ACT (Vaccination)

Act-HIB®

Connaught

Haemophilus b Conjugate Vaccine (Tetanus Protein – Conjugate)

Active Immunizing Agent

Action And Clinical Pharmacology: Clinical Data (PRP-T): Haemophilus b Conjugate Vaccine has been administered during clinical trials to over 110 000 infants and children in Canada, the U.S., Finland, France, Chile, Israel, and the United Kingdom using local immunization schedules, and has been used widely in immunization programmes.

In clinical trials where 921 infants were given the vaccine at 2, 4 and 6 months, a titer of at least 0.15 g/mL was achieved after dose 3 in 99% and a titre of at least 1 g/mL in 93%. The weighted GMT achieved was 7 g/mL (95% confidence limits are 3.4 to 14.2 g/mL). Protective levels of anti-PRP developed after the second dose in 92.8% of these infants.

Two clinical trials supported by the U.S. National Institutes of Health (NIH) compared the anti-PRP response of 4 Hib conjugate vaccines in a racially mixed population of infants. In these studies, infants were immunized with Hib conjugate vaccines at 2, 4 and 6 months of age. Connaught Laboratories, Inc.’s DPT vaccine was given concomitantly, at a separate site.

Multicenter trials in the U.S. have evaluated a single dose of Act-HIB in 12 to 15, 18, and 17 to 24 month-old children. In this age group, a single dose of Act-HIB produced an anti-PRP response which was comparable to that seen after 3 doses were administered in infants.

Following 3 doses of Act-HIB at 6 weeks, 4 and 6 months of age, 81% of native Alaskan infants showed an anti-PRP titre of 1 g/mL with a GMT of 4.17 g/mL.

In clinical trials conducted in England and France, infants received 3 doses of Act-HIB at one month intervals. Anti-PRP responses were comparable to those trials where 2-month intervals were used.

Clinical Data – Act-HIB Reconstituted with DPT Adsorbed: In a clinical trial conducted in Canada, 424 infants received 3 doses of either Act-HIB reconstituted with Connaught’s DPT Adsorbed or the same vaccines administered simultaneously at separate sites. Anti-PRP responses were comparable after either vaccination regimen.

Protective antitoxin levels (0.01 IU/mL) against diphtheria and tetanus toxoids were achieved in 100% of recipients.

Pertussis agglutinins were detected in 99.6% of participants. Over 96% had titers 1:64. The combination of Act-HIB with DPT Adsorbed resulted in lower titers to pertussis when compared to administration at separate sites; GMT’s differed by 11.5% to 32%. However, 95% of recipients receiving the vaccine at the same site still had titers 1:64.

Three hundred and fifty-eight of these infants were available for follow-up and received one dose of either Act-HIB reconstituted with Connaught’s DPT Adsorbed (n=180) or the same vaccines administered at separate sites (n=178) at age 18 months. Anti-PRP levels were 1 g/mL in 100%. This demonstrates T-cell dependent (memory) responses for anti-PRP.

Clinical Data – Act-HIB Reconstituted with DPT Polio Adsorbed: In a clinical trial conducted in Canada, 427 infants received 3 doses of either Act-HIB reconstituted with Connaught’s DPT Polio Adsorbed or the same vaccines administered simultaneously at separate sites. Anti-PRP responses following the third dose did not differ significantly between groups.

Pertussis agglutinins were detected in all but 2 subjects and 92.4% had titers 1:64. The responses in terms of distribution of titers and GMT’s were similar in the combined and separate groups.

There was no difference in diphtheria antitoxin response after combined and separate vaccine, with 99.1% of infants developing a minimum protective antitoxin level (0.01 IU/mL) after the third dose of combined vaccines.

Protective levels of tetanus antitoxin (0.01 IU/mL) developed in 99.5% of infants after the third dose of combined vaccines, and 100% of infants after separate vaccines. However, the geometric mean antitoxin concentrations were significantly lower after combined (0.50 g/mL) than after separate vaccine (0.76 g/mL).

There were no significant differences in the polio neutralizing antibody in response to separate or combined vaccine. The proportions of infants with titers of 8 after 3 doses of combined vaccines were 98.6% to type 1, 98.1% to type 2, and 100% to type 3.

