Rotavac 5D

ROTAVAC 5D is pinkish yellow colored sterile liquid oral use, may contain white suspended particles, in the final container of the product. Vigorous shaking/mixing, does not dissolve the particles.
Rotavirus Vaccine (Live Attenuated, Oral) is a monovalent vaccine containing suspension of live attenuated rotavirus 116E prepared in Vero cells. Rotaviruses are double-stranded RNA virus of the genus Reoviridae. Rotaviruses are classified in a dual classification system based on two proteins on the surface of the virus into G and P types. Based on this nomenclature, Rotavirus 116E is classified as G9P[11]. A single human dose of ROTAVAC 5D is 0.5 mL containing not less than [NLT] 10^5.0 FFU [Focus Forming Unit] of live rotavirus 116E.
Composition: Each dose of 0.5 mL contains: Vero cell derived Rotavirus 116E bulk, Live attenuated NLT 10^5.0 FFU, Neomycin Sulphate BP 15 μg, Kanamycin Acid Sulphate BP 15 μg, Sucrose BP 0.25 gms, Trehalose BP 2.5 mg, Lactalbumin Hydrolysate (LAH) 2.5 mg, Human Albumin BP 0.35%, Potassium Di-Hydrogen Orthophosphate BP 1.65 mg, Di-Potassium Hydrogen Orthophosphate BP 10 mg, Trisodium Citrate Dihydrate BP 7.75 mg, Water for Injections BP q.s.
pH range: 6.50 to 7.50.
Excipients/Inactive Ingredients: Neomycin Sulphate, Kanamycin Acid Sulphate, Sucrose, Trehalose, Lactalbumin Hydrolysate (LAH), Human Albumin, Potassium Di-Hydrogen Orthophosphate, Di-Potassium Hydrogen Orthophosphate, Trisodium Citrate Dihydrate.

