CHANGCHUN CHANGSHENG LIFE SCIENCES LTD. Address: No.1615Yueda Road, Changchun, China Postcode: Summary of Product Characteristics

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1 Summary of Product Characteristics 1. Name of the medicinal product Generic name: Varicella Vaccine (live) I.P, Freeze-dried 2. Qualitative and quantitative composition The composition of the product is listed s following: Composition Name Quantitative Active Oka strain 3.4Lg PFU Inactive Fucose g Sorbierite g L-Arginine 0.006g Monosodium Glutamate 0.003g Dextran 0.015g 3. Pharmaceutical form Freeze-dried. 4. Clinical particulars 4.1 Therapeutic indications BIOVAC-V is indicated for: the active immunization against varicella of healthy subjects from 12 months of age and above. the active immunization against varicella of susceptible high risk patients and their susceptible healthy close contacts. 4.2 Posology and method of administration 1. Specifications: 0.5ml of reconstituted vaccine per vial, 0.5ml per single human dose containing not less than 3.4Lg PFU Oka virus. 2. Posology: To reconstitute the vaccine, inject all of the diluent in the prefilled syringe into the vial of lyophilized vaccine and gently agitate to mix thoroughly. Withdraw the entire contents into the syringe and inject the total volume of reconstituted vaccine subcutaneously, preferably into the outer aspect of the upper arm (deltoid region). It is recommended that the vaccine be administered immediately after reconstitution, to minimize loss of potency. Discard if reconstituted vaccine is not used within 30 minutes. Do not freeze reconstituted vaccine. 3. Administration and dosage: 1

2 a) Reconstitute the vaccine with the stated amount of sterile water for injection (SWFI) and shake the container till the content is reconstituted completely before use. b) Inject 0.5ml s.c. the reconstituted vaccine at deltoid insertion area of the lateral upper arm. c) The alcohol and other disinfectant can inactivate the attenuated virus in the vaccine; therefore the vaccine can be injected immediately after the disinfector is evaporated completely from the skin. Contact with disinfectants should be avoided. d) BIOVAC-V is recommended in 2 doses (0.5 ml each) to ensure optimal protection against varicella with a minimum interval of 6 weeks between doses. e) For high risk patients additional doses of vaccine may be required. BIOVAC-V should not be administered intradermally or intravascularly. It is recommended to use the vaccine within 30 minutes of reconstituting it with SWFI. 4.3 Contraindications The vaccine should not be used under the following conditions: 1) Those who had hypersensitivity history to the vaccine or any component of the formulation. 2) Those who are pregnant. 3) Those who had serious diseases (including acute or chronic infection), at the period of acute attack of chronic disease and fever. 4) Those who had immunodeficiency, low immune function or in the period of receiving immunosuppressive therapy. 5) Those who had a history of innate immunity defects or contacting with family members who suffer the innate immunity defects. 6) Those who had a history of encephalopathy, epilepsy and other nervous system disease. 4.4 Special warnings and precautions for use 1) Use the product with caution in case of: the family or individual with history of convulsions, chronic disease, epilepsy, allergic reaction, or pregnant women. 2) Adequate treatment provisions, including epinephrine injection (1:1000), should be available for immediate use should an anaphylactoid reaction occur. The recipients should be observed for at least 30 minutes after injection. 3) S.C is recommended, intradermal injection cannot be used, and intravenous injection is forbidden. 4) Care should be taken to avoid contacting the vaccine by disinfectant during the vial opening and injection. The immunization of the vaccine should be done as soon as possible after reconstitution. 5) Do not use the vaccine if any leakage of vial, foreign matters on the label, or turbidity of content is found. 2

