Infanrix-IPV+Hib, powder and suspension for suspension for injection

4.1 Therapeutic indications INFANRIX-IPV+Hib is indicated for active immunisation against diphtheria, tetanus, pertussis, poliomyelitis and *Haemophilus influenzae* type b disease from the age of 2 months.4.2 Posology and method of administration Posology *Primary vaccination:* The primary vaccination schedule consists of two or three doses given in accordance with official recommendations. The minimum age at the time of the first dose is 2 months. Subsequent doses of the primary course should be separated by a minimum interval of four weeks. *Booster vaccination:* After primary vaccination with two doses, a booster dose of INFANRIX-IPV+Hib must be given at least 6 months after the last priming dose, preferably between 11 and 13 months of age. After primary vaccination with three doses, a booster dose of Hib conjugate vaccine (monovalent or combined) must be administered. The timing of this Hib conjugate vaccine booster dose should be in accordance with official recommendations. INFANRIX-IPV+Hib may be used for this booster dose if administration of the additional antigens at the same time is in accordance with official recommendations. INFANRIX-IPV+Hib may be used as a booster dose for children who have previously been immunised with other vaccines that contain DTP, polio and Hib antigens. *Paediatric population:* The safety and efficacy of INFANRIX-IPV+Hib in children over 3 years of age have not been established. No data are available. Method of administration INFANRIX-IPV+Hib is for deep intramuscular injection, in the anterolateral aspect of the thigh. It is preferable that each subsequent dose is given into alternating limbs. INFANRIX-IPV+Hib should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects. Firm pressure should be applied to the injection site (without rubbing) for at least two minutes. INFANRIX-IPV+Hib should under no circumstances be administered intravascularly. For instructions on reconstitution of the medicinal product before administration, see section 6.6.4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or formaldehyde, neomycin or polymyxin. Hypersensitivity after previous administration of diphtheria, tetanus, pertussis, polio or Hib vaccines. INFANRIX-IPV+Hib is contra-indicated if the child has experienced an encephalopathy of unknown aetiology, occurring within 7 days following previous vaccination with pertussis containing vaccine. As with other vaccines, the administration of INFANRIX-IPV+Hib should be postponed in subjects suffering from an acute severe febrile illness. The presence of a minor infection, however, is not a contraindication.4.4 Special warnings and precautions for use As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine. If any of the following events have occurred in temporal relation to receipt of any DTP-containing vaccine, the decision to give subsequent doses of vaccine containing a pertussis component should be carefully considered. • Temperature of ≥ 40.0 °C (rectal) 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 circumstances, such as a high incidence of pertussis, when the potential benefits outweigh possible risks, particularly since the events are not associated with permanent sequelae. According to available clinical data, the risk of such reactions is lower with acellular pertussis vaccines than with whole cell pertussis vaccines. As for any vaccination, the risk-benefit of immunising with INFANRIX-IPV+Hib or deferring this vaccination should be weighed carefully in an infant or in a child suffering from a new onset or progression of a severe neurological disorder. The Hib component of the vaccine does not protect against diseases due to other types of *Haemophilus influenzae* nor against meningitis caused by other organisms. A history of febrile convulsions, a family history of convulsions, a family history of Sudden Infant Death Syndrome (SIDS) and a family history of an adverse event following DTP, IPV and/or Hib vaccination do not constitute contra-indications to administration of INFANRIX-IPV+Hib. Human Immunodeficiency Virus (HIV) infection is not considered to be a contraindication to administration of INFANRIX-IPV+Hib. The expected immunological response may not be obtained after vaccination of immunosuppressed patients, e.g. patients on immunosuppressive therapy. Excretion of capsular polysaccharide antigen in the urine has been described following receipt of Hib vaccines. Therefore false positive antigen detection test results are possible within 1-2 weeks of vaccination. Administration of INFANRIX-IPV+Hib should be recorded in the patient's International Vaccination Certificate. The potential risk of apnoea and the need for respiratory monitoring for 48-72h 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 the vaccination is high in this group of infants, vaccination should not be withheld or delayed. Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. It is important that procedures are in place to avoid injury from faints. Excipients with known effect INFANRIX-IPV+Hib contains para-aminobenzoic acid. It may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm. The vaccine contains 0.036 microgram phenylalanine in each dose. Phenylalanine may be harmful if you have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly. The vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'. The vaccine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially 'potassium-free'. Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.4.5 Interaction with other medicinal products and other forms of interaction If INFANRIX-IPV+Hib is to be given at the same time as another injectable vaccine(s), the vaccines should always be administered at different injection sites. As with other vaccines it may be expected that, in patients receiving immunosuppressive therapy or patients with immunodeficiency, an adequate response may not be achieved.4.6 Fertility, pregnancy and lactation As INFANRIX-IPV+Hib is not intended for use in adults, information on the safety of the vaccine when used during pregnancy or lactation is not available.4.7 Effects on ability to drive and use machines Not relevant.4.8 Undesirable effects

• *Clinical trials* Summary of the safety profile The safety profile presented below is based on data from more than 3500 subjects. As has been observed for DTPa and DTPa-containing combinations, an increase in local reactogenicity and fever was reported after booster vaccination with INFANRIX-IPV+Hib with respect to the primary course. List of adverse reactions Frequencies per dose are defined as follows: | | | | --- | --- | | Very common: Common: Uncommon: Rare: Very rare: | (≥1/10) (≥ 1/100 to < 1/10) (≥ 1/1,000 to < 1/100) (≥ 1/10,000 to < 1/1,000) (< 1/10,000) | Infections and infestations Uncommon: upper respiratory tract infection Blood and lymphatic system disorders Uncommon: lymphadenopathy Metabolism and nutrition disorders Very common: appetite lost Psychiatric disorders: Very common: crying abnormal, irritability, restlessness Nervous system disorders Very common: somnolence Respiratory, thoracic and mediastinal disorders Uncommon: bronchitis, cough, rhinorrhoea Gastrointestinal disorders Common: diarrhoea, vomiting Skin and subcutaneous tissue disorders Uncommon: urticaria, rash Rare: pruritus, dermatitis General disorders and administration site conditions Very common: fever (≥38.0°C), injection site reactions such as pain and redness, local swelling at the injection site (≤50 mm) Common: injection site reactions including induration, local swelling at the injection site (>50 mm)1 Uncommon: diffuse swelling of the injected limb, sometimes involving the adjacent joint1, fever2>39.5°C, fatigue *- Post-marketing surveillance* Immune system disorders Allergic reactions (including anaphylactic3 and anaphylactoid reactions) Nervous system disorders: Collapse or shock-like state (hypotonic-hyporesponsiveness episode), convulsions (with or without fever) Respiratory, thoracic and mediastinal disorders: Apnoea 3[see 4.4 for apnoea in very premature infants (≤ 28 weeks of gestation)] Skin and subcutaneous tissue disorders: Angioneurotic oedema3 General disorders and administration site conditions: Swelling of the entire injected limb1, injection site vesicles3 1Children primed with acellular pertussis vaccines are more likely to experience swelling reactions after booster administration in comparison with children primed with whole cell vaccines. These reactions resolve over an average of 4 days. 2common with booster vaccination 3reported with GSK's DTPa containing vaccines 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose Some cases of overdose have been reported during post-marketing surveillance. Adverse events, when reported following overdosage, were similar to those observed after administration of the recommended dose of INFANRIX-IPV+Hib.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Bacterial and viral vaccines combined, ATC code: J07CA06 Results obtained in the clinical studies for each of the components are summarised in the tables below: **Percentage of subjects with antibody titres ≥ assay cut-off after primary vaccination with INFANRIX-IPV+Hib:** | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | **Antibody** **(cut-off)** | **3-5 months** **N= 86** **(1 trial)** **%** | **1.5-3.5-6 months** **N= 62** **( 1 trial) %** | **2-3-4 months** **N= 337** **( 3 trials)** **%** | **2-4-6 months** **N= 624** **(6 trials)** **%** | **3-4-5 months** **N= 127** **(2 trials)** **%** | **3-4.5-6 months** **N=198** **(1 trial)** **%** | | **Anti-diphtheria** (0.1 IU/ml)\* | 94.1 | 100 | 98.8 | 99.3 | 94.4 | 99.5 | | **Anti-tetanus** (0.1 IU/ml)\* | 100.0\\ | 100 | 99.7 | 99.8 | 99.2 | 100 | | **Anti-PT** (5 EL.U/ml) | 99.5\\ | 100 | 99.4 | 100 | 98.4 | 100 | | **Anti-FHA** (5 EL.U/ml) | 99.7\\ | 100 | 100 | 100 | 100 | 100 | | **Anti-PRN** (5 EL.U/ml) | 99.0\\ | 100 | 100 | 100 | 100 | 100 | | **Anti-Polio type 1** (1/8 dilution)\* | 93.0 | ND | 99.1 | 99.5 | 100 | 100 | | **Anti-Polio type 2** (1/8 dilution)\* | 95.3 | ND | 95.7 | 99.0 | 99.2 | 100 | | **Anti-Polio type 3** (1/8 dilution)\* | 98.8 | ND | 100 | 100 | 99.2 | 99.4 | | **Anti-PRP (Hib)** (0.15 µg/ml)\* | 83.7 | 100 | 98.5 | 98.5 | 100 | 98.4 | | **Anti-PRP (Hib)** (1.0 µg/ml) | 51.2 | 87.1 | 68.5 | 76.0 | 97.6 | 81.2 | \* cut-off accepted as indicative of protection \\ Post dose 2 results from studies where DTPa-HBV-IPV+Hib was administered in a