Pharmacotherapeutic group: Rotavirus diarrhea vaccines. ATC code: J07BH01.
Pharmacology: Pharmacodynamics: Protective efficacy.
Efficacy: In total 12 clinical trials, approximately ~15000 subjects were vaccinated with different formulations of ROTAVAC vaccines consisting ORV116E as the active ingredient with a virus titer of NLT 10^5.0 FFU. These ORV116E strain containing ROTAVAC formulations (ROTAVAC, ROTAVAC 5C & ROTAVAC 5D) were tested for their Safety, Immunogenicity and Non-inferiority. The adverse reaction and immunogenicity profile observed in subjects administered with these three formulations were similar. ROTAVAC & ROTAVAC 5C formulations were tested for their Lot consistency and Non-interference with EPI vaccines and concluded that ROTAVAC formulations do not interfere with EPI vaccines and their manufacturing consistency was established. Since ROTAVAC 5D has also been evaluated for safety and immunogenicity in comparison to ROTAVAC while being co-administered with EPI vaccines, it is concluded that ROTAVAC 5D formulation is equally safe and immunogenic as ROTAVAC and ROTAVAC 5C. Efficacy, non-interference with EPI vaccines and manufacturing consistency of ROTAVAC and ROTAVAC 5C formulations can be extrapolated to ROTAVAC 5D formulation.
ROTAVAC (ORV 116E): A Multi-center clinical study was conducted in India to evaluate the efficacy of ROTAVAC to prevent severe rotaviral gastroenteritis. Data for vaccine efficacy has been presented for the first year and second year of life. The results of these two analyses were similar, suggesting that the vaccine efficacy persists into second year of life.
Vaccine efficacy (VE) for severe non-vaccine RVGE was 56.4% [95% CI 36.6, 70.1] and 34.6 [95% CI 19.7, 46.6] for non-vaccine RVGE of any severity, during the first year of life. In the same study, the VE against severe non-vaccine RVGE in the second year of life was 49% (95% CI 17.5, 68.4) and 35.0% [95% CI 19.1, 47.7] against non-vaccine RVGE of any severity. Non-vaccine RVGE requiring hospitalization and of any cause ROTAVAC prevented 47.7% (95% CI: 24.5, 63.8) of all hospitalization ≥24hrs due to severe non-ROTAVAC vaccine rotavirus gastroenteritis. ROTAVAC was also efficacious against severe GE of any etiology (VE=18.6% [95% CI 1.9, 32.3]).
EPI - noninterference study & Lot to Lot consistency: Post-vaccination, seroprotective level of antibodies against poliovirus type 1,2, and 3 were 98.2%, 99.4% and 92.4%, respectively, in infants receiving OPV along with ROTAVAC and 99%, 98.3% and 92.7%, respectively, in infants receiving OPV along with placebo. Difference in proportions between these groups was 0.8% (95% CI -1.1%, 2.2%) for type 1 strain, -1.2% (95% CI -3.3%, 0.2%) for type 2 strain and 0.3% (95% CI -3.5%, 3.6%) for type 3 strains of polio virus. Almost all infants, irrespective of the treatment group, developed protective antibody titre against diphtheria toxoid, tetanus toxoid and Hib (anti-PRP antibodies). Over 93% developed protective titre against HepB (anti-HBs antibodies).
The difference in proportion of infants who developed protective antibody titres was 0.5% (95% CI -1.3, 2.3) for diphtheria toxoid, 0.9% (95% CI -0.3, 2.4) for tetanus-toxoid, 2.2% (95% CI -1.7, 6.0) for anti-HBs antibodies and 0% (95% CI -1.3, 1.1) for anti-PRP antibodies. The ratio of GMCs between the placebo and ROTAVAC groups for pertussis toxin was 1.0 (95% CI: 0.8, 1.1).
The baseline and post 3^rd dose vaccination GMTs of IgA antibodies according to lot of ROTAVAC; Baseline GMT was similar across the three groups (2.7-2.8); post vaccination GMTs had a rise of 10.8 from 8.5.
ROTAVAC 5C (ORV 116E): There were no statistically significant differences in the pre- and post-vaccination IgA titers between the ROTAVAC 5C and ROTAVAC (mean baseline titer 22.3 and 24.2 U/mL respectively (p=0.84 comparing all arms); and post vaccination titer 59.1 and 76.0 U/mL, respectively (p=0.12)).
Seroconversion occurred by day 84 in 37.6% (95% CI: 31.1%, 44.2%) of the ROTAVAC 5C arm, and 41.3% (95% CI: 34.7%, 47.8%) of the ROTAVAC. There was no significant difference in seroconversion rates between the ROTAVAC and ROTAVAC 5C (p=0.489).
EPI - noninterference study & Lot to Lot Consistency: In the immunogenicity population, all three lots of ROTAVAC 5C were non-inferior to the ROTAVAC with the lower bound of the 95% confidence interval for the GMT ratio (ROTAVAC 5C/ROTAVAC) being greater than 0.5: Lot 1 GMT ratio 1.069 (95% CI 0.827 to 1.382; p<0.0001); Lot 2 GMT ratio 1.096 (95% CI 0.840 to 1.429; p<0.0001) and Lot 3 GMT ratio 1.129 (95% CI 0.867 to 1.471; p<0.0001). When all lots were combined, the GMT ratio was 1.097 (95% CI 0.888 to 1.357; p<0.0001).
There were no statistically significant differences in the pre- and post-vaccination IgA titers between the ROTAVAC 5C and ROTAVAC arms (mean baseline titer 24.0, 23.6, 21.5 and 28.5 for ROTAVAC 5C Lot 1, 2 and 3; and ROTAVAC, respectively; p=0.7275 ANOVA comparing the four arms).
There was no difference in the GMT titers between ROTAVAC 5C (all lots) and ROTAVAC -20°C for Bordetella pertussis, Diphtheria, Haemophilus influenzae type B, Hepatitis B or Tetanus (the lower limit for all was >0.50). There was no difference between lots for any of the vaccines. Thus, ROTAVAC 5C can be successfully co-administered with other childhood vaccines.
ROTAVAC 5D (ORV 116E): There were no statistically significant differences in the pre and post vaccination IgA titers between the ROTAVAC 5D and ROTAVAC (mean baseline titer 10.31 and 11.57 U/mL respectively (p=0.29 comparing all arms); and post vaccination titer 18.70 and 19.55 U/mL, respectively (p=0.77)).
Four-fold Seroconversion occurred by day 84 in 22.18% (95% CI: 17.01%, 27.35%) of the ROTAVAC 5D arm, and 21.25% (95% CI: 12.29%, 30.21%) of the ROTAVAC. There was no significant difference in seroconversion rates between the ROTAVAC and ROTAVAC 5D (p=0.86).
Post-marketing surveillance data: Post-marketing surveillance has been carried out for the Rotavirus 116E strain-based vaccine ROTAVAC and no significant safety signals of concern have been noted thus far.
Pharmacokinetics: Evaluation of pharmacokinetic properties is not required for vaccines.
Toxicology: Pre-clinical safety data: Repeated dose non-clinical toxicity study on oral rotavirus candidate vaccine 116E live strain was carried out in mice, rats and rabbits. These studies were initiated with 0.5 mL formulations and later on in continuation of developing formulations with buffer wherein the dose volume is 1.5 mL and 2.0 mL (ROTAVAC 5C) were subjected for pre-clinical toxicology studies. In both the cases, the excipients used were same except for concentration used. ROTAVAC 5D is having similar excipients as in ROTAVAC 5C but only difference is the concentration. Dose volume, concentration of buffer system and excipients were tested in animal model for toxicity and found to be safe. The pre-clinical safety data establish the safety of the vaccine for ROTAVAC 5D formulation.