3 6) The individuals susceptible to varicella and especially those with skin reaction within 2 or 3 weeks after inoculation should avoid contacting with pregnant women and the patients of leukemia who are very susceptible to varicella as well as those who are receiving immunosuppressive therapy, and especially avoid the contact with the women in the first three months of pregnancy. 7) After the inoculation of the vaccine, women of childbearing age should use contracepted for at least three months. 8) There should be a one-month interval between the inoculation of other live attenuated vaccines. 9) Do not apply the medication of whole blood, plasma or immunoglobulin within 5 months prior to the injection or within three weeks after injection because it will decrease the effect of the product. 10) Avoid the use of drugs such as salicylates within 6 weeks after inoculation of the vaccine. 4.5 Interaction with other medicinal products and other forms of interaction 1) Use of whole blood, plasma or immunoglobulins 5 months prior to the injection or within three weeks after injection is not recommended as it may decrease the effect of the vaccine. 2) In subjects who have received immune globulins or a blood transfusion, vaccination should be delayed for at least three months because of the likelihood of vaccine failure due to passively acquired varicella antibodies. 3) Usage of salicylates within 6 weeks of vaccination should be avoided. 4) When administering with other live attenuated vaccines, should be administered either on the same day or at an interval of at least a month apart. 4.6 Pregnancy and lactation The possible effects of the vaccine on fetal development are unknown at this time. However, wild-type varicella is known to sometimes cause fetal harm. If vaccination of women in reproductive age is undertaken, pregnancy should be avoided for three months following vaccination. It is not known whether the vaccine is excreted in human milk. Cautions should be paid to women in lactation period. 4.7 Effects on ability to drive and use machines It is not known whether the vaccine may affect the ability to drive and use machines, cautions should be paid. 4.8 Undesirable effects Common adverse reactions (>10%): 3

4 1) Redness, swelling, pain, itching etc. at the site of injection within 24 hours following the injection may be found, which could generally be relieved spontaneously within 2 or 3 days. 2) Temporal fever reaction may be found within 1 to 3 weeks after inoculation. It is mostly slight (ranging between 37.1~37.5 C) and can be relieved spontaneously after one or two days. No specific treatment is necessary. If necessary, rest and increase in fluid intake may prevent secondary infection. For moderate fever (ranging between 37.6~39.0 C) or fever lasting for more than 48 hours, physical treatment or medication can be taken when necessary. 3) Interspersed rash or blebs may appear to few recipients probably within two weeks after injection. No special treatment is necessary. Symptomatic treatment could be helpful in case of need. Rare adverse reactions (>1% and <10%): Serious fever (body temperature above 39 C): Physical treatment or medication is needed to avoid febrile seizures. Very rare adverse reactions (<1%): 1) Allergic skin rash: Urticaria allergic reaction may appear to several individuals within 72 hours after inoculation, and at this time immediate anti-allergic therapy should be given. 2) Allergic purpura: It may appear to very rare individuals. Timely therapy should be given properly with Cortico-Steroids drug. Improper therapy may induce purpura nephritis. 3) Occasional thrombocytopenic purpura may appear to several recipients. Adverse Drug Reactions reported from Clinical Trial A multicentric Phase III clinical trial was conducted in India involving a total of 268 healthy children between the age of 12 months to 12 years. The data presented below is based on the 128 children who received BIOVAC-V in the study. Majority of the subjects presented with pain at the vaccination site within 48 hours post vaccination. Overall, the incidence of systemic AEs within 48 hr was very low and all were mild in nature and lasting for one to five days without any sequel. 4

5 4.9 Overdose Not known. 5. Pharmacological properties 5.1 Pharmacodynamic properties No information available. 5.2 Pharmacokinetic properties No information available. 5.3 Preclinical safety data Hypersensitivity test Standard method of hypersensitivity test The method refers to injecting appropriate doses of test solution into the abdominal cavity and vein of a Guinea pig. Then to observe the allergy action of the animals in the stipulated time to judge whether the test solution complies with the stipulation or not. Test animal:healthy Guinea pigs, male or female, 250~350 g, feed normally before and during the test. Those animals who experienced the test can not be use repeatedly. Test method: Get six Guinea pigs, intraperitoneally inject 0.5ml of test solution every other day for continuously three times. Then divide the 6 Guinea pigs into two equal groups, inject 1.0ml of test solution at the 14 th and 21 st day after the first injection. Result judgment: No allergic reaction happens within 15 minutes after injection. If more than 2 kinds of such allergy symptoms like hair-erection, sneezing, vomiturition, continuous coughing and atemnot or one kind of allergy symptoms like convulsing, shocking or death happen to the animals, the result is defined as positive. B. Test material 1. Varicella vaccine(live), Freeze-dried (Contain 1.0% of Human serum albumin) % of Human serum albumin solution (Diluted by physiological saline) 3. Lyophilized protective agent (Not containing Human serum albumin) 4. Liquid Varicella vaccine(not containing Human serum albumin) solution (Diluted by WFI) C. Test and Results According to standard testing method, to sensitize each Guinea pigs by intraperitoneally injecting 0.5ml of test solution every other day for continuously three times. Then 5

