Hexaxim (DTaP-IPV-HB-Hib) is indicated for primary and booster vaccination of infants and toddlers from six weeks of age against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive diseases caused by Haemophilus influenzae type b (Hib).
The use of this vaccine should be in accordance with official recommendations.

Posology
Primary vaccination:
The primary vaccination consists of two doses (with an interval of at least 8 weeks) or three doses (with an interval of at least 4 weeks) in accordance with the official recommendations.
All vaccination schedules including the WHO Expanded Program on Immunisation (EPI) at 6, 10, 14 weeks of age can be used whether or not a dose of hepatitis B vaccine has been given at birth.
Where a dose of hepatitis B vaccine is given at birth, Hexaxim can be used for supplementary doses of hepatitis B vaccine from the age of six weeks. If a second dose of hepatitis B vaccine is required before this age, monovalent hepatitis B vaccine should be used.
When a dose of hepatitis B vaccine is given at birth, the sequential infant primary vaccination hexavalent/pentavalent/hexavalent schedule with Hexaxim and a pentavalent DTaP-IPV/Hib vaccine can be used in accordance with official recommendations.
Booster vaccination:
After a 2-dose primary vaccination with Hexaxim, a booster dose must be given. After a 3-dose primary vaccination with Hexaxim, a booster dose should be given.
Booster doses should be given at least 6 months after the last priming dose and in accordance with the official recommendations. At the very least, a dose of Hib vaccine must be administered.
In addition:
In the absence of hepatitis B vaccination at birth, it is necessary to give a hepatitis B vaccine booster dose. Hexaxim can be considered for the booster.
After a 3-dose WHO EPI schedule with Hexaxim (6, 10, 14 weeks) and in the absence of hepatitis B vaccination at birth, a hepatitis B vaccine booster must be given. At the very least, a booster dose of polio vaccine should be given. Hexaxim can be considered for the booster.
When a hepatitis B vaccine is given at birth, after a 3-dose primary vaccination, Hexaxim or a pentavalent DTaP-IPV/Hib vaccine can be administered for the booster.
Hexaxim may be used as a booster in individuals who have previously been vaccinated with another hexavalent vaccine or a pentavalent DTaP-IPV/Hib vaccine associated with a monovalent hepatitis B vaccine.
Other paediatric population
The safety and efficacy of Hexaxim in infants less than 6 weeks of age have not been established. No data are available

No data are available in older children (see sections 4.8 and 5.1).

Method of administration
Immunisation must be carried out by intramuscular (IM) injection. The recommended injection site is preferably the antero-lateral area of the upper thigh and the deltoid muscle in older children (possibly from 15 months of age).
For instructions on handling see section 6.6.

Hexaxim will not prevent disease caused by pathogens other than Corynebacterium diphtheriae,
Clostridium tetani, Bordetella pertussis, hepatitis B virus, poliovirus or Haemophilus influenzae
type b. However, it can be expected that hepatitis D will be prevented by immunisation as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.
Hexaxim will not protect against hepatitis infection caused by other agents such as hepatitis A, hepatitis C and hepatitis E or by other liver pathogens.
Because of the long incubation period of hepatitis B, it is possible for unrecognised hepatitis B infection to be present at the time of vaccination. The vaccine may not prevent hepatitis B infection in such cases.
Hexaxim does not protect against infectious diseases caused by other types of Haemophilus influenzae or against meningitis of other origins.
Prior to immunisation
Immunisation should be postponed in individuals suffering from moderate to severe acute febrile illness or infection. The presence of a minor infection and/or low-grade fever should not result in the deferral of vaccination.
Vaccination should be preceded by a review of the person’s medical history (in particular previous vaccinations and possible adverse reactions). The administration of Hexaxim must be carefully

considered in individuals who have a history of serious or severe reactions within 48 hours following administration of a vaccine containing similar components.
Before the injection of any biological, the person responsible for administration must take all precautions known for the prevention of allergic or any other reactions. As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic reaction following administration of the vaccine.
If any of the following events are known to have occurred after receiving any pertussis containing vaccine, the decision to give further doses of pertussis containing vaccine should be carefully considered:
• Temperature of ≥ 40°C within 48 hours not due to another identifiable cause;
• Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours of vaccination;
• Persistent, inconsolable crying lasting ≥ 3 hours, occurring within 48 hours of vaccination;
• Convulsions with or without fever, occurring within 3 days of vaccination.
There may be some circumstances, such as high incidence of pertussis, when the potential benefits outweigh possible risks.
A history of febrile convulsions, a family history of convulsions or Sudden Infant Death Syndrome (SIDS) do not constitute a contraindication for the use of Hexaxim. Individuals with a history of febrile convulsions should be closely followed up as such adverse events may occur within 2 to 3 days post vaccination.
If Guillain-Barré syndrome or brachial neuritis has occurred following receipt of prior vaccine containing tetanus toxoid, the decision to give any vaccine containing tetanus toxoid should be based on careful consideration of the potential benefits and possible risks, such as whether or not the primary vaccination has been completed. Vaccination is usually justified for individuals whose primary vaccination is incomplete (i.e. fewer than three doses have been received).
The immunogenicity of the vaccine may be reduced by immunosuppressive treatment or immunodeficiency. It is recommended to postpone vaccination until the end of such treatment or disease. Nevertheless, vaccination of individuals with chronic immunodeficiency such as HIV infection is recommended even if the antibody response may be limited.
Special populations
No data are available for premature infants. However, a lower immune response may be observed and the level of clinical protection is unknown.
Immune responses to the vaccine have not been studied in the context of genetic polymorphism.
In individuals with chronic renal failure, an impaired hepatitis B response is observed and administration of additional doses of hepatitis B vaccine should be considered according to the antibody level against hepatitis B virus surface antigen (anti-HBsAg).
Precautions for use
Do not administer by intravascular, intradermal or subcutaneous injection.
As with all injectable vaccines, the vaccine must be administered with caution to individuals with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration.

The potential risk of apnoea and the need for respiratory monitoring for 48 to 72 hours should be considered when administering the primary immunisation series to very premature infants (born ≤ 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed.
Interference with laboratory testing
Since the Hib capsular polysaccharide antigen is excreted in the urine, a positive urine test can be observed within 1 to 2 weeks following vaccination. Other tests should be performed in order to confirm Hib infection during this period.

Data on concomitant administration of Hexaxim with a pneumococcal polysaccharide conjugate vaccine have shown no clinically relevant interference in the antibody response to each of the antigens.
Data on concomitant administration of a booster dose of Hexaxim with measles-mumps-rubella vaccines have shown no clinically relevant interference in the antibody response to each of the antigens. There may be a clinically relevant interference in the antibody response of Hexaxim and a varicella vaccine and these vaccines should not be administered at the same time.
Data on concomitant administration of rotavirus vaccines have shown no clinically relevant interference in the antibody response to each of the antigens.
Data on concomitant administration of Hexaxim with a meningococcal C conjugate vaccine or a meningococcal group A, C, W-135 and Y conjugate vaccine have shown no clinically relevant interference in the antibody response to each of the antigens.
If co-administration with another vaccine is considered, immunisation should be carried out on separate injections sites.
Hexaxim must not be mixed with any other vaccines or other parenterally administered medicinal products.
No significant clinical interaction with other treatments or biological products has been reported except in the case of immunosuppressive therapy (see section 4.4).
Interference with laboratory testing: see section 4.4.

Not applicable. This vaccine is not intended for administration to women of child-bearing age.

Not applicable.

a- Summary of the safety profile
In clinical studies in individuals who received Hexaxim, the most frequently reported reactions include injection-site pain, irritability, crying, and injection-site erythema.
Slightly higher solicited reactogenicity was observed after the first dose compared to subsequent doses.

The safety of Hexaxim in children over 24 months of age has not been studied in clinical trials.
b- Tabulated list of adverse reactions
The following convention has been used for the classification of adverse reactions; 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 available data)

Table 1: Adverse Reactions from clinical trials and reported during commercial use

c- Description of selected adverse reactions
Extensive limb swelling: Large injection-site reactions (>50 mm), including extensive limb swelling from the injection site beyond one or both joints, have been reported in children. These reactions start within 24-72 hours after vaccination, may be associated with erythema, warmth, tenderness or pain at the injection site and resolve spontaneously within 3-5 days. The risk appears to be dependent on the number of prior doses of acellular pertussis containing vaccine, with a greater risk following the 4th and 5th doses.
d- Potential adverse events (i.e. adverse events which have been reported with other vaccines containing one or more of the components or constituents of Hexaxim and not directly with Hexaxim)
Nervous system disorders
- Brachial neuritis and Guillain-Barré Syndrome have been reported after administration of a tetanus toxoid containing vaccine

- Peripheral neuropathy (polyradiculoneuritis, facial paralysis), optic neuritis, central nervous system demyelination (multiple sclerosis) have been reported after administration of a hepatitis B antigen containing vaccine
- Encephalopathy/encephalitis
Respiratory, thoracic and mediastinal disorders
Apnoea in very premature infants (≤ 28 weeks of gestation) (see section 4.4)
General disorders and administration site conditions
Oedematous reaction affecting one or both lower limbs may occur following vaccination with Haemophilus influenzae type b containing vaccines. If this reaction occurs, it is mainly after primary injections and within the first few hours following vaccination. Associated symptoms may include cyanosis, redness, transient purpura and severe crying. All events should resolve spontaneously without sequel within 24 hours.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
To reports any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Other GCC States:
- Please contact the relevant competent authority.

No cases of overdose have been reported.

Pharmaco-therapeutic group: Vaccines, Bacterial and viral vaccines combined, ATC code: J07CA09
The immunogenicity of Hexaxim in children over 24 months of age has not been studied in clinical trials.
Results obtained for each of the components are summarised in the tables below:

Immune responses to Hib and pertussis antigens after 2 doses at 2 and 4 months of age
The immune responses to Hib (PRP) and pertussis antigens (PT and FHA) were evaluated after 2 doses in a subset of subjects receiving Hexaxim (N=148) at 2, 4, 6 months of age. The immune responses to PRP, PT and FHA antigens one month after 2 doses given at 2 and 4 months of age were similar to those observed one month after a 2-dose priming given at 3 and 5 months of age: anti-PRP titers ≥ 0.15 μg/ml were observed in 73.0% of individuals, anti-PT vaccine response in 97.9% of individuals and anti-FHA vaccine response in 98.6% of individuals.
Persistence of immune response
Studies on long-term persistence of vaccine induced antibodies following varying infant / toddler primary series and following Hepatitis B vaccine given at birth or not have shown maintenance of levels above the recognized protective levels or antibody thresholds for the vaccine antigens
(see Table 3).
In addition, immunity against the hepatitis B component of the vaccine has been shown to persist up to 9 years of age after a primary series consisting of one dose of Hepatitis B vaccine given at birth followed by a 3-dose infant series at 2, 4, and 6 months of age without a toddler booster where 49.3% of vaccinees had antibodies ≥ 10 mIU/ml with geometric mean concentrations at 13.3 (95% CI: 8.82 – 20.0) mIU/ml. Immune memory against Hepatitis B had been demonstrated by the presence of an anamnestic response to a challenge Hepatitis B vaccination at the age of 9 years in 93% of vaccinees with development of geometric mean concentrations at 3692 (95% CI: 1886 – 7225) mIU/ml after vaccination.

Efficacy and effectiveness in protecting against pertussis
Vaccine efficacy of the acellular pertussis (aP) antigens contained in Hexaxim against the most severe WHO-defined typical pertussis (≥ 21 days of paroxysmal cough) is documented in a randomised double-blind study among infants with a 3 dose primary series using a DTaP vaccine in a highly endemic country (Senegal). The need for a toddler booster dose was seen in this study.
The long term capability of the acellular pertussis (aP) antigens contained in Hexaxim to reduce pertussis incidence and control pertussis disease in the childhood has been demonstrated in a 10-year national pertussis surveillance on pertussis disease in Sweden with the pentavalent DTaP-IPV/Hib vaccine using a 3, 5, 12 months schedule. Results of long term follow-up demonstrated a dramatic reduction of the pertussis incidence following the second dose regardless of the vaccine used.

Effectiveness in protecting against Hib invasive disease
The vaccine effectiveness against Hib invasive disease of DTaP and Hib combination vaccines (pentavalent and hexavalent including vaccines containing the Hib antigen from Hexaxim) has been demonstrated in Germany via an extensive (over five years follow-up period) post-marketing surveillance study. The vaccine effectiveness was of 96.7% for the full primary series, and 98.5% for booster dose (irrespective of priming).

No pharmacokinetic studies have been performed.

Non-clinical data reveal no special hazard for humans based on conventional repeat dose toxicity and local tolerance studies.
At the injection sites, chronic histological inflammatory changes were observed, that are expected to have a slow recovery.

Disodium hydrogen phosphate 1.528 mg
Potassium dihydrogen phosphate 1.552 mg
Trometamol 0.1515mg
Saccharose 10.625mg
Essential amino acids including L-phenylalanine 1.115mg
Water for injections. Up to 0.5mL
Sodium hydroxide, acetic acid or hydrochloric acid (for pH adjustment). These components are only present in trace amount.
per Human Dose of 0.5 mL
For adsorbent: see section 2.

In the absence of compatibility studies, this vaccine must not be mixed with other vaccines or medicinal products.

Store in a refrigerator (2°C – 8°C). Do not freeze.
Keep the container in the outer carton in order to protect from light.
Stability data indicate that the vaccine components are stable at temperatures up to 25°C for 72 hours. At the end of this period, Hexaxim should be used or discarded. These data are intended to guide healthcare professionals in case of temporary temperature excursion only.

0.5 ml suspension in pre-filled syringe (type I glass) with plunger stopper (halobutyl) and tip cap (halobutyl), with 2 separate needles.
Pack size of 1 or 10.
Not all pack sizes may be marketed.

Hexaxim in pre-filled syringes
Prior to administration, the pre-filled syringe should be shaken in order to obtain a homogeneous, whitish, cloudy suspension.
The suspension should be visually inspected prior to administration. In the event of any foreign particulate matter and/or variation of physical aspect being observed, discard the pre-filled syringe.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.