schedule 3, 5 and 11 months of age N = number of subjects ND = not determined **Percentage of subjects with antibody titres ≥ assay cut-off after booster vaccination with INFANRIX-IPV+Hib:** | | | | | | | | --- | --- | --- | --- | --- | --- | | **Antibody** (cut-off) | | **Booster vaccination at 11/12 months of age following a 3-5 month primary course** **N =184** **(1 trial)** **%** | | **Booster vaccination during the second year of life following a three dose primary course** **N = 1326 (9 trials)** **%** | | | **Anti-diphtheria** (0.1 IU/ml)\* | | 100 | | 99.8 | | | **Anti-tetanus** (0.1 IU/ml)\* | | 99.9\\ | | 99.9 | | | **Anti-PT** (5 EL.U/ml) | | 99.9\\ | | 99.7 | | | **Anti-FHA** (5 EL.U/ml) | | 99.9\\ | | 100 | | | **Anti-PRN** (5 EL.U/ml) | | 99.5\\ | | 99.9 | | | **Anti-Polio type 1** (1/8 dilution)\* | | 99.4 | | 99.9 | | | **Anti-Polio type 2** (1/8 dilution)\* | | 100 | | 100 | | | **Anti-Polio type 3** (1/8 dilution)\* | | 99.4 | | 100 | | | **Anti-PRP (Hib)** (0.15 µg/ml)\* | | 100 | | 100 | | | **Anti-PRP (Hib)** (1.0 µg/ml) | | 96.7 | | 99.2 | | \* cut-off accepted as indicative of protection \\ Post dose 3 results from studies where DTPa-HBV-IPV+Hib was administered in a schedule 3, 5 and 11 months of age N = number of subjects The effectiveness of the Hib component (when combined with DTPa, DTPa-IPV or DTPa-HBV-IPV) was investigated via an extensive post-marketing surveillance study conducted in Germany. Over a 4.5 year follow-up period, the effectiveness of DTPa+Hib or DTPa-IPV+Hib vaccines was 96.7% for a full primary series and 98.5% for a booster dose (irrespective of priming). Over a seven year follow-up period, the effectiveness of the Hib components of two hexavalent vaccines was 89.6% for a full primary series and 100% for a full primary series plus booster dose (irrespective of the Hib vaccine used for priming).5.2 Pharmacokinetic properties Evaluation of pharmacokinetic properties is not required for vaccines.5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety, specific toxicity and compatibility of ingredients.

6.1 List of excipients Hib powder: Lactose DTPa-IPV suspension: Sodium chloride Medium 199 (as stabilizer containing amino acids (including phenylalanine), mineral salts (including sodium and potassium), vitamins (including para-aminobenzoic acid) and other substances) Water for injections For adjuvants, see section 2.6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.6.3 Shelf life The shelf life of the vaccine components before reconstitution is 3 years. After reconstitution, the vaccine should be injected immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should normally not be longer than 8 hours at 2°C - 8°C (in a refrigerator).6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C) Do not freeze. Store in the original package, in order to protect from light. For storage conditions after reconstitution of the medicinal product, please see section 6.3.6.5 Nature and contents of container Powder in vial (type I glass) containing 1 dose with a stopper (butyl rubber) and 0.5 ml of suspension in a pre-filled syringe (type I glass) with a plunger stopper (butyl rubber) and with a rubber tip cap. The tip cap and rubber plunger stopper of the pre-filled syringe and the stopper of the vial are made with synthetic rubber. Pack sizes of 1 and 10, with or without needles. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling Upon storage of the DTPa-IPV suspension, a white deposit and clear supernatant can be observed in the syringe. This is not a sign of deterioration. The pre-filled syringe should be well shaken to obtain a homogeneous suspension. The DTPa-IPV suspension in the pre-filled syringe, the Hib powder in the vial and the reconstituted vaccine should be inspected visually for any foreign particulate matter and/or abnormal physical appearance prior to administration. In the event of either is observed, the vaccine should be discarded. The vaccine is reconstituted by adding the entire contents of the pre-filled syringe of DTPa-IPV suspension to the vial containing the Hib powder. The mixture should then be injected immediately. The full reconstitution instructions are:

1. Shake the pre-filled syringe containing the DTPa-IPV suspension
2. Attach a needle to the pre-filled syringe of DTPa-IPV and inject the contents of the syringe into the Hib vial.
3. With the needle still inserted, shake the Hib vial vigorously and examine for complete dissolution.
4. Withdraw the entire mixture back into the syringe.
5. Replace the needle with an appropriate size needle for injection and administer the vaccine.
6. If the vaccine is not administered immediately, shake the solution vigorously again before injection. Instructions for the pre-filled syringe | | | | --- | --- | | SMPC_28678_image1_10.png | Hold the syringe by the barrel, not by the plunger. Unscrew the syringe cap by twisting it anticlockwise. | | SMPC_28678_image2_10.png | To attach the needle, connect the hub to the Luer Lock Adaptor and rotate a quarter turn clockwise until you feel it lock. Reconstitute the vaccine as described above. Do not pull the syringe plunger out of the barrel. If it happens, do not administer the vaccine. | Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements.