following keeping under observation for 6-8 hours, the patient may be discharged.

Degree I (mild severity cases):
Light tissue tubercles, light ecchymosis, no systemic findings and laboratory findings are normal (Thrombocyte number is normal), systolic pressure blood pressure > 90mmHg. Antivenin need not be used. But the patient shall be discharged following keeping under observation for 12 hours.

Degree II (mean severity cases):
Increasing local tubercles, edema, fain in the bitten area, ecchymosis, elevated prothrombin time, thrombocyte value <80.000 and systolic blood pressure >90mmHg. Systemic symptoms and findings exist at moderate level. Laboratory changes are at moderate level (Decreased fibrinogen and thrombocytes, hemoconcentration and like). 2 or 3 vials of antivenin may be applied in those cases according to the severity of the poisoning. The patient shall be kept in a unit to monitor.

Degree III (severity cases):
Progressing tubercles, pain in the area, bulla, and necrosis may be seen. Elevated prothrombin time, thrombocyte value <80.000 and systolic blood pressure >80mmHg. Severe systemic finding, coagulopathy (such as nose and stomach bleeding). Findings may cover the bitten area and all extremity, even may progress out of extremities. Besides the severe systemic findings and symptoms, prominently distorted laboratory values are seen. Neurological findings are apparent. In those cases, 4-5 vials of antivenin shall be applied according to the severity of the poisoning. The patient shall be monitored in the intensive care unit.

4.3. Contra-indications
POLISERA has contraindications on the patients who are sensitive to the antivenin itself, and active substances and adjuvants of the antivenin. When POLISARA is administered, as a result of foreign matter injection, hypersensitivity reactions may be observed. The reactions may be higher for the patients who got equine or other animal proteins; serum sickness (Type III hypersensitivity reaction) may develop at those patients. It is contraindicated for the patient with serum history clinic.

4.4. Special usage warnings and precautions
Special precautions shall be taken against anaphylactic shock (which develops rapidly and seriously as permeability in capillary vessels, vasodilatation in artery and veins as a result of being re-exposed an antibody which developed sensitivity previously ) and serum sickness (fever, arthralgia, nausea, vomiting or skin rash following administration of antiserum due to use of equine origin proteins) which rarely develop when using or in 7-12 day following the administration of Polisera, which contains heterologous proteins.

•  Patient’s history shall be examined to find out whether he/she has ever been exposed to equine proteins and developed reaction. Patients who have developed allergic reactions before have higher risk of developing allergic and anaphylactic shock.
•  Antiserum treatment shall be administered for the patients known to have serum allergy and serious atopic history, and children administered antiserum treatment before.
•  Intravenous calcium preparations or oral antihistaminic can be administered For serum sicknesses. Serum sickness develops as a result of emerging immune complexes due to combination of IgG or IgM antibodies antigens, and existence of these immune complexes in systemic circulation.
•  POLISERA shall be used cautiously in cases of asthmas and infantile eczema.
•  Bedreska test is recommended before administration of POLISERA. 0,1-0,2 mL (1:10 dilution) serum is injected intradermally. If the patient has allergy history administration shall be as (1:100) dilution. Whether the test will be done and the time when it will be done is decided by the doctor according to the patient’s general situation and with the consideration of life threat. Positive skin tests come out with or without peripheral erythema in 30 minutes. When intradermal tests were proved positive, patients shall be given antihistamines and adrenalin with intravenous application before antiserum application (0,1% adrenalin solution, 05 mL and 0,01 mL/kg respectively subcutaneous or intravenous for children and adults) and antiserum shall be applied after keeping the patient under observation at least for an hour. Even the intradermal test results negative, adrenalin shall be kept available for all patients before serum application. Antiserum application shall be ceased immediately if myalgia, nausea, vomiting, sudden fever or eruption is observed. In case of emerging of serum sicknesses, intravenous calcium preparations or oral antihistamines shall be applied. Antihistamine treatment shall continue for ten days after the shock treatment.
•  Antiserum shall not be used if it is cloudy or has sediment in any kind.
•  If applied after being bitten, tourniquet shall be undone after the serum application.
•  After POLISERA application, patient shall be kept under observation for at least 6-8 hours according to the severity of the poisoning. If acute hypersensitivity symptoms develop, infusion shall be ceased immediately.
•  Normalization of pulse from tachycardia, warming up in extremities in cases of sweating and cool moist skin, normalization in blood pressure in patients with hypertension and normalization in breathing in tachypnea patients are recovery symptoms.
•  This medicinal product contains 33,42-37,35 mg natrium in each dose. This fact shall be considered for the patients on controlled natrium diet.