For prophylactic use only.
ROTAVAC 5D is indicated for active immunization of infants from the age of 6 weeks for the prevention of gastroenteritis due to rotavirus infection when administered as a 3-dose regimen.

Posology: ROTAVAC 5D should be administered as a 3-dose regimen, 4 weeks apart, beginning at 6 weeks of age. ROTAVAC 5D may be co-administered with other routine childhood vaccination (i.e., Diphtheria, Tetanus and Pertussis [DTwP], Haemophilus Influenzae type B, Hepatitis B vaccine and Oral/injectable Polio Vaccine [OPV&IPV]). Based on recommendations from the World Health Organization (Rotavirus vaccines WHO Position Paper, January 2013 in Weekly Epidemiological Report No.5, 2013, 88, 49-64), if the routine childhood vaccination are initiated later than 6 weeks of age and/or at a longer dose interval than 4-weeks, ROTAVAC 5D can still be co-administered with DTaP & DTwP.
It is recommended that infants who receive ROTAVAC 5D as the first dose should complete the 3-dose regimen with ROTAVAC 5D. There is no data on safety, immunogenicity or efficacy when ROTAVAC 5D is administered interchangeably with other rotavirus vaccines.
Pediatric Population: The upper age limit for the 3-dose primary schedule of Rotavirus vaccine should be administered to children by the age of 8 months (34 weeks) (Centre for Disease Control and Prevention, http://www.cdc.gov/vaccines/vpd-vac/rotavirus/vac-faqs.htm).
In case of interrupted primary series, resume vaccination without repeating previous dose (1). According to the WHO recommendation, rotavirus immunisation is permitted up to 24 months of age (2,3).
Method of administration: ROTAVAC 5D is for oral use only and SHOULD NOT BE INJECTED. Care should be taken not to contaminate the multi-dose dropper of the vaccine with saliva of the babies. Once opened, multi-dose vials should be kept at +2°C and +8°C.
In case, an incomplete dose is administered (the baby spits up or regurgitates most of the vaccine), it is not recommended to administer a single replacement dose at the same vaccination visit. The baby may continue to receive the remaining doses as per schedule. However, in clinical trials, the reported incidence of spitting or vomiting is <0.5%.
*Physician's discretion is advised.
Multi-dose vials of ROTAVAC 5D from which one or more doses of vaccine have been removed during an immunization session may be used in subsequent immunization sessions for up to a maximum of 28 days after opening, provided that all of the following conditions are met (as described in the WHO Policy Statement: Multi-Dose Vial Policy (MDVP) Revision 2014 WHO/IVB/14.07).
Once opened, multi-dose vials should be kept between +2°C and +8°C.
The Vaccine is currently pre-qualified by WHO.
The vaccine is approved for use for up to 28 days after opening of the vial, as determined by WHO (http://www.who.int/immunization_standards/vaccine_quality/PQ_vaccine_list_en/en/).
The expiry date of the vaccine has not passed.
The vaccine vial has been, and will continue to be, stored at the recommended temperature; furthermore, the vaccine vial monitor is visible on the vaccine label and is not past its discard point, and the vaccine has not been damaged by freezing.

No case of overdose has been reported.

Hypersensitivity to any component of the vaccine. Babies who develop symptoms suggestive of hypersensitivity after receiving a dose of ROTAVAC 5D should not receive further doses of ROTAVAC 5D.
Babies with Severe Combined Immunodeficiency Disease (SCID). Cases of gastroenteritis associated with live rotavirus vaccines have been reported in infants with SCID.
History of intussusception (IS)/intestinal malformations predisposing to intussusception.
Ongoing Gastroenteritis.