Clinical Data – Act-HIB Reconstituted with Quadracel: In clinical trials conducted in Canada, 215 infants received 3 doses of either Act-HIB reconstituted with Quadracel or the same vaccines administered simultaneously at separate sites at 2, 4 and 6 months of age. An additional 186 18-month old children received a single dose of either Act-HIB reconstituted with Quadracel or the same vaccines administered simultaneously at separate sites. With the exception of tetanus, no differences were found in immunogenicity between the 2 methods of immunization. Tetanus antitoxin levels were lower in the combined vaccine groups, but all children had protective levels (0.01 EU/mL). Following the 18-month dose, all children had tetanus antitoxin levels 0.10 EU/mL and all but one had diphtheria antitoxin levels 0.10 EU/mL. Anti-PRP responses were comparable. All children were protected against polio. Pertussis responses were not affected by method of administration.

Indications And Clinical Uses: Routine: For the routine immunization of all children between 2 and 59 months of age. In infants, 3 injections are to be given i.m. at 2, 4, and 6 months of age, followed by a booster at 18* months of age.

Infants starting their primary immunization series between the age of 3 and 6 months should receive 3 doses at 2 month intervals with a booster dose at 18* months of age. (While an interval of 2 months between doses is recommended, an interval as short as 1 month is acceptable.)

For infants between the age of 7 and 11 months, 2 doses should be given at an interval of 2 months, followed by a booster at 18* months of age.

Children between 12 and 14 months of age who have not previously received any Haemophilus b vaccine should receive one dose of the vaccine followed by a booster at or after 18 months* of age.

Unvaccinated children between 15 and 59 months of age should receive a single dose of vaccine.

*The booster dose may be given as early as 15 months of age provided that at least 2 months have elapsed since the previous dose.

Older children or adults with chronic conditions associated with increased risk of invasive Hib disease such as persons with splenic dysfunction (e.g., sickle cell disease, asplenia), antibody deficiency, HIV infection or certain malignancies may be immunized with a single dose of the vaccine.

Connaught’s DPT Adsorbed may be used for the reconstitution of lyophilized Act-HIB in place of the saline diluent. This provides an efficient means of administering routine immunization against diphtheria, tetanus, pertussis and H. influenzae type b in a single injection at a single visit.

Connaught’s DPT Polio Adsorbed may be used for the reconstitution of lyophilized Act-HIB in place of the saline diluent. This provides an efficient means of administering routine immunization against diphtheria, tetanus, pertussis, poliomyelitis and H. influenzae type b in a single injection at a single visit.

Connaught’s Quadracel may be used for the reconstitution of lyophilized Act-HIB in place of the saline diluent. This provides an efficient means of administering routine immunization against diphtheria, tetanus, pertussis, poliomyelitis and H. influenzae type b in a single injection at a single visit.

Act-HIB may be administered simultaneously with DPT, DT, DPT Polio, IPV, Quadracel, or Tripacel at separate sites with separate syringes and OPV.

Act-HIB may also be given simultaneously with MMR at separate sites with separate syringes. This is based on data for MMR and Act-HIB alone. Because simultaneous administration of common childhood vaccines is not known to affect the efficacy or safety of any of the routine recommended childhood vaccines, if return of a vaccine recipient for further immunization is doubtful, simultaneous administration of all vaccines appropriate for age and previous vaccination status (including MMR, other H. influenzae type b conjugate vaccines, hepatitis B vaccine) at separate sites with separate syringes is indicated.

Data on whether vaccination prevents acquisition and carriage of Hib are still limited. Thus, rifampin or other appropriate chemoprophylaxis should be used, in accordance with the usual recommendations, for families and people in day-care centres in which a case of invasive Hib disease has occurred and in which there are one or more contacts less than 48 months of age who have not been fully vaccinated against Hib.

At the present time, Haemophilus b conjugate vaccines are not recommended for infants younger than 2 months of age.

Contra-Indications: General: Immunization with Act-HIB should be deferred in the presence of any acute illness, including febrile illness. A minor afebrile illness such as mild upper respiratory infection is not usually reason to defer immunization.

Allergy to any component of Haemophilus b Conjugate Vaccine including tetanus protein, or an allergic or anaphylactic reaction to a previous dose of Act-HIB are contraindications to vaccination. When Act-HIB is reconstituted with Connaught’s DPT Adsorbed, DPT Polio Adsorbed or Quadracel the contraindications for DPT Adsorbed, DPT Polio Adsorbed or Quadracel must also be considered.