4.5. Interactions with other medicinal products and other forms of interaction
No data available.

4.6. Pregnancy and lactation
General advises
Pregnancy Category: C
No adequate data is available for the use of POLISERA for pregnant women.

Women have been child fecundity / Contraception
No data is available for Women of childbearing potential regarding use of POLISERA.

Gestation
Data regarding use of POLISERA for pregnant women is insufficient. Animal studies showed reproduction toxicity. No evidence was found that might cause teratogenicity. It is recommended not to be used for pregnant patients as it contains equine immunoglobulin and thus may have adverse effects. The shock or hypoxemia which may develop as a result of anaphylactic reaction may harm fetus. However, when the mother is exposed to sever poisoning and the potential harm of venom is higher, considering the benefit-harm rate, an aggressive treatment shall be carried out and antiserum shall be applied.

Lactation
No negative effect of breastfeeding is known after application of POLISERA. Then mothers can breastfeed their babies while being treated with POLISERA and kept under observation.
Reproductive ability / Fertility
POLISERA has no known effects on reproductive ability.

4.7. Effects on usage drive machine
POLISERA has no know effect on driving and using machines. But patients are recommended not driving or using machines during antiserum application and being kept under observation.

4.8. Undesirable effects
Frequency of undesired effects is as follows:
Very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1.000 to <1/100), rare (≥ 1/10.000 to <1/1.000); very rare (<1/10.000), not known (cannot be estimated from the data available).
Emergence of reaction is possible following the application any kind of animal origin serum.
Immune system disorders:

Common: Serum sicknesses, anaphylactic reaction
Ig E is a mediative or non-mediative anaphylactic reaction (the shock which develops rapidly and seriously as permeability in capillary vessels, vasodilatation in artery and veins as a result of being re-exposed an antibody which developed sensitivity previously). It develops nearly in 20% of the patients. Anaphylactic reaction, which is non-mediative and develops with hypotension, is related to mast cell degranulation which develops against foreign proteins. A second vascular access shall be available for anaphylaxis treatment.

Nervous system disorders
Not known. Headache.

Digestive system disorders
Not known: stomach ache, nausea.
Cutaneous and subcutaneous tissue disorders
Not known: skin eruption.

Kidney and urinal disorders
Not known: Disorders in kidney functions.

General disorders and disorder developing in application area
Not known: Local reactions such as pain and sensitivity in the injection area.
Reporting adverse effects of the product after authorization is of vital importance. It enables monitoring the benefit/risk balance of the product. Health care professionals shall report any suspected adverse effect to Türkiye Farmakovijilans Merkezi (TÜFAM) (Turkish Pharmacovigilance Center). (www.titck.gov.tr; e-mail:tufam@titck.gov.tr; tel: 0 800 314 00 08; fax : 0 312 218 35 99)

4.9. Overdose and treatment
The dose can be increased according to the course of the case and doctor recommendation.

5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
ATC code:
Immunoserums, immunoglobulins J06
Snake antiserum J06 AA03
POLISERA is an injectable solution with light smell, clear, almost colorless or light yellow liquid solution. It is used as snakebite antiserum against Macrovipera lebetina, Montivipera xanthia and Vipera ammodytes viper species, which are from the viperedae family and encountered in our country. It contains F(ab’)2 fragments which emerge as a result pepsin and enzymatic reaction IgG which has been acquired from the purified plasmas immunized against the mentioned snakes.
Lethal doses of Macrovipera lebetina, Montivipera xanthia and Vipera ammodytes snake species were determined through intravenous injection LD50 tests carried out on 18-20 gr rats/mice. According to test, 1 mL of POLISERA venom antiserum contains protective antibodies at least 50 LD50 neutralized units against Macrovipera lebetina, at least 50 LD50 neutralized units against Montivipera xanthia and at least 100 LD50 neutralized units against Vipera ammodytes

5.2. Pharmacokinetic properties
After intramuscular application of POLISERA, active ingredients; Immunoglobulin F(ab’)2 fragments against Macrovipera lebetina snake venom (Equine), Immunoglobulin F(ab’)2 fragments against Montivipera xanthia snake venom (Equine) and Immunoglobulin F(ab’)2 fragments against Vipera ammodytes snake venom (Equine) take place in blood circulation. F(ab’)2 fragments with nearly 100-110 kDa molecular magnitude, compared to nearly 160 kDa Immunoglobulin rate of motion, diffuses faster, however, its diffusion into the tissue compartments is weak. Hence its neutralization ability of antigens in tissue compartments is weak.
F(ab’)2 fragments which have not reacted are extracted through renal ways. Renal damage risk is probable as a result of combination of snake venom proteins with F(ab’)2 fragments (antigen-antibody combinations), and appears in the form of significant decrease in clearance of keratin.

5.3. Preclinical safety data
Preclinical data about antitoxin against snake bite (equine) is not observed for special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, or carcinogenic potential.
Workings about reproductive toxicity are not enough in animal.
Preclinical safety test includes innocuity test (abnormal toxicity) in animals: mice (Swiss white) and guinea-pigs. One person dose but not more than 1.0 ml has injected to five healthy and 17 g to 22 g weighing mice by intraperitoneally. Animals have observed for 7 days. The preparation passes the test if animals not show signs of ill health. If more than one animal dies, the preparation not passes the test. If one of the animals dies or shows signs of ill health, test should be repeated. The preparation passes the test if none of the animals in the second group dies or shows signs of ill health in the time interval specified.
The test also is carried out on two healthy guinea-pigs weighing 250 g to 350 g. One person dose but not more than 5.0 ml has injected to each animals by intraperitoneally way. Animals are observed for 7 days. The preparation passes the test if animals not show signs of ill health. If more than one animal dies, the preparation not passes the test. If one of the animals dies or

shows signs of ill health, test should be repeated. The preparation passes the test if none of the animals in the second group dies or shows signs of ill health in the time interval specified.

6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Cresol
Sodium chloride
Water for injection (WFI)

6.2. Incompatibilities
As no data is available about the product, it shall not be used mixed with other medicinal products.

6.3. Shelf life
24 months.

6.4. Special precautions for storage
Keep in refrigerator between 2-8 oC. Do not freeze, if frozen, do not use after melting. Keep away from sun light.
Each vial is for one use only, the remaining shall be disposed.

6.5. Feature and contents of container
Type I or type II vial, with gray bromobutyl stopper, aluminum flip-off cap, containing solution in each box.

6.6. Special precautions for disposal and other special precautions for handling the remaining medicinal products
Non used products or waste materials should be destroyed accordingly to “Regulations of Medical waste disposal” and “Regulations Control of packing wastes”

7. LICENCE HOLDER
Vetal Sera and Biological Products Production and Marketing CO.
Organize Sanayi Bölgesi
ADIYAMAN, TURKEY
Phone : +90 416 227 07 53 - 54
Fax : +90 416 227 07 55
E-mail : vetalserum@vetalserum.com.tr
Web : www.vetalserum.com.tr

8. LICENCE NUMBER
2014/785

9. DATE OF FIRST AUTHORISATION/RENEWAL OF LICENCE
First registration Date : 16.10.2014
Renewal Date :

10. DATE OF REVISION OF THE SmPC