No safety or efficacy data are available from clinical trials regarding the administration of ROTAVAC 5D to immune-compromised infants, infants infected with HIV or infants with chronic gastroenteritis. Administration of ROTAVAC 5D may be considered with caution in immune-compromised infants and infants in close contact with immune-deficient persons, if in the opinion of the physician, withholding the vaccine entails a greater risk. Similarly, acute infection or febrile illness may be reason for delaying the administration of ROTAVAC 5D, unless in the opinion of the physician, withholding the vaccine entails a greater risk. Low-grade fever and mild upper respiratory tract infection are not contraindications to ROTAVAC 5D.
Available published data shows a small increased incidence of Intussusception (IS) following the first dose of Rotavirus vaccines (WHO position paper, January 2013, http://www.who.int/wer/2013/wer8805.pdf?ua=1). However, the safety data from the clinical trials of ROTAVAC 5D did not show an increased risk or incidence of IS. Yet, it is advised to healthcare providers to look into any symptoms suggestive of IS e.g., continuous vomiting, blood in stools and abdominal lump or distension of the abdomen. Parents/caregivers should be advised promptly to inform such symptoms to healthcare providers.
Similar to other vaccines, vaccination with ROTAVAC 5D may not result in complete protection against rotavirus induced gastroenteritis or gastroenteritis due to other pathogens.
There is no data to support use of ROTAVAC 5D for post exposure-prophylaxis.
*ROTAVAC 5D should not be injected at any circumstances.
Effect on ability to drive and use machines: Not applicable.

ROTAVAC 5D is a pediatric vaccine and should not be administered to adults including pregnant women. Breast-feeding of infants was permitted in clinical studies. There was no evidence to suggest that breast-feeding reduced the protection against rotavirus gastroenteritis conferred by ROTAVAC 5D. There are no restrictions on the infant's liquid consumption including breast-milk, either before or after vaccination with ROTAVAC 5D.

Clinical Trial Experience: The most commonly observed Adverse Events during the clinical trial were Fever, Diarrhea, Cough and others like running nose and irritability. No vaccine related SAEs were reported. There was no vaccine related case of intussusception observed/reported. Fever could be due the concomitant injectable vaccines.
List of adverse reactions: Adverse reactions reported are listed according to the following frequency.
Frequency is defined as: Very common: (≥1/10), Common: (≥1/100, <1/10), Uncommon: (≥1/1000, <1/100), Rare: (≥1/10000, <1/1000).
Clinical Trial Data: Very common: Fever, Cough, Crying.
Common: Diarrhea.

In this clinical trial, OPV, IPV and Pentavalent (DTwP, HepB and Hib) vaccines were administered concurrently with ROTAVAC 5D. Three doses of ROTAVAC 5D can be safely administered with three doses of pentavalent vaccine and three doses of OPV as well as IPV without diminishing the antibody response to each component of these vaccines. It is well tolerated when administered concomitantly with routine childhood vaccines.

Incompatibilities: This product should not be mixed in same dropper/syringe with any other medicinal products/active immunizing agents.
The Vaccine Vial Monitor7 (VVM7): Vaccine Vial Monitor7 (VVM7) dot is a part of the label on ROTAVAC 5D vials. This is a time-temperature sensitive dot that provides an indication of the cumulative heat to which the vial has been exposed. It warns the end user when exposure to heat is likely to have degraded the vaccine beyond an acceptable level.
Vaccine Vial Monitors: USE: Square is lighter than outer circle.
The color of the inner square of the VVMs begins with a shade that is lighter than the outer circle and continues to darken with time and/or exposure to heat.
DO NOT USE: Square matches circle.
Square is darker than circle.
Once a vaccine has reached or exceeded the discard point, the colour of the inner square will be the same colour or darker than the outer circle.
Inform the supervisor.
Cumulative heat exposure over time.
The interpretation of VVM7 is simple. Focus on the central square. Its colour will change progressively. As long as the colour of this square is lighter than the colour of the ring, the vaccine can be used. As soon as the colour of the central square is the same colour as the ring or of a darker colour than the ring, the vial should be discarded.
Administration of Rotavac 5D Vaccine: 1. Vaccine Vial & Dropper(s).
2. Pull out the aluminum seal along the indicated mark.
3. Tear off to remove aluminum seal.
4. Vaccine Vial without aluminum seal.
5. Pull out the Rubber Stopper.
6. Connect the dropper firmly to the Vial.
7. Open the Dropper cap.
8. Position Dropper at 45° angle. Administer 5 drops into the mouth of the baby.
0.5 mL=5 Drops*.
*The dropper should not touch the mouth of the baby.
10. Once opened, the multidose vial should be stored at +2°C to +8°C used within 28 days.

Special precautions for storage: The vaccine should be stored at +2°C to +8°C. Do not freeze.
Do not use the vaccine after the expiration date shown on the label.

Vaccines, Antisera & Immunologicals

J07BH01 - rota virus, live attenuated ; Belongs to the class of rota virus diarrhea viral vaccines.

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