Elective immunization of individuals over 6 months of age should be deferred during an outbreak of poliomyelitis.

Manufacturers’ Warnings In Clinical States: I.M. injections should be given with care in patients suffering from coagulation disorders because of the risk of hemorrhage.

If Haemophilus b Conjugate Vaccine is used in persons with malignancies, receiving immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, or who are otherwise immunocompromised (including HIV infected individuals), the expected immune response may not be obtained.

Corticosteroid therapy can result in immunosuppression although the exact dose and duration of therapy required to suppress the immune system is not well defined. Persons treated with high doses of systemic steroids, e.g., 2 mg/kg/day of prednisone orally for more than 2 weeks, should be considered to have a compromised immune system.

As with any vaccine, immunization with Haemophilus b Conjugate Vaccine may not protect 100% of susceptible individuals.

Capsular polysaccharide antigen can be detected in the urine of vaccinees for up to 2 weeks following immunization with conjugate vaccines. This phenomenon should not be confused with invasive Hib infections.

Precautions: General: Care is to be taken by the health-care provider for the safe and effective use of Haemophilus b Conjugate Vaccine.

The possibility of allergic reactions in individuals sensitive to components of the vaccine should be evaluated. Epinephrine (1:1 000) and other appropriate agents should be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs. When Act-HIB is reconstituted with Connaught’s DPT Adsorbed or DPT Polio Adsorbed or Quadracel, the possibility of allergic reactions to the components of these vaccines must also be evaluated. Health care providers should be familiar with current recommendations for the initial management of anaphylaxis in non-hospital settings.

Before an injection of any vaccine, all appropriate precautions should be taken to prevent adverse reactions. This includes a review of the patient’s history with respect to possible hypersensitivity to the vaccine or similar vaccine, determination of previous immunization history, and the presence of any contraindications to immunization, current health status, and a current knowledge of the literature concerning the use of the vaccine under consideration.

Special care should be taken to ensure that the product is not injected into a blood vessel.

A separate, sterile needle and syringe or a sterile disposable unit must be used for each individual patient to prevent the transmission of infectious agents. There have been case reports of transmission of HIV and hepatitis by failure to scrupulously observe sterile technique.

Needles should not be recapped and should be disposed of properly.

Before administration of Act-HIB, health-care personnel should inform the parent or guardian of the patient of the benefits and risks of immunization, and also inquire about the recent health status of the patient to be injected.

Act-HIB may be of benefit in preventing the occurrence of secondary cases. However, epidemiological studies have not been done and rifampin or other appropriate prophylaxis is still recommended. Because the vaccine will not protect against non-typeable strains of H. influenzae which cause recurrent upper respiratory disease, otitis media and sinusitis, the vaccine is not recommended for these conditions.

Although some immune response to the tetanus protein component may occur, immunization with this vaccine does not substitute for routine tetanus immunization. Individuals who have received multiple doses of products containing tetanus toxoid show no differences in reaction rates when immunized with this vaccine.

Pregnancy: Animal reproduction studies have not been conducted with Act-HIB. It is also not known whether Act-HIB can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Act-HIB is not recommended for use in pregnant women.

Children with Symptomatic HIV Infection: Available data suggest that routine childhood immunizations are not hazardous to HIV-infected children. Furthermore, there is no evidence that immunization with routine vaccines leads to deterioration of the clinical condition of HIV-infected persons. Immunization with DPT (Diphtheria, Pertussis and Tetanus), IPV (Inactivated Poliomyelitis Vaccine) and Act-HIB is recommended, although immunization may be less effective than it would be for immunocompetent children.

Adverse Reactions: Physicians, nurses and pharmacists should report any occurrences temporally related to the administration of the product in accordance with local requirements and to the Medical Director, Connaught Laboratories Limited, 1755 Steeles Avenue West, Toronto, Ontario, Canada, M2R 3T4.

Local Reactions: Pain, redness, swelling or induration are seen in 5 to 30% of vaccinees. It is generally early, transient, and of moderate intensity. There have been rare cases of edematous reactions of the lower extremities reported. These consist of oedema with cyanosis or transient purpura which appears within soon after immunization and resolves rapidly and spontaneously. There has been no accompanying cardiorespiratory signs or symptoms. These reactions have been reported mainly when Haemophilus b Conjugate Vaccine is administered concurrently with another vaccine.