6 intravenously inject 1.0ml of test solution on the 14 th and 21 st day after first sensitization and observe the allergic action of the animals. Different test solutions were intravenously injected to the Guinea pigs which were sensitized by Varicella Vaccine, Live. The reaction of the Guinea pigs are listed below: Sensitization Samples Reaction sensitized Guinea pigs of Intravenously samples attack Reaction Guinea pigs 14 th day of 21 s t day Varicella vaccine(live), Freeze-dried 199 solution 1.0% of Human serum albumin solution % of Human serum albumin solution Liquid Varicella vaccine(live), Freeze-dried (Not containing Human serum albumin) Lyophilized protective agent Lyophilized protective agent (Not containing Human serum albumin) Liquid Varicella vaccine(live), Freeze-dried (Not containing Human serum albumin) Varicella vaccine(live), Freeze-dried (Contain 1.0% of Human serum albumin) 1.0% of Human serum albumin solution Liquid Varicella vaccine(not containing Human serum albumin) Lyophilized protective agent

7 (Not containing Human serumalbumin) (Not containing Human serum albumin) The test results showed that the sensitized Guinea pigs have no allergic reactions to Lyophilized protective agent (Not containing Human serum albumin) and Liquid Varicella vaccine (Not containing Human serum albumin); Allergy reaction of guinea pigs is caused by human serum albumin. Because Human serum albumin is a kind of foreign protein to guinea pigs, but it has homoeology to human. And most of the vaccines (such as Measles and Hepatitis A vaccines etc.)include 1.0% of human serum albumin as protective agent. As a result, the Varicella vaccine(live), Freeze-dried can be treated as not allergic to human bodies. Clinical Studies in India for Evaluation of Clinical Immunogenicity BIOVAC-V was evaluated in children between 12 months to 12year of age in a study conducted in China. The subjects were further subdivided in age 1 to 5 years and 6 to12 years. After being immunized with the vaccines, the sub-group aged between 1 and 5 gained antibody seroconversion rate as 99.04% and the other sub-group aged between 6 and 12 acquired the 100%. Phase III multicentric study conducted in India involving children between aged 12 months - 12 years, the seroconversion rate, when measured by ELISA after vaccination, was 98.3% after one vaccine dose. A significant increase in the Geometric Mean Titer (GMT ) of anti Varicella Zoster Vaccine IgG antibodies, a good immunogenicity of the vaccine, was seen from baseline after a single dose across all age groups. The age wise distribution of the GMT is as follows: months was (95% CI: ), months was (95% CI: ) and > 60 months was (95% CI: ). In a randomized, double-blind, non-inferiority, phase III clinical trial conducted in China involving 930 subjects, > 13 years of age, BIOVAC-V was evaluated in 620 healthy subjects compared to 310 healthy subjects receiving an already approved international control vaccine. Both the vaccines were administered in a 2 dose schedule, 4-6 weeks apart. Immunogenicity was estimated after 6 weeks of administering the second dose using Fluorescent Antibody to Membrane Antigen (FAMA) test. A higher seroconversion rate was found in subjects of BIOVAC-V group than the control group (95.22% vs 84.56%, P<0.0001) and the superiority was maintained even when subjects were analysed based on age-wise stratification (13-16 years: 95% vs 81.56%, p< and > 17 years: 95.44% vs 87.50%, p=0.0027). Subjects achieving FAMA titers of > 1:128 were also higher in BIOVAC-V group as compared to control group (95.50% vs 84.56%; p<0.001). 7

8 6. Pharmaceutical particulars 6.1 List of excipients Excipients are listed as following: Number Name Fucose Sorbierite L-arginine Sodium glutamate Dextran 6.2 Incompatibilities Not known. 6.3 Shelf life Validity period: 24 months. Shelf life after dilution or reconstitution: The reconstituted vaccine should be used within 30 minutes; otherwise, it shall be discarded. Shelf life after first opening the container: According to practice use, the SWFI should be used as soon as it is opened. 6.4 Special precautions for storage Stored and transported at 2 C- 8 C, protected from light. 6.5 Nature and contents of container Vaccine: 1ml of Vial (butyl rubber) Sterile Water for injection: 0.5ml of pre-filled syringe 6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product The vaccine must be administrated by a professional health care personnel or Doctor. The vaccine should not be inoculated with the same syringe for other vaccines. The vaccine must under no circumstances be administrated intravascularly. 7. Marketing authorization holder Changchun Changsheng Life Sciences Ltd. No.1615 Yueda Road, Changchun, China 8. Marketing authorization number GYZZS Date of first authorization/renewal of the authorization No information available. 8

9 10. Date of revision of the text No information available. 9