Systemic Reactions: Systemic reactions including fever, irritability, drowsiness, prolonged or abnormal crying, anorexia and vomiting have occurred after immunization with Act-HIB in conjunction with DPT. The rates of reactions observed were generally comparable to those usually reported following DPT with the exception that there were slightly more febrile reactions reported among PRP-T recipients within 6 to 24 hours of vaccination. Table IV shows systemic reactions reported in a controlled clinical trial.

Act-HIB reconstituted with DPT Adsorbed: In a clinical trial conducted in Canada, 442 infants received at least one dose of Act-HIB reconstituted with Connaught’s DPT Adsorbed or the same vaccines administered simultaneously at separate sites.

Local adverse reactions to Act-HIB when administered alone were infrequent and mild. No increase was seen with successive doses. Mixed Act-HIB and DPT vaccines did not cause local redness or swelling more often than did DPT vaccine alone but tenderness increased from 18.1% with DPT alone to 26.2% with the combination.

In the Canadian study, one hypotensive-hyporesponsive episode occurred after the administration of Act-HIB reconstituted with DPT Adsorbed. This child recovered fully with no sequelae. No other serious adverse reactions were reported.

Act-HIB reconstituted with DPT Polio Adsorbed: In a clinical trial in Canada, 427 infants received 3 doses of Act-HIB reconstituted with DPT Polio Adsorbed or the same vaccine administered simultaneously at separate sites. Local adverse reactions to Act-HIB alone were infrequent and mild. A slight increase was seen with successive doses. Although local redness, swelling and tenderness were significantly more common after vaccines containing DPT Polio Adsorbed compared to Act-HIB alone, reaction rates were lower after the combined vaccines than after DPT Polio Adsorbed alone.

No significant differences in systemic adverse events was seen following Act-HIB and DPT Polio Adsorbed administered at separate sites or combined.

Three severe adverse events temporally associated with vaccination resulted in hospitalization. These included one infant who developed supraventricular tachycardia 48 hours after dose 1 (combined), one infant who woke 3 hours after dose 1 (separate) with cough, respiratory distress and cyanosis whose diagnosis was suspected aspiration or gastroesophageal reflux, and one infant with an episode of screaming and apnea 4 hours after dose 1 (separate). All three infants recovered completely. No causal relationship between the adverse events and vaccination was demonstrated.

Act-HIB reconstituted with Quadracel: In clinical trials conducted in Canada, 215 infants received 3 doses of either Act-HIB reconstituted with Quadracel or the same vaccines administered simultaneously at separate sites at 2, 4 and 6 months of age. An additional 186 18-month old children received a single dose of either Act-HIB reconstituted with Quadracel or the same vaccines administered simultaneously at separate sites. The rates of local and systemic reactions for the combination of Act-HIB and Quadracel were consistently lower than for the combination of Act-HIB and DPT-Polio Adsorbed (PENTA 1). The incidence of local reactions at the Quadracel site was lower when the vaccines are given separately, but severe local reactions are uncommon (
Rare cases of allergic reactions including urticaria, pruritus, and facial and laryngeal edema have been reported.

Physicians should be aware that recipients of Haemophilus b vaccine are not protected against Hib disease in the week after vaccination, prior to the onset of the protective effects of the vaccine.

As with any vaccine, there is the possibility that broad use of the vaccine could reveal rare adverse reactions not observed in clinical trials. A temporal association of neurological disorders has been reported following the parenteral injection of other biological products and should always be carefully considered when an immunization is indicated.

Dosage And Administration: Parenteral biological products should be inspected visually for extraneous particulate matter and/or discoloration before administration whenever solution and container permit. If these conditions exist, the product should not be administered.

This vaccine is indicated for routine immunization against invasive disease caused by H. influenzae type b in infants and children starting at 2 months of age (see Indications). Each dose is a single injection of 0.5 mL given i.m.

Reconstitution of Freeze-Dried Vaccine: Reconstitute the vaccine using only the diluent supplied, Connaught’s DPT Adsorbed, DPT Polio Adsorbed, or Quadracel. The use of any other vaccine to reconstitute Haemophilus b Conjugate Vaccine is not recommended.

Do not remove the rubber stopper from the vial.

Apply a sterile piece of cotton moistened with a suitable antiseptic to the surface of the rubber stopper of the vial of vaccine. Withdraw the diluent into a syringe. Holding the plunger of the syringe containing the diluent steady, pierce the centre of the rubber stopper in the vial and slowly inject the 0.5 mL of diluent into the freeze-dried vaccine. Shake the vial gently until a clear, colorless solution results. Avoid foaming since this will prevent withdrawal of the proper dose. Withdraw the entire contents of the reconstituted vaccine into the syringe and inject the total volume (about 0.5 mL).

When Connaught’s DPT Adsorbed, DPT Polio Adsorbed or Quadracel is used for the reconstitution of Act-HIB, shake the single dose ampul or vial well to uniformly distribute the suspension before withdrawing entire contents (about 0.5 mL). Before withdrawing the contents from an ampul, tap the container first to ensure that all the vaccine is in the lower portion. Once the ampul has been opened, any of its contents not used immediately should be discarded. Before withdrawing the contents from a rubber-stoppered vial, do not remove either the rubber stopper or the metal seal holding it in place. Inject all the DPT Adsorbed, DPT Polio Adsorbed or Quadracel into the vial of Act-HIB vaccine. Swirl the vial until a cloudy, uniform suspension results. Avoid foaming since this will prevent withdrawal of the proper dose. Use a sterile needle and syringe to withdraw the entire contents for 1 dose.

Before injection, the skin over the site to be injected should be cleansed with a suitable germicide.

Administer the vaccine i.m. The preferred site is into the anterolateral aspect of the mid-thigh (vastus lateralis muscle) or into the deltoid muscle.

In children >1 year of age, the deltoid is the preferred site since use of the anterolateral thigh results in frequent complaints of limping due to muscle pain.

After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel.

Do not inject i.v.

Each person who is immunized should be given a permanent personal immunization record. In addition, it is essential that the physician or nurse record the immunization history in the permanent medical record of each patient. This permanent office record should contain the name of the vaccine, date given, dose, manufacturer and lot number.

Availability And Storage: Act-HIB – Haemophilus b Conjugate Vaccine (Tetanus Protein-Conjugate) (PRP-T) is a lyophilized vaccine of purified polyribose ribitol phosphate capsular polysaccharide (PRP) of H. influenzae type b, covalently bound to tetanus protein. Each single dose of 0.5 mL after reconstitution contains 10 g of purified capsular polysaccharide covalently bound to 20 g of tetanus protein.

Act-HIB reconstituted with Diluent: The diluent for reconstitution is a 0.4% saline solution. After reconstitution the vaccine appears clear and colourless and does not contain a preservative.

Act-HIB reconstituted with Connaught’s DPT Adsorbed: After reconstitution, the vaccine appears cloudy and uniform and the solution contains thimerosal 0.01% used in DPT Adsorbed as a preservative.

Act-HIB reconstituted with Connaught’s DPT Polio Adsorbed: After reconstitution, the vaccine appears cloudy and uniform. From the DPT Polio Adsorbed, the solution contains 2-phenoxyethanol 0.5% as preservative and trace amounts of polymyxin B and neomycin may be present from the cell growth medium.

Act-HIB reconstituted with Connaught’s Quadracel: After reconstitution, the vaccine appears cloudy and uniform. From the Quadracel, the solution contains 0.6%±0.1% 2-phenoxyethanol as preservative and trace amounts of polymyxin B and neomycin may be present from the cell growth medium.

Packages containing 5 single dose vials of Act-HIB and 5´0.5 mL (single dose) ampuls of Connaught’s diluent, 0.4% Saline for reconstitution of Haemophilus b Conjugate Vaccine. Packages containing 5 single dose vials of Act-HIB and 5´0.5 mL (single dose) ampuls of Connaught’s DPT Adsorbed for reconstitution in place of the diluent. Packages containing 5 single dose vials of Act-HIB and 5´0.5 mL (single dose) ampuls of Connaught’s DPT Polio Adsorbed for reconstitution in place of the diluent. Packages containing 5 single dose vials of Act-HIB and 5´0.5 mL (single dose) ampuls of Connaught’s Quadracel to be used for reconstitution in place of the diluent and sold under the trade name Pentalel.

Store between 2 and 8°C. Do not freeze. The vaccine should be used immediately after reconstitution. Do not use after the expiration date.

Act-HIB® Connaught Haemophilus b Conjugate Vaccine (Tetanus Protein – Conjugate) Active Immunizing